SLC37A4 gene encoding microsomal glucose‐6‐phosphate (G6P) transporter in the endoplasmic reticulum (ER) membrane. Ineffective G6P transport into the ER leads to hypoglycaemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hepato‐ and/or nephromegaly. Clinical manifestations of the disease include recurrent, severe infections and inflammatory bowel (Crohn‐like) caused by neutropenia and diminished bactericidal and fungicidal activity of neutrophils. Granulocyte colony‐stimulating factor (G‐CSF) administration is currently a standard therapy to prevent adverse effects of neutropenia, but the treatment is associated with a high risk of severe side effects. On the other hand, short‐treatment with sodium‐glucose cotransporter type 2 inhibitor – empagliflozin (EMPA) was reported to act directly on the mechanism of neutropenia and neutrophil dysfunction in GSD 1b. We observed significant improvement in clinical and laboratory parameters after introducing EMPA to treatment, that is reduced frequency of infections, lower number of bowel movements, and improved postoperative wound healing. EMPA is effective in the treatment of neutropenia in our GSD 1b patients, which allows for dose reduction and even withdrawal of G‐CSF. We did not observe any significant side effects of EMPA treatment in our patients.Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by biallelic mutations in the  SLC37A4 gene encoding microsomal glucose‐6‐phosphate transporter in the endoplasmic reticulum membrane. The main symptoms of the disease include short stature, hepatomegaly, hypoglycaemia, hyperlactatemia, hypertriglyceridemia, and neutropenia.Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by balletic mutations in the Neutropenia leads to severe infections and the development of inflammatory bowel disease despite G‐CSF treatment.We observed significant improvement in clinical and laboratory parameters after introducing empagliflozin to treatment without significant side effects.1SLC37A4 gene. It leads to a deficiency of microsomal glucose‐6‐phosphate (G6P) transporter in the endoplasmic reticulum (ER) membrane. G6P hydrolysis to glucose is possible only inside ER. Therefore transporter absence/deficiency in ER results in hypoglycaemia.Glycogen storage disease type 1b (GSD 1b) is a rare  autosomal recessive metabolic defect caused by biallelic mutations in the Metabolic aberrancies in G6P transport also negatively affect neutrophil count and function. As a result, GSD 1b patients demonstrate an increased frequency of severe infections and predisposition to inflammatory bowel (Crohn‐like) disease.The granulocyte colony‐stimulating factor (G‐CSF) treatment of neutropenia in patients with GSD 1b aims to improve the absolute neutrophil count and reduce the severity of infections. Unfortunately, pathological effects are not eliminated, and life‐threatening infections are still observed, while inflammatory bowel disease is often poorly controlled.Empagliflozin (EMPA), a renal sodium‐glucose cotransporter type 2 (SGLT2) inhibitor approved for the treatment of diabetes mellitus type 2, inhibits the reuptake of 1,5 anhydroglucitol  in renal tubules.2The aim of this study is to describe the effects of EMPA treatment (3–18 months of treatment) in four patients with GSD 1b respect to clinical symptoms and laboratory parameters.3The study included four patients with GSD 1b, two girls and two boys, remaining under the combined care of the Department of Paediatrics, Nutrition and Metabolic Diseases, Children's Memorial Health Institute (IP‐CZD) in Warsaw and the Department of Paediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok. Due to unsatisfactory improvement on G‐CSF, we started treatment with EMPA. Clinical data and laboratory parameters in similar follow‐up periods before and after the introduction of EMPA were retrospectively analysed to evaluate the effects of EMPA treatment.The collected data included the number of urgent hospitalisations due to infection, the number of infections requiring antibiotic therapy, the mean number of stools per day, and the average number of days per month with mucosal lesion before and after the implementation of EMPA therapy. In addition, we evaluated the metabolic response by assessing the concentration of glucose, lactic acid, uric acid, and triglyceride in serum and by evaluating the absolute neutrophil count. Finally, results of all analysed parameters were compared for similar periods before and after introducing EMPA treatment.4SLC37A4 variant, c.1042_1043del.P1: Male patient, currently 17.5 years old, was born by Caesarean section from pregnancy G1 at 41 weeks, with Apgar score of 10 and birth weight of 3.800 g. Congenital pneumonia complicated the neonatal period. At 2 months of age, perirectal abscess drainage was required. Two weeks later, the patient developed a generalised infection of unknown aetiology. Hepatomegaly, hypoglycaemia of 1.7 mmol/L after a 3‐h feeding break, and neutropenia  were detected. Molecular testing revealed a homozygous The boy was repeatedly hospitalised during several subsequent months due to hypoglycaemia, recurrent severe bacterial infections , episodes of stomatitis, and/or diarrhoea. Due to severe, persistent neutropenia , G‐CSF at 5 μg/kg/24 h dose was introduced to the therapy when the patient was 22 months old. By 16 years of age, the boy was hospitalised approximately 50 times due to recurrent bacterial infections, diarrhoea, mouth sores, and skin abscesses. Despite G‐CSF treatment, no significant increase in the neutrophil count was achieved. At 3 years, the patient developed severe Crohn‐like bowel disease and periodically required parenteral nutrition. At 16 years of age, the patient started zoledronic treatment due to significant thinning of bone structure and numerous vertebral compression fractures found in dual‐photon X‐ray absorptiometry (DXA).Despite G‐CSF and mesalazine, during the year preceding the introduction of EMPA, the patient demonstrated poor control of inflammatory bowel disease, and he experienced several episodes of severe infections Table . LaboratSLC37A4 gene  performed at 9 months of age, lipid disorders, hypoglycaemia, hepatomegaly, and neutropenia were discovered. The patient was transferred to the Department of Metabolic Diseases in Warsaw. At 9 months of life, the patient demonstrated normal body weight  and length . Laboratory tests revealed hyperlactatemia , hypertriglyceridemia , hyperaminotransferasaemia , neutropenia , and high normal uric acid   and low neutrophil count (900 cells/μl), G‐CSF was introduced at a 2.5 μg/kg/24 h when the patient was 2 years old. Despite normalisation of the neutrophil count, the patient went through numerous infections with three episodes of acute otitis media, four episodes of pneumonia and several surgeries for granulomatous otitis media and renal abscesses during 10 years of follow‐up under treatment with G‐CSF. Additionally, the patient developed inflammatory bowel disease requiring mesalazine at 9 years .We started an “off‐label” EMPA treatment because of recurrent infections, low neutrophil count, and lack of inflammatory bowel disease remission on G‐CSF (2.5 μg/kg/24 h) and mesalazine (40 mg/kg/day).During 1 year preceding the introduction of EMPA, the patient experienced submandibular lymphadenitis, three episodes of respiratory tract infection, and one episode of skin abscess. In addition, multiple stools per day (on average 7–8) and ulcer‐like lesions in the mouth for 10 days per month were observed . At 5 months of age, an in‐depth diagnostic procedure was initiated after an episode of generalised seizures accompanying low serum glucose (1.66 mmol/L). Hepatomegaly and neutropenia (190 cells/μl)  confirming the diagnosis  and mesalazine (2× 500 mg), the parameters reflecting metabolic control  remained within normal limits. However, during the year preceding the introduction of EMPA, a gradual reduction of neutrophil count has been observed. The patient has been hospitalised six times for severe infections, and five times she required outpatient therapy with antibiotics Table . RemissiMSSA aetiology at 2 months of age. Laboratory results demonstrated a high triglyceride level (18–27.36 mmol/L) (Table SLC37A4 gene (c.1042_1043del and c.1175del)  was administered in combined treatment with G‐CSF (2.7 μg/kg/24 h). Good general condition, improvement in blood differential, and lack of infections prompted reducing the G‐CSF dose to 1.4 μg/kg/24 h and subsequently withdrawing it. Currently, the boy is off G‐CSF for 6 months (Table P2: We started filgrastim (2.5 μg/kg/24 h) and EMPA (0.4 mg/kg/24 h), and for 1 year, the patient received both. As a result, we observed a reduced frequency of infections, mean number of stools per day, and lower incidence of mouth sores. Significant clinical improvement and satisfactory neutrophil counts (above 1000 cells/μl) allowed gradual withdrawal of G‐CSF (Table P3: Combined treatment with G‐CSF (6 μg/kg/24 h) and EMPA (0.4 mg/kg/24 h) resulted in clinical improvement, that is reduced frequency of hospitalisations for infections down to three per year, the need for outpatient treatment down to two per year, with fewer stools per day and only a few mouth sores Table . We recoP4: The patient was treated with G‐CSF (2 μg/kg/24 h) and EMPA (0.4 mg/kg/dl) for 2 months. Acceleration of wound healing was observed 3 days after introducing EMPA Figure . Two mon6In the maturation process, neutrophils lose most of their mitochondria and become dependent on the energy coming from anaerobic glycolysis. As a result, glucose 6‐phosphate, the product of the first glycolysis stage, is also used in the pentose phosphate cycle. The pentose phosphate pathway serves, among others, in production of NADPH, which is used by NADPH oxidase to produce free oxygen radicals.1,5 AG is common in food, but its function in vivo is still unknown.Treatment with G‐CSF positively affects the neutrophil count, it reduces frequency and severity of infections observed in patients with GSD 1b. Unfortunately, pathological effects are not eliminated and life‐threatening infections are still observed, while inflammatory bowel disease is often poorly controlled. Moreover, such treatment is not free of adverse reactions, with osteoarticular pain, gingival hypertrophy and bleeding, splenic enlargement often accompanied by hypersplenism, and an increased risk of hematologic neoplasms.EMPA inhibits the reabsorption of glucose from primary urine, therefore leading to reduced glucose concentration in serum. The drug is successfully used in adult patients to control diabetes mellitus type 2, providing cardio‐ and nephroprotective effects due to reduced blood pressure.The most common adverse reactions of EMPA treatment include episodes of hypoglycaemia (when the drug is used with another hypoglycaemic agent) and an increased frequency of genitourinary infections.Auspicious results of treating neutropenia with EMPA in patients with GSD 1b suggest a need to perform further studies. In addition, considering the reported nephro‐ and cardioprotective effect of the drug, a longer follow‐up might show whether there are any other beneficial effects of EMPA treatment in patients with GSD 1b.7The case reports presented above confirm the efficacy of EMPA in the short‐term treatment of neutropenia in GSD1b patients, as described by Wortmann et al. and Grünert et al.Magdalena Kaczor, Milena Greczan, Karolina Kierus, Ewa Ehmke vel Emczyńska‐Seliga, Elżbieta Ciara, Barbara Piątosa, Dariusz Rokicki, Janusz Książyk and Dorota Wesół‐Kucharska declare that they have no conflict of interest.Magdalena Kaczor: designed the study, collected data, data analyses, data interpretation and wrote the manuscript. Milena Greczan: designed the study, collected data, data analyses, data interpretation, contributed to the drafting of the manuscript. Karolina Kierus: designed the study, collected data, data analyses, data interpretation, contributed to the drafting of the manuscript. Ewa Ehmke vel Emczyńska‐Seliga: collected data, contributed to the drafting of the manuscript, critically reviewed the manuscript. Elżbieta Ciara: collected data, contributed to the drafting of the manuscript, critically reviewed the manuscript. Barbara Piątosa: collected data, data analyses, contributed to the drafting of the manuscript, critically reviewed the manuscript. Dariusz Rokicki: designed the study, data analyses, data interpretation, contributed to the drafting of the manuscript, critically reviewed the manuscript. Janusz Książyk: data analyses, contributed to the drafting of the manuscript, critically reviewed the manuscript. Dorota Wesół‐Kucharska: corresponding author, designed the study, collected data, data analyses, data interpretation, wrote part of the manuscript, critically reviewed the manuscript.All procedures followed were in accordance with ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.This article does not contain any studies with animal subjects performed by any of the authors.


The purpose of this study is to find prognostic factors associated with low visual acuity in patients experiencing vitreous loss during cataract surgery.  A retrospective, noncomparative, interventional, case study of patients experiencing vitreous loss during cataract surgery. Data collected included demographics, best corrected visual acuity (BCVA), axial length (AL), presence of ocular comorbidity affecting central vision, timing of intraocular lens (IOL) implantation, position of the implanted lens, and the presence of corneal sutures. Low visual outcome was defined as BCVA < 20/40. P > 0.05).  Overall, 179 patients  with a mean age of 73 ± 12 years and axial length of 23.5 ± 1.3 mm with a mean follow-up of 12 ± 13 months were included. In multivariable logistic regression analysis, low visual outcome was independently associated with persisting postoperative complications , preexisting ocular comorbidities , and secondary intraocular lens (IOL) implant . Conversely, pars plana vitrectomy (PPV) for dislocated fragments of lens material, age > 70 years, gender, axial length, degree of surgeon, corneal suturing, and anterior chamber lens implantation were not found to have significant associations with low visual outcomes ( Low visual outcome after vitreous loss during cataract surgery was associated with ocular comorbidities, secondary IOL implantation, development of cystoid macular edema, and additional surgical complications. The frequency of vitreous loss during cataract surgery using phacoemulsification techniques ranges from 1.1% to 5% . Risk faThe aim of this study is to try and determine what factors are associated with a low visual acuity in patients experiencing vitreous loss during cataract surgery.This study was approved by the Institutional Review Board of the University of Auckland, Auckland, New Zealand. A retrospective study was conducted of all patients who underwent phacoemulsification surgery complicated by vitreous loss from 2004 through 2010 at the University of Auckland, Auckland, New Zealand. All surgeries were performed by one of the four consultants or four trainees during that period. All of the consultants and trainees had previously performed over 500 operations and 50 surgeries, respectively. Surgeries performed by a trainee were all supervised by a consultant and if a complication was encountered, the consultant guided the trainee or took over the operation to provide the patient with a guarded operation. Medical records from the hospital computer database include intraoperative complications, and this vehicle was used to identify this cohort.n = 16), glaucoma (n = 15), proliferative diabetic retinopathy (n = 7), and cystoid macular edema (n = 7)). Intraoperative data included timing of intraocular lens (IOL) implantation, position of the implanted lens, and the presence or absence of corneal sutures. Additional data included was the surgeon grade, with surgeries performed by a consultant surgeon, a fellow, or a registrar. Postoperative follow-up time, final BCVA, and any subsequent surgical intervention were recorded. Low visual outcome was defined as BCVA < 20/40.Preoperative parameters recorded included sex, age, best corrected visual acuity (BCVA), and axial length (AL). The presence or absence of ocular comorbidity affecting central vision was noted  relation with both the outcome variable and the predictor of interest was included in multivariate model analyses. Statistical significance was defined as P ≤ 0.05.All statistical analyses were performed with SPSS version 21.0. Chi-square was used to compare proportions and student's T test to compare means. Any potential confounder that had at least a modest (n = 108) and the mean follow-up time was 12.4 ± 13.4 months (range: 1–60 months).Overall, 179 cases of vitreous loss during cataract surgery using phacoemulsification were identified. Mean age and axial length were 73 ± 12 years and 23.5 ± 1.3 mm. There were 60.3% males (n = 54) with the most common being dense/mature cataract (n = 33). Additional factors were narrow pupils, pseudoexfoliation glaucoma, zonular weakness, posterior polar cataract, and lack of patient cooperation.Risk factors for capsular rupture were identified in 30% (P < 0.05) with 82% ≥ 20/40. BCVA was reduced by 1 or more lines in 8.4% (n = 15) and by 2 or more lines in 5.6% (n = 10).There was a significant improvement in BCVA from 1.13 ± 0.83 to 0.32 ± 0.43 logMAR at last follow-up (P ≥ 0.05). Ocular comorbidity was the only preoperative parameter significantly associated with low visual outcome in univariate analysis. Ocular comorbidity was present in 36% (n = 63). Patients undergoing cataract surgery with additional pathologies were 4 times more likely to have low visual outcome. In 31% of eyes with ocular comorbidity, final BCVA was worse than 20/40 compared to 7.7% in eyes without comorbidity. There was no significant association between specific comorbidities  and low visual outcome.Age, sex, BCVA, and axial length were not found to have significant associations with low visual outcome , in the bag in 19% (n = 34), and in the anterior chamber in 7% (n = 1). Twelve of the eyes where the lens was implanted in the bag had a capsular tension ring inserted. Surgeon category was not associated with low visual outcome, with 59% eye (n = 106) operated by a consultant, 11% (n = 20) by a fellow, and 30% (n = 53) by a registrar.The IOL was positioned in the sulcus in 74% (n = 12) increased the risk for low visual outcome by nearly 3 times (P=0.034). Other complications included increased intraocular pressure (n = 9), mild ERM (n = 4), and retinal detachment (n = 3).Postoperative CME  and surgical intervention (n = 3).Following primary surgery, 12 eyes were noted to be vitreous in the anterior chamber directed towards the cataract section. Treatment included Nd : YAG laser (n = 14), IOL repositioning (n = 4), anterior vitrectomy (n = 3), and iris prolapse (n = 1).Overall, 22 eyes required additional surgery. Reasons included retained lens material (P=0.09).The median interval between cataract surgery and PPV for retained lens material was one day (range: 0 to 60 days), with all but two patients operated within the first week. Data regarding patients that required PPV are summarized in This study and others , 16–18 cSurgically demanding cases are at increased risk for capsular rupture. These include small pupils, dense/mature cataract, instillation of trypan blue, and loose zonules with or without pseudoexfoliation . In our P=0.03), it was both not significant and clinically negligible when compared to the presence of an ocular comorbidity . As such, though eyes with low preoperative visual acuity may have a tendency towards a more complicated surgery and perhaps worse outcomes, this is not always the case. Some will have a thick posterior subcapsular cataract which does not increase the challenge of such an operation and explains the very low vision. Therefore, we speculate that the preoperative visual acuity is not as good of an indicator of outcomes when compared to a preexisting ocular comorbidity.Identifying factors influencing final visual acuity results, in eyes experiencing capsular rupture with and without vitreous loss, has been the purpose of the previous studies . Low preAs in previous studies, ocular comorbidity and CME were found to be associated with low visual outcome. Shah et al. found glaucoma but not diabetes was an adverse indicator while Konstantantopoulos et al.  found AMThe optimal timing for a PPV to remove retained lens material in the vitreous is still under debate , 18–20. P=0.009). To the best of our knowledge, other studies have not assessed the association of this factor with visual outcomes following vitreous loss during cataract surgery. We speculate that this may stem from two different causes. One, cases where an IOL was not implanted during primary surgery were probably more complicated to begin with than those in which an IOL was implanted. Two, it may be that additional surgery may expose the eye to further complications which can be avoided if the IOL is implanted during primary surgery.In the case of a posterior capsular rupture with vitreous loss, the IOL can be placed in front of the anterior capsule if the rhexis is round and the rim is adequate in size. But if the support is less than adequate, it may be necessary to place an anterior chamber IOL, iris fixated IOL, or scleral fixated IOL . In casePostoperative endophthalmitis is a serious complication of cataract surgery, with the incidence varying from 0.02% to 0.71%. Soliman et al. published a case series of 237 eyes with acute endophthalmitis secondary to cataract surgery, secondary lens implantation, or intravitreal injections. They concluded that pars plana vitrectomy was frequently performed regardless of the presenting vision in eyes with endophthalmitis and that increased vitreous opacification was associated with a higher probability for performing PPV .n = 8). Future studies may consider analyzing the outcomes of a single surgeon to focus on the best strategy to achieve the best visual outcomes following vitreous loss.This study has several limitations, first of which is its retrospective nature. Additional factors such as narrow pupils, pseudoexfoliation glaucoma, zonular weakness, and lack of patient cooperation were not considered in the analyses. Future, prospective studies may consider meticulously recording and thereafter analyzing these data. Second, results of surgeries from several surgeons were included in this study (This study recognizes ocular comorbidity, secondary IOL implantation, and subsequent postoperative CME as risk factors for low visual outcome in patients experiencing vitreous loss during cataract surgery. However, most patients with this complication do have good outcomes, especially if no comorbidities are present at the time of surgery. Similarly, patients requiring PPV for retained lens material can have good visual results although the timing of this additional intervention is not defined. Ophthalmologists, specifically cataract surgeons, should be aware of these findings in order to give their patients more accurate prognosis.


CPT Pharmacometrics Syst. Pharmacol. (2020) 9, 718–730; https://doi.org/10.1002/psp4.12569Neeraj Gupta, Xiaohui Wang, Elliot Offman, Benjamin Rich, David Kerstein, Michael Hanley, Paul M. Diderichsen, Pingkuan Zhang, Karthik Venkatakrishnan. In the published version of the above article, a coding error in the simulation code was discovered that affected the results of the exposure‐response analyses for efficacy endpoints of the progression‐free survival (PFS), intracranial PFS (iPFS), and overall survival (OS) parametric time‐to‐event models. Upon correction of the coding error, the recalculated results were mostly comparable to those in the original publication, which are reflected in the revised figures and text presented hereafter. The predicted median PFS and iPFS for the 90 and 180 mg every day (q.d.) regimens were slightly shorter than previously calculated. Consequently, the model‐predicted probabilities of OS for these regimens were lower than previously calculated, resulting in probabilities that were similar to, rather than higher than, the observed data estimates.These errors do not change the conclusion that a favorable benefit‐risk profile exists for the approved dosing regimen (180 mg q.d. with 7‐day lead‐in at 90 mg) versus 90 mg q.d.Revisions in the Text are tabulated and shown below:The revised figures are shown below:Revised Figure Revised Figure Revised Figure


N = 22) were analyzed using 6,996 participants. The estimated FA prevalence was 15% (95% CI 11–19%) for all samples, 12% (95% CI 8–17%) for community samples, and 19% (95% CI 14–26%) for overweight/obese samples. Meta‐regression indicated that weight status was associated with FA severity (p = 0.002) and marginally with FA prevalence (p = 0.056). Healthcare providers should consider and address the high FA prevalence among pediatric population.Food addiction (FA) has been as a construct that is associated with childhood obesity. However, relatively little is known regarding the prevalence of FA among children and adolescents. An instrument designed to assess FA among youth, the Yale Food Addiction Scale for Children and Adolescents (YFAS‐C), has been developed and used to estimate FA prevalence among pediatric populations. The present systematic review and meta‐analysis aimed to synthesize the results of FA prevalence among youth. Using keywords related to FA and children to search PubMed, Embase, Scopus, and Web of Science, we identified and analyzed 22 cross‐sectional studies. No longitudinal studies were identified in the search. Meta‐analysis with Freeman‐Tukey Double Arcsine transformation was conducted to estimate FA prevalence. Meta‐regression was applied to understand whether weight status  is associated with FA. Eligible studies ( A 5‐point Likert scale  is applied to all 18 YFAS items, and a dichotomous (yes/no) scale is first used for the seven items. Following this, all the items are converted dichotomously  according to specific scoring thresholds for each item. Using the converted dichotomous scores, a symptom count scoring version (ranging between 0 and 7) and a diagnostic scoring version  can be generated.Specifically, the YFAS characterizes food addiction via the following items and criteria: Items 1 to 3 assess Recent neurobiological studies provide insight into potential mechanisms underlying FA.Currently, several reviews have evaluated the prevalence of FA.Although FA studies are increasing and initial information regarding FA prevalence has been disseminated, little is known about FA prevalence among children and adolescents. Indeed, among the reviews mentioned above, only Imperatori et al.In order to understand FA prevalence in children and adolescents , we conducted a systematic review and meta‐analysis. Specifically, the present systematic review and meta‐analysis is now feasible because (1) a children and adolescents version of the YFAS has been developed  with promising psychometric properties 2The study was registered at PROSPERO (CRD42020142198).2.1This systematic review and meta‐analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) checklist.2.2The search included observational studies including cohort, case–control, and cross‐sectional studies.2.3All studies that reported prevalence of FA in children as an outcome were reviewed. Peer‐reviewed publications were included if they reported the YFAS‐C score (in children aged under 21 years). We defined 21 years as the upper limit of the children's age because the statement made by the American Academy of Pediatrics identified the upper age limit of pediatrics as 21 years.2.4After finalizing the included papers, each was assessed for quality by calculating the Newcastle‐Ottawa score (NOS) via the Newcastle‐Ottawa checklist. The Newcastle‐Ottawa checklist assesses quality of a study by considering eight domains. It considers the use of appropriate statistical tests, assessment of outcomes, controlling for potentially confounding factors, ascertainment of exposure, approaching non‐respondents, sample size, representativeness of the sample, and clear goals as main determinants of a study's quality. Highest quality papers get the maximum score (16), and those with a NOS of 5 or less were excluded.2.5z‐scores and FA.The prevalence of FA among children as measured by the YFAS‐C score was calculated, along with the mean YFAS‐C score and the correlations between BMI 2.6I2 index and Egger's and Begg tests were performed to determine heterogeneity and publication bias. Funnel plots are also provided in this regard.After extensive review, a meta‐analysis was conducted using the STATA software version 15.0 (StataCorp LLC). The STATA metaprop and metan commands were used. Forest plots are provided to illustrate the point and interval estimations. In meta‐analysis for prevalence, Freeman‐Tukey Double Arcsine transformation was used to stabilize the variances. The metaninf command was used for sensitivity analysis via evaluating the effect of each study on overall estimates. The z‐score were performed according to this categorization.Studies were divided into community samples and overweight/obese samples among studies reporting this information. Stratified analysis for prevalence, mean score of YFAS‐C and linear correlation of FA and BMI z‐scores were used if available. BMI z‐scores were available or calculated from percentile values for 15 studies , NOS score, sample size, and continent on prevalence of FA and YFAS‐C scores was performed in separate models for each covariate using metareg command in STATA.33.1Extensive systematic review of the literature initially identified 400 studies. Among these, 320 were excluded after screening the titles and abstracts. Full texts of the remaining 80 papers were further evaluated. After removing adult studies, animal studies, other review articles, and those without reported YFAS‐C scores, 22 studies were included Table . Sample 3.2The NOSs for the 22 included publications3.3p = 0.084 and 0.82, respectively) . Heterogeneity assessed by I2 values is depicted in each of the corresponding forest plots  and 19% (95% CI: 14–26%) in the overweight/obese samples  index was 98.8%. The mean YFAS‐C score in the community samples was 1.54 (95% CI: 1.23–1.85) and 2.63 (2.48–2.77) in the overweight/obese samples.The mean YFAS‐C score was calculated to be 2.06 (95% CI: 1.66–2.46) among the 12 studies3.6z‐scores were available for nine studies with four studiesz‐scores and FA (as determined by YFAS‐C) revealed a mild to moderate correlation coefficient of 0.30 (95% CI: 0.24–0.36). Heterogeneity index (I2) for this meta‐analysis was 78% (p < 0.001). Even the strongest coefficient found in the study by Lin et al.The correlation coefficients between FA (as determined by YFAS‐C) and BMI y index I2 for thi3.7p = 0.002) and borderline significant effect on prevalence (p = 0.056) (Table p = 0.637 and 0.902), BMI z‐score (p = 0.241 and 0.450), NOS score (p = 0.588 and 0.160), continent (p = 0.320 and 0.388), size of sample (p = 0.253 and 0.663), and sex ratio (p = 0.154 and 0.648) were not significantly associated with YFAS‐C score and FA prevalence.In the meta‐regression analysis, the target sample had a significant effect on YFAS‐C score (6) Table . Specifi3.8Sensitivity analysis showed that no considerable impacts were found in the estimates of FA prevalence and YFAS‐C scores after omitting any of the included studies Tables  and 3.4p = 0.056) and that of the YFAS‐C score reached statistical significance (p = 0.002).Given limited information on the prevalence of FA among children and adolescents, the present systematic review and meta‐analysis assessed FA in this population. After identifying 22 studiesThe relatively high FA prevalence found in children and adolescents is comparable with that in adults.However, unlike weight status, other factors proposed to be relevant to FA prevalence by Pursey et al.All analyzed studies used the same instrument, the YFAS‐C, to assess FA. The YFAS‐C is a “gold standard” in assessing FA among children and adolescents. Specifically, it has been developed with rigorous methodologies, including the adoption of addiction criteria proposed in the DSM‐5The present systematic review and meta‐analysis has the following strengths. First, the comprehensive search uses multiple major databases  and recommended keywords (identified according to the PECO framework). Therefore, the included studies are relevant to the study aims. Second, rigorous methodology was adopted in this systematic review and meta‐analysis. We used NOS to verify quality assurance; that is, only publications passing a specific study quality threshold were included. Moreover, publication bias, meta‐regression, and sensitivity testing were performed. Therefore, there is considerable confidence regarding the accuracy of the estimates in our meta‐analysis. Third, as mentioned earlier, all included studies used the same instrument with promising psychometric properties . Therefore, the present systematic review and meta‐analysis has little instrument measurement bias.z‐score and provided information regarding whether the studied sample was overweight/obese or not. Therefore, we only relied on some studies providing such information to estimate effects of BMI z‐scores and weight status on FA prevalence and YFAS‐C scores. Lastly, although the included studies were located across the continents of America, Africa, Europe, Australia, and Asia, some specific areas  did not have information on this topic. Therefore, future studies are needed in these regions.There are some limitations in this study. First, causality between weight status and FA prevalence cannot be determined by our meta‐regression findings because all analyzed studies were cross‐sectional. Longitudinal studies are needed to understand better temporal relationships between FA and weight status. Additionally, the present systematic review and meta‐analysis included no randomized controlled trials. As such, relative impacts of targeting in treatment FA on weight status or weight status on FA cannot be evaluated and should be examined in future studies. Second, although the YFAS‐C is designed for assessing FA in youth and its consistent use across included studies is an advantage of the present systematic review and meta‐analysis, it is based on self‐report. Thus, general limitations of self‐report measures should be considered. Specifically, we cannot control biases of social desirability and inaccurate responses. Third, not every included study reported the BMI Together with the consideration of the aforementioned limitations, future studies could consider the following steps to provide additional understanding of FA impacts on children and adolescents. First, a recent study5In conclusion, FA is an important topic among youth. With the relatively high prevalence of FA among children and adolescents found in the present systematic review and meta‐analysis, healthcare providers, policymakers, and other stakeholders should design appropriate interventions to address FA in this age group. Moreover, higher estimates of FA were observed among children and adolescents with overweight/obesity as compared with lean/normal‐weight individuals. Thus, targeted interventions may be particularly relevant to children and adolescents with overweight/obesity.We declare no conflicts of interest. Dr. Potenza has the following disclosures. He has consulted for and advised Game Day Data, the Addiction Policy Forum, AXA, Idorsia, and Opiant/Lakelight Therapeutics; received research support from the Veteran's Administration, Mohegan Sun Casino, and the National Center for Responsible Gaming ; participated in surveys, mailings, or telephone consultations related to addictions, impulse‐control disorders or other health topics; consulted for law offices and gambling entities on issues related to impulse control and addictive disorders; provided clinical care in the Connecticut Department of Mental Health and Addiction Services Problem Gambling Services Program; performed grant reviews for the National Institutes of Health and other agencies; edited journals and journal sections; given academic lectures in grand rounds, CME events and other clinical/scientific venues; and generated books or chapters for publishers of mental health texts. Other authors declare that they have no disclosures.


Dear Editor,Colorectal cancer (CRC) is a major cause of cancer‐related mortality worldwide.t‐test or Wilcoxon's rank‐sum test with an adjusted P‐value was applied to test the metabolites between cases and controls .A two‐stage case–control study involving 170 cases and 197 controls was performed. All patients were diagnosed at the Third Affiliated Hospital of Harbin Medical University. Controls were recruited from patients in the orthopaedic and ophthalmology departments and volunteers from Xiangfang District of Harbin City during the same period. Fasting peripheral venous blood was obtained in the morning in the hospital or medical examination centre. Metabolic profiling analysis was conducted on a ultra performance liquid chromatography (UPLC)/Q–time‐of‐flight (TOF)–mass spectrometry (MS)/MS platform. Principal component analysis and orthogonal projections to latent structures discriminant analysis were performed to check the separation tendency. Student's − and ESI+) in the first stage, and 6630 and 7760 variables in ESI− and ESI+ in the second stage, respectively, were imported for multivariate statistical analyses. By excluding ion fragments from the same parent ions and the duplicated variables in ESI− and ESI+, 388 variables were selected after univariate analysis. Finally, 147 metabolites were identified. Pathway‐enrichment analysis was conducted using a hypergeometric test, and six pathways (including 62 of the 147 metabolites) were enriched . Eleven of the 147 metabolites were introduced into binary logistic regression because of an area under the curve (AUC) of > 0.85, and 4 showed statistical significance . The combined AUCs  were higher than the AUC of any individual marker. However, all markers except LysoPC(16:1(9Z)) failed to be enriched in any biological pathway. Small‐molecule metabolites perform biological functions in pathways. Our findings indicated that these three metabolites have unknown biological function or may not be functional. Thus, although these metabolites exhibited the greatest efficacy in distinguishing CRC cases, this lack of biological significance may result in false‐positive diagnoses.No significant differences in age, sex or body mass index were observed between the cases and controls in either the first or second stage Table . The datPavlova and Thompsonl‐tryptophan, 13‐OxoODE, IDP, glycochenodeoxycholate, and LysoPC(16:0)] were selected as CRC panel 1 because they had the highest AUCs in the pathways . Ninety‐three differential metabolites were identified . Thirteen with an AUC of > 0.65 in plasma were overlapped in tissue (Dataset A). Five of the 13  were selected when focusing on the reported frequency. The combined AUCs were 0.971 (0.949–0.994) and 0.948 (0.921–0.976) in plasma ] were finally identified from the overlap of Datasets A and B (Dataset C) because they had multiple advantages of favourable AUCs, biological significance, tumor tissue reproducibility, and the highest reported frequency . The AUCs were 0.942 (0.901–0.983) and 0.937 (0.906–0.968) in plasma. In particular, the AUCs were > 0.93 in the diagnosis of stage I/II , LysoPC(16:0), and LysoPC(18:0)] in the targeted analysis. A batch of 504 plasma samples (251 patients with CRC and 253 controls) was detected . The AUC of l‐tryptophan, linoleic acid, LysoPC(14:0), and LysoPC(18:0) was 0.728 (0.681–0.775) in plasma (Figure Ultimately, we quantified five metabolites [, LysoPC1:0, LysoPThis study had some limitations. First, the fact that the biomarkers were not well validated might have been due to some other parameters that were either unknown or not tightly controlled. Second, change variation was not taken as a strict standard in the screening process because we did not want to exclude metabolites that may have better sensitivity in early cancer. The response of small molecular metabolites to nutritional or disease states is so sensitive that even subtle disturbances can be detected much earlier than genomic and proteomic variation. Third, UPLC/Q–TOF–MS/MS is not a good technique for quantitative analysis. Fourth, the model discrimination performance still requires validation internally and externally using targeted quantitative analyses. Finally, comparisons with the metabolites of other diseases are still required.In conclusion, we revealed the most promising metabolic biomarkers of CRC in plasma using the herein‐described multi‐step analysis strategy. Future application of multi‐omics markers may achieve accurate noninvasive diagnosis.The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Compared with singleton pregnancy, twin gestation is featured by a greater increase in cardiac output. Therefore, norepinephrine might be more suitable than phenylephrine for maintaining blood pressure during cesarean section for twins, as phenylephrine causes reflex bradycardia and a resultant decrease in cardiac output. This study was to determine whether norepinephrine was superior to phenylephrine in maintaining maternal hemodynamics during cesarean section for twins.Informed consent was obtained from all the patients before enrollment. In this double-blinded, randomized clinical trial, 100 parturients with twin gestation undergoing cesarean section with spinal anesthesia were randomized to receive prophylactic norepinephrine (3.2 μg/min) or phenylephrine infusion (40 μg/min). The primary outcome was the change of heart rate and blood pressure during the study period. The secondary outcomes were to compare maternal complications, neonatal outcomes, Apgar scores and umbilical blood acid-base status between the two vasopressors.P = .0567). The mean standardized area under the curve of systolic blood pressure (SBP) was significantly lower in parturients with norepinephrine, as the mean of differences in standardized AUC of SBP was 6 mmHg, with a 95% CI from 2 to 9 mmHg (P = .0013). However, requirements of physician interventions for correcting maternal hemodynamical abnormalities  and neonatal outcomes were also not significantly different between two vasopressors.There was no significant difference observed for the change of heart rate between two vasopressors. The mean standardized area under the curve of heart rate was 78 ± 12 with norepinephrine vs. 74 ± 11 beats/min with phenylephrine .Chinese Clinical Trial Registry ( Compared those with singleton pregnancy, the intensified cardiovascular adaptations with twin pregnancy are characterized by more profound increase in cardiac output (CO) starting from the mid-trimester , 2. As mPhenylephrine (PE) is currently the recommended vasopressor of choice for treating/preventing spinal anesthesia -induced hypotension during cesarean section . As a puThe primary objective of this randomized, double-blinded study was to compare the changes in heart rate and blood pressure following prophylactic intravenous infusions of norepinephrine or phenylephrine in women with twin pregnancies undergoing cesarean section under spinal anesthesia. The secondary objectives were to compare maternal complications, neonatal outcomes, Apgar scores and umbilical blood acid-base status between the two vasopressors.http://www.chictr.org.cn/showproj.aspx?proj=35234). Informed consent was obtained from all patients before enrollment. This manuscript adheres to the applicable CONSORT guidelines . Study protocol was registered in the Chinese Clinical Trial Registry prior to patient enrollment . One code for each patient was placed into a sealed, opaque, sequentially numbered envelope by one investigator (Z.C.), who was not involved in patient management or data collection. After epidural space was reached, another investigator (L.W.), who was not involved in subsequent patient care or assessment either, opened the topmost of these consecutively numbered the envelops. According to the code contained in the envelops, patients were randomly allocated to receive PE or NE infusion. All the PE and NE solutions were prepared in identical 20 ml syringes by J.Z., who was not involved in subsequent patient care or assessment either. All the syringes were labelled as “study drug”, therefore it was impossible for the anesthesiologists involved in patient care to identify whether it contained 8 μg/ml NE  or 100 μg/ml PE . The infusion rate was 24 ml/hour for both vasopressors by using an infusion pump , corresponding to 3.2 μg/min for NE and 40 μg/min for PE. In our department, continuous PE infusion at 40 μg/min is the standard protocol for post-spinal hypotension prophylaxis during cesarean delivery. The infusion rate of NE was determined based on the estimated potency of 12.5:1 for NE:PE, according to the previously reported potency from 11.3 [Blood pressure was measured and recorded every minute till delivery of the second twin. Hypotension, defined as a systolic blood pressure (SBP) < 90 mmHg or 80% of the baseline SBP, was rescued by 1-ml bolus of the study drug, i.e. NE 8 μg for parturients with NE infusion and PE 100 μg for parturients with PE. These boluses were prepared beforehand in 10-ml syringes labelled as “rescuing drug”. Hypertension, defined as a SBP > 140 mmHg or 120% of the baseline, was managed by temporarily stopping study drug infusion, which would be restarted as soon as SBP was within the normal range. HR was monitored continuously and recorded at 1-min interval. Bradycardia was defined as a heart rate < 60 beats/min and 0.5 mg atropine would be given when heart rate further decreased below 50 beats/min. Oxygen 5 L/min was given by a facemask during the study period.Apgar scores were assessed by midwives 1, 5 and 10 min after delivery, who were unaware of the patients’ assignment. Umbilical arterial (UA) and venous blood (UV) were sampled from a double-clamped segment of umbilical cord by using Pulset arterial 3 ml blood gas syringes . Within 20 min after clamping, umbilical blood gas was analyzed with the bedside epoc® Blood Analysis System  in the operating room.The primary outcome was the change in heart rate and blood pressure during the study period, from intrathecal injection to delivery of the second twin, which was calculated as the standard area under the curve of heart rate and systolic blood pressure . The secondary outcomes included the incidences of hypotension, hypertension, bradycardia, nausea and vomiting, umbilical blood gas status, Apgar scores, both maternal and neonatal length of post-operative stays, and rates of maternal and neonatal intensive care unit (NICU) admission.p value < 0.05 was considered statistically significant.Continuous data such as pH values were assessed for normal distribution using Kolmogonov-Smirnov test and were then compared using the Student’s t-test or Mann-Whitney U test, as appropriate. Categorical data such as the incidence of bradycardia were analyzed using chi-square test. A survival analysis with log-rank test was used to compare the requirement of physician interventions for correcting maternal hemodynamic abnormalities (including injection of rescuing bolus of vasopressors or atropine and temporary cessation of vasopressor infusion). The area under the curves (AUC) for SBP and heart rate plotted against time were calculated using the trapezium rule . As the The sample size was calculated based on our unpublished preliminary data, in which parturients with twin pregnancy received NE or PE infusion following spinal anesthesia. The means of standardized AUC for heart rate were 79 ± 12 and 72 ± 8 beats/min for NE and PE, respectively. A minimal sample size of 46 per group was required to detect a significant difference (10% of the baseline heart rate) between two groups, with 90% power and a two-sided type I error of 0.05. Considering the potential withdraw of consent or loss of follow-up, a final sample size of 50 per group was determined.This study was conducted in West China Second University Hospital, Chengdu, China, from November 2019 to April 2020. The CONSORT recruitment diagram is showed in Fig. P = .0567). The incidence of bradycardia, i.e. heart rate < 60 beats/min, was 6% (3/50) in patients receiving NE and 30% (15/50) in patients with PE , as showed in Table P = .242). And 86.7% (13/15) of the bradycardia episodes in group PE occurred before surgical skin preparation followed by a rapid and spontaneous recovery and only two patients had heart rate less than 60 beats/min when the neonates were delivered.Patients’ baselines and surgical characteristics were similar between two groups Table . No patiP = .0013). The incidence of hypotension was 24% (12/50) with NE and 6% (3/50) with PE . None of the hypotensive patients required more than one bolus of rescuing vasopressor to restore blood pressure. As rescuing bolus was used more frequently in patients with NE, the total volume of vasopressor was greater in group NE: 9.9 ± 2.3 versus 8.5 ± 2.9 mL with mean difference of 1.45; 95%CI, 0.42 to 2.48 (P = .006). Hypertension occurred in 6 patients receiving NE  and in 13 patients receiving PE , OR with NE = 0.39; 95%CI, 0.13–1.12, (P = .074). Taking all the above-mentioned maternal hemodynamic abnormalities into consideration , there was no difference in requirements of physician interventions between the two groups . There was no difference in umbilical blood gas status between the two groups, except that neonates from group NE had a slightly higher glucose level, in both UA blood  and UV blood .No newborn had Apgar’s score less than 8 or unplanned NICU admission in either group. As showed in Table P = 0.057); nevertheless, incidence of bradycardia was significantly lower with NE . In addition, with these vasopressor infusion settings, there was a higher incidence of hypotension in the NE group . Overall, requirements of physician interventions to correcting maternal hemodynamic abnormalities  were similar with these two vasopressor infusion regimen. There was no difference in fetal outcomes either.Our study shows that infusion of NE at a fixed rate of 3.2 mcg/min failed to provide less overall decrease in HR compared to PE infused at 40 mcg/min during caesarean delivery for twin pregnancy performed under spinal anesthesia . In addition, the incidence of bradycardia was significantly higher in patients receiving PE, although the requirements of atropine were not different between the two vasopressors. Nevertheless, most of the bradycardia episodes (13/15) occurred before skin incision and spontaneously recovered afterwards. The similar umbilical blood gas status and fetal outcomes we found between NE and PE is furthermore reassuring. In a recent study recruiting more than 600 parturients with singleton pregnancy, it was also found that umbilical arterial pH was similar between NE and PE, although PE was associated with higher incidence of bradycardia [In our study, NE failed to produce a greater overall HR after spinal anesthesia during cesarean section for twins, although this nearly achieved statistical significance . In two recently published papers, which were not available when our study was designed, the ED95 of NE, NE bitartrate to be more specific, for maintaining blood pressure for cesarean delivery after spinal anesthesia was estimated to be 0.07 [− 1 · min− 1. And the incidence of hypotension with NE infusion at the rate of 0.05 μg · kg− 1 · min− 1 was as high as 30% [The infusion rate of NE was determined based on the estimated potency of 11.3  for NE:  be 0.07  to 0.08  be 0.07  μg · kg−h as 30%  or even h as 30%  in theseh as 30% .In this study, we included a wide spectrum of gestational ages, which is not uncommon in studies of twin pregnancy . AlthougThere are several limitations in our study. First, vasopressors were infused at a fixed rate for all the patients, instead of manually adjusted infusion  or closeIn conclusion, in parturients with twin pregnancy undergoing cesarean delivery under spinal anesthesia, infusion of NE at the rate of 3.2 mcg/min failed to provide less overall decrease in HR, compared to PE infused at 40 mcg/min, although there was a significant decrease in incidence of bradycardia. The requirements of physician intervention to correcting maternal hemodynamic abnormalities and the fetal outcomes were also similar with these two vasopressors infusion regimen.


As a crucial biophysical property, red blood cell (RBC) deformability is pathologically altered in numerous disease states, and biochemical and structural changes occur over time in stored samples of otherwise normal RBCs. However, there is still a gap in applying it further to point-of-care blood devices due to the large external equipment (high-resolution microscope and microfluidic pump), associated operational difficulties, and professional analysis. Herein, we revolutionarily propose a smart optofluidic system to provide a differential diagnosis for blood testing via precise cell biophysics property recognition both mechanically and morphologically. Deformation of the RBC population is caused by pressing the hydrogel via an integrated mechanical transfer device. The biophysical properties of the cell population are obtained by the designed smartphone algorithm. Artificial intelligence-based modeling of cell biophysics properties related to blood diseases and quality was developed for online testing. We currently achieve 100% diagnostic accuracy for five typical clinical blood diseases  via real-world prospective implementation; furthermore, personalized blood quality (for transfusion in cardiac surgery) monitoring is achieved with an accuracy of 96.9%. This work suggests a potential basis for next-generation blood smart health care devices. For example, as a typical and practical diagnostic indicator, blood cell morphology is widely used for blood testing7. However, complex equipment, well-trained operation, and dyes are often required to achieve high diagnostic accuracy for cell morphology-assisted blood diagnosis10 because of the inhomogeneity and inconsistency of cell morphological transition dynamics13. Cell deformability serves as an important indicator of the real-time response to cell status. However, monitoring cell deformability has not been applied to the field of POC blood smart health care due to complex equipment requirements and associated operational difficulties22.Label-free disease diagnosis and quality monitoring by natural biophysics properties of cells is expected to be significant for the future of smart health care and point-of-care (POC) applications24 are characterized by high integration28, precise optical manipulation31, and portability33, and they provide a good platform for studying cell biophysics properties. Currently, a series of good works have been reported for cell deformability monitoring, which implies a potential clinical application for POC blood cell analysis35. Here, we introduce a smart optofluidic engineering platform for multifunctional blood testing via precise cell biophysics property recognition both in mechanics and morphology with high accuracy, low cost, and ease of operation. Based on the elastic strain and stress coupling of the hydrogel, blood cell deformation is achieved by manipulating a hydrogel actuator using a mechanical transfer device. A tunable imaging platform (depth of field: 10 µm) was designed for capturing blood cell images at different focusing surfaces. Images, morphologic , and mechanical (deformability and distribution width) parameters of blood cells were obtained via a developed image algorithm employed on a smartphone39. The integrated data were then used as input for cloud computing, and they were then transformed into vector tables and loaded into image vectors to perform pathological diagnosis and quality monitoring based on a trained neural network41. The strong system performance was validated with clinical samples, which provides a new strategy for future POC blood smart health care.Optofluidicsd = 800 µm, h = 20 µm) deformation–relaxation test was conducted using a confocal microscope . The deformation–relaxation fluorescence distribution maps of the hydrogel are recorded and analyzed in Fig. σ = 4.345 SDs, and n = 60). These results indicate a basis for cell imaging and deformation in flexible photocurable hydrogel actuators. The longitudinal hydrogel (phosphate-buffered solution (PBS)-filled, blood sample: hydrogel precursor = 1: 100) grid was compressed, forcing the red blood cells (RBCs) in the grid to deform regularly with stress  was based on the settling process. A total of 2362 RBCs were randomly selected to measure the deformation rates of 3 and 6 kPa. Figure σ = 0.045) and 1.241 (σ = 0.033), respectively, which indicates that when the RBCs accept higher stress, the deformability is larger and the range of variation becomes narrower. RBCs undergo internal osmotic pressure and the cell membrane morphology changes during the deformation process. To study the morphological changes in the cell membrane in the RBC process, the light intensity distribution was analyzed before and after RBC deformation. Furthermore, as shown in Fig. y = 0) directly illustrates the RBC deformation and recovery process in this system.The developed optofluidic chip integrated with a flexible photocurable hydrogel actuator is shown in Fig. ess Fig. . Then, tH × V, mm): 1.81 × 1.02, resolution: 1 µm)39. The image processing steps are illustrated in Fig. P = 0.07). Based on the Passing–Bablok regression analysis (n = 50), the A intercept value was 1.6380 with a confidence interval (CI) of 1.0959–2.1988, and the B slope value was 0.8794 with a CI of 0.8587–0.8977. Bland–Altman analysis (n = 50) was used to compare this intelligent system, and the manual RBC count showed a mean bias of −1.492 million RBCs/mL with a standard deviation (SD) of 1.57 × 106 RBCs/mL  and specificity of 84.62% (CI: 65.1–95.6) for this system to count RBC samples; furthermore, the area under the curve (AUC) was 0.970 with CI ranging between 0.877 and 0.988. Bland–Altman analysis (n = 56) was performed to evaluate the imaging/analysis system performance in the diameter, axis ratio, and circularity analyses of healthy RBC samples from the hospital compared to the expert microscopic examination and Countstar cell counter. As shown in Fig. Figure /mL Fig. . The lim/mL Fig. , and theσ = 0.0082) based on the results of a laser optical rotational red cell analyzer  and RBC deformability value -based finger-pressing method obtained via a mechanical transfer device (Stress = 3 kPa) for 63 healthy RBC samples. We conducted Bland–Altman analysis and mountain plot analysis to analyze the performance and accuracy of the finger-pressing method for cell deformability. The Bland–Altman analysis (n = 63) results comparing the finger-pressing method and laser optical rotational red cell analyzer indicated a mean bias of 0.6723 with an SD of 0.0059 ; furthermore, the diagnostic accuracy was consistent with the examination conducted by professional physicians, thereby indicating a potential method via cell multirecognition to further improve diagnostic accuracy.We performed neural network training for five typical clinical blood diseases, including megaloblastic anemia (MA), myelofibrosis (MF), iron deficiency anemia (IDA), thrombotic thrombocytopenic purpura (TTP), and thalassemia . Through cell imaging and analysis Fig. 36, the m42. Based on this system, we performed blood-quality monitoring of 98 cryopreserved RBC (4 °C) samples during storage. Among them, 48 RBC samples were cryopreserved within 14 days, and 50 were cryopreserved for more than 14 days (14–21 days). The results showed that there was no significant statistical correlation between RBC counts in the two intervals, and the P value was 0.1105, whereas a significant statistical correlation was observed in the diameter, circularity, axis ratio, and deformability. The corresponding AUCs were 0.7594 (CL: 0.6651–0.8537), 0.7629 (CL: 0.6703–0.8556), 0.9224 (CL 0.8819–0.9769), and 0.8821 (CL: 0.8194–0.9448)  Fig. . Then, n48) Fig. . Misdiag48) Fig. . Figure n = 432, 100% accuracy) and the personalized assessment of the stored blood quality  demonstrated the feasibility of all key functional aspects as well as the practical utility of this system in the smart health care field. Furthermore, this smart optofluidic system can be extended to disease diagnosis accompanied by abnormal morphology and mechanics of blood cells, etc.; it can also be used to evaluate the recovery of patients with blood diseases after treatment. Moreover, this system can be expanded into in vitro cultured cell quality monitoring of sperm, oocytes, follicles, etc., and provides a potential platform for further drug and target screening.This paper introduces an innovative biophysics property recognition platform that enables multifunctional POC blood smart testing. The comparison of this system diagnostic performance among experts in five clinical blood diseases via real-world prospective implementation  and precise mechanical manipulation  are required for the measurement; however, they have portability limitations and associated operational difficulties for untrained users. In this study, we propose a revolutionary OPOC platform that uses hydrogel actuator-assisted compression imaging to achieve precise cell recognition both in morphology and mechanics with high accuracy, low cost, and ease of operation in a miniaturized integrated system. Furthermore, this can be combined with microneedles to achieve continuous blood extraction and analyses in a chip. The developed deep learning algorithms and cloud computing enable label-free and automatic blood disease-assisted diagnosis/evaluation of blood quality. Furthermore, the construction of an ecological POC engineering system for blood , which can expand the number of human participants and increase the range of types of typical blood diseases, deep learning-based mixed-blood disease model development will be a powerful tool in promising smart health care.The replaceable microfluidic chip (1.2 cm × 0.6 cm × 20 µm) was fabricated using the standard soft lithography process. First, the SU8 photoresist  was dropped on the silicon wafer and rotated by a homogenizer (KW-4A) to obtain a 20 μm photoresist coating layer. After prebaking, the master was exposed to UV light under a glass/chromium mask using a mask aligner . Then, a positive relief of the photoresist on the surface was generated, which was used as the mold for future replications. The 20 g polydimethylsiloxane (PDMS) prepolymer  prepolymer was then poured over the master (5 in.) and stored in an oven for 1 h at 75 °C. The PDMS replica was then peeled off and sealed against a flat PDMS slab to form the microchannel after oxygen plasma bonding.Ten milliliters of PBS was added to a brown bottle containing lithium phenyl phosphinate  and heated at 40–50 °C in the dark for 30 min, and it was shaken several times (>5 times) during this period to obtain an initiator solution. Then, 10% mass Gelma material  was added to the initiator solution (Gelma: Initiator solution = 1:10), heated at 40–50 °C in the dark for 30 min, and shaken several times (>5 times) during the period. A 0.22-micron sterile syringe filter was used to filter and sterilize the hydrogel precursor solution immediately, storing at 4 °C afterward (storage period > 2 weeks).D = 800 µm, H = 20 µm) in the microfluidic chamber through blue light  exposure under a photomask . The data measurements need to be completed within 10 min because of the natural changes in blood cells in vitro.For each test Fig. , the bloAs shown in Fig. Sd denotes the pixel area after deformation and Sud denotes the pixel area before deformation. Mean diameter is defined as diameter = π × area/perimeter2; circularity = 1 indicates a perfect circle.Through the tunable optical imaging system, the smartphone collected the field of view of the RBCs through autofocus. The RBC images were then converted into a grayscale image (8-bit). After the light intensity and contrast were automatically adjusted by the software, the RBC images were converted into binary images using the threshold operation. The threshold setting was used to remove the stacked cells. Then, a hole-filling operation was performed to fill the contour and improve the calculation accuracy. Finally, the morphologic and mechanical parameters were calculated via software pixel analysis. The deformation index (Dr) is defined as Input images were obtained after data augmentation was applied to the raw images by randomly rotating, cutting, and flipping. Then, we used AlexNet with pretrained weight coefficients on the ImageNet dataset for training. The layer before the last layer was set to have 32 neurons. After training, these vectors were extracted as feature vectors in the embedded space where the neural network learns. All inputs were resized to 224 × 224 pixels for images with a scale of 0.1 mm × 0.1 mm for cell imaging in the hydrogel actuator, and the images were cropped to the same scale—0.1 mm × 0.1 mm—before being used as an input. The 32-dimensional feature vectors extracted in images were combined with the 8-dimensional mechanical and morphological data obtained from imaging analysis and the combined feature vectors to train a neural network with two hidden fully connected layers. The dropout method was used in the training process to avoid overfitting and increase generalization performance.All experiments were conducted in accordance with the Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Anonymized tissue samples were retrieved from the Hematology Laboratory patient database after obtaining approval from the Ethics Committee of Zhongnan Hospital of Wuhan University (No. 2020153).The hospital pathological diagnosis of the patients (432 participants with this device) after an intelligent diagnosis was performed. Peripheral blood specimen smears, typical bone marrow smears, and bone marrow biopsy smears are shown in Fig. Venous blood (2–3 mL) was placed in ethylenediaminetetraacetic acid (EDTA) anticoagulation tube, and the complete blood count test was performed on a Beckman Coulter LH750 .Each patient took one drop of fingertip blood and quickly pushed it into a peripheral blood smear. All slides were subsequently manually stained with May-Gruenwald-Giemsa staining by the same technician, and they were visually examined by two independent experienced clinical technicians using light microscopy.Bone marrow puncture was performed at the posterior superior iliac spine. Bone marrow fluid (0.1–0.2 mL) was slowly aspirated, and the bone marrow fluid was pushed onto the slide to quickly generate eight smears. Bone marrow smears were stained with Wright Giemsa, and immunohistochemical detection was carried out based on specific conditions. The cytoplasm and quantity of the bone marrow were observed under a microscope. The morphological analysis was performed jointly using two senior laboratory physicians.Supplementary_MaterialsEthical approve


Approval of the research protocol: N/A.Informed consent: The patient provided written consent for the publication.Registry and registration no. of the study/trial: N/A.Animal studies: N/A.Conflict of interest: None.Dear Editor,Systemic capillary leak syndrome (SCLS) is a rare disease characterized by episodic exacerbation of hypovolemia, hemoconcentration, and hypoalbuminemia due to capillary hyperpermeability. Although the overall pathophysiology remains unknown, transient endothelial dysfunction is believed to be associated with the disease.A 60‐year‐old woman presented to the emergency department with a 1‐day history of fever, dyspnea, and nausea. She received a series of SARS‐CoV‐2 vaccinations , two shots given 3 weeks apart, with the second dose given 2 days before the visit. Her medical history was relevant to a diagnosis of SCLS, with a life‐threatening attack of capillary leakage, complicated by cardiac arrest, that required intensive care. Her vital signs at presentation were: body temperature, 37.1°C; blood pressure, 81/60 mmHg; pulse rate, 122 beats/min; respiratory rate, 16 breaths/min; and oxygen saturation, 97% with ambient air. She was also alert, with oriented consciousness. Laboratory results showed an increased hematocrit level of 47% and a hemoglobin level of 15.1 g/dl. Nasal swab polymerase chain reaction testing for SARS‐CoV‐2 yielded negative results, and imaging studies did not indicate an infection source.Although her hypotension and tachycardia temporarily resolved after a bolus of fluids, she continued to require a large amount of fluid, which made us consider SCLS possibly provoked by SARS‐CoV‐2 vaccination. She was admitted to the intensive care unit and required further resuscitative treatment with fluid and vasopressors. On hospital day 2, she developed hoarseness due to laryngeal edema and was intubated to secure her airway. During the first 24 hours, she received 12 L of fluids, but her hematocrit level and hypoalbuminemia worsened (Table Adverse reactions to SARS‐CoV‐2 vaccination are usually local and mild; however, some serious reactions have been reported, including anaphylaxis, myocarditis, thromboembolic events, and Guillain‐Barré syndrome.Being a rare disease, SCLS may not be recognized or may be treated under a similar differential diagnosis. When patients present with hypovolemic shock from an unknown cause after SARS‐CoV‐2 vaccination, exacerbation of SCLS should be considered among the differential diagnoses.


In the interaction analysis for favourable neurological outcome, significant interactions were noted between SB use and time to SB . In the interaction analysis for survival to hospital discharge, significant interactions were noted between SB use and blood pH . SB should not be empirically administered for patients with IHCA since its effects may be influenced by blood pH and administration timing.To investigate whether the effects of sodium bicarbonate (SB) during cardiopulmonary resuscitation (CPR) would be influenced by blood pH and administration timing. Adult patients experiencing in-hospital cardiac arrest (IHCA) from 2006 to 2015 were retrospectively screened. Early intra-arrest blood gas data were obtained within 10 min of CPR. Multivariable logistic regression analysis and generalised additive models were used for effect estimation and data exploration, respectively. A total of 1060 patients were included. Only 59 patients demonstrated favourable neurological status at hospital discharge. Blood pH ≤ 7.18 was inversely associated with favourable neurological outcome (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11–0.52;  Approximately 24% of patients with IHCA survive to hospital discharge; among these patients, 14% demonstrate severe neurological disability1.Annually, a total of 209,000 patients sustain in-hospital cardiac arrest (IHCA) in the United States4 because of increased anaerobic metabolism and cessation of pulmonary gas exchange. Buffering acidosis with sodium bicarbonate (SB) was intuitive; therefore, it had been recommended as a first‐line treatment for cardiopulmonary resuscitation (CPR)5. Nevertheless, SB administration during CPR was not without risks, such as worsening intracellular acidosis6, which may cause worse outcomes.Cardiac arrest may lead to severe acidosis7 did not recommend routine use of SB during CPR, except for hyperkalaemia-related arrest and tricyclic overdose. Using the American Heart Association Get With The Guidelines–Resuscitation database, Moskowitz et al.8 found a significant increase in SB use for IHCA between the years 2001 and 2016. Compared to the year 2001, patients with IHCA in the year 2016 had two-fold higher odds of receiving SB8, which resulted in half of them receiving SB during CPR8. This suggests SB may be used beyond the guideline-recommended indications7.The guidelines9 revealed that approximately 31% (27 out of 88) of patients with IHCA received SB during CPR without any blood gas data and 11% (10 out of 88) of patients receiving the first SB injection empirically were later found to have alkalemia. Furthermore, a large retrospective study10 demonstrated that SB was often given late during CPR, probably as a “last-ditch effort,” which could have biased the results toward harmful association11. Therefore, it was probably not SB that worsened CPR outcomes. It just failed to improve outcomes.A small retrospective studyEarly blood gas analysis may reduce the frequency of unwarranted use of SB and clarify its effects during CPR. Therefore, in this exploratory analysis, we attempted to (1) investigate the therapeutic effects of SB during CPR, and (2) explored whether the effects of SB would be influenced by intra-arrest blood pH and timing of administration in the interaction analysis, thereby identifying the optimal indications for SB use during CPR.13. Briefly, this retrospective study was conducted at National Taiwan University Hospital (NTUH), a tertiary medical centre, which had 2600 beds, including 220 beds in intensive care units (ICUs). This study was performed in accordance with the Declaration of Helsinki amendments and approved by the Research Ethics Committee of the NTUH (reference number: 201805098RINC). The requirement for informed consent was waived because of the retrospective and non-interventional study design. In NTUH, a code team is activated whenever a cardiac arrest event occurs in the general wards. For IHCA in the ICUs, resuscitation is performed by the ICU staff without activating the code team. CPR is performed according to guideline recommendations15. In NTUH, point-of-care blood gas analysers are deployed in every ward floor, including floor of general wards and ICUs. Physicians are instructed to obtain blood samples as soon as possible for blood gas analysis in order to identify potential causes leading to IHCA.We used previously established IHCA database for analysis2) and bicarbonate (HCO3−) data. If a single patient suffered from multiple IHCA events during hospitalisation, only the first event was analysed. Trauma-related IHCA was excluded. Patients were also excluded if the timing of SB use was not documented.Patients sustaining IHCA at NTUH between 2006 and 2015 were screened by the following inclusion criteria: (1) age ≥ 18 years; (2) receiving CPR for ≥ 2 min; (3) absence of a do-not-resuscitate order before arrest and (4) early intra-arrest blood gas analysis with available blood pH, partial pressure of carbon dioxide . Sustained ROSC was defined as ROSC lasting for 20 min consecutively without resuming repeated CPR. Early intra-arrest blood gas analysis, including measurement of blood pH, PCO2 and HCO3−, was defined as the first available blood gas data measured within 10 min of initiating CPR, which was usually obtained in the beginning of CPR from the arterial source. Severe metabolic acidaemia was defined as blood pH ≤ 7.2, PaCO2 ≤ 45 mm Hg and HCO3− concentration ≤ 20 mmol/ L17. Time to SB was defined as elapsed time from the first chest compression to the first time of SB administration. Duration of CPR was defined as the period from the initiation of chest compression to the termination of resuscitation attempts, either due to sustained ROSC or due to declaration of death.The following information was abstracted for each patient: age, sex, comorbidities, variables suggested by the Utstein template18. The secondary outcome was survival to hospital discharge. The Cerebral Performance Category scale score was determined by retrospectively reviewing the medical records of each patient.The primary outcome was favourable neurological recovery at hospital discharge, defined as a Cerebral Performance Category scale score of 1 or 2Categorical variables are expressed as counts with percentages, while continuous variables are expressed as medians with interquartile ranges. Categorical and continuous variables were compared by Chi-squared test and Wilcoxon rank-sum test, respectively.19 were employed to explore nonlinear effects of the continuous variables on outcomes and to define the potential cut-off points for transforming a continuous variable into a categorical variable during the model-fitting process. The stepwise variable selection procedure with iterations between the forward and backward steps was utilized to build the final regression model. Significance levels for entry and to stay were defined at 0.15 to avoid exclusion of candidate variables. The final regression model was obtained by sequentially excluding individual variables with a p value > 0.05 until all regression coefficients were significant. If the variable of interest, SB use, was not included in the final model, this variable would be forcibly entered into the model to assess its effect estimate.The odds ratio (OR) was designated as the outcome measure. Univariate and multivariable logistic regression analyses were conducted to investigate the associations between independent variables and outcomes. All available independent variables were accounted for in the regression model, regardless of whether they were considered as significant in univariate analyses. Generalised additive models (GAMs)c statistics, the adjusted generalised R2 and the Hosmer–Lemeshow goodness-of-fit test. Analysis was performed using R 3.3.1 software . A two-tailed p value < 0.05 was considered significant.In the prespecified interaction analyses, the interactions of SB use with blood pH, severe metabolic acidaemia and time to SB were assessed. The goodness-of-fit of the fitted regression model was examined using Between 2006 and 2015, a total of 1698 adult non-trauma patients receiving CPR for ≥ 2 min after IHCA were screened. Of these, 599 patients were excluded due to the lack of early intra-arrest blood gas analysis; 39 patients were further excluded because the timing of SB use was not documented. Finally, a total of 1060 patients were included for further analysis. The differences between patients included and excluded from the analysis were shown in Supplemental Tables 2 and HCO3- levels were 7.2, 50.1 mm Hg and 20.2 mmol/L, respectively. There were 115 patients (10.8%) categorised as having severe metabolic acidaemia. Only 124 patients (11.7%) survived to hospital discharge; of these, 59 patients (5.6%) demonstrated favourable neurological status.The characteristics of the included patients are provided in Tables The GAM plots demonstrated the association of logit (p), where p represented the probability for favourable neurological status, with blood pH Fig. A and timp value < 0.001) while SB use was not. In the interaction analysis, significant interactions were noted between SB use and blood pH  or time to SB , but no significant interaction was noted between SB use and severe metabolic acidaemia.For the primary outcome Table , in the p value = 0.04) while SB use was not. In the interaction analysis, non-SB use × blood pH > 7.18 was positively associated with survival .For the secondary outcome Table , in the Overall, SB use was not associated with IHCA outcomes when the confounding effects of blood pH were adjusted. Blood pH ≤ 7.18 was significantly associated with worse outcomes. Therefore, by interaction analysis, we tested the hypothesis, i.e. whether the effect of SB would be different in different populations. These populations included patients with blood pH ≤ 7.18 versus > 7.18, patients with versus without severe metabolic acidaemia and patients with CPR duration < versus ≥ 20 min. The results demonstrated that for patients with blood pH > 7.18, non-SB use was associated with survival while for patients with CPR duration ≥ 20 min, SB use was associated with better neurological recovery.20. During CPR, point-of-care blood testing may yield important diagnostic information and guide management21. Compared with out-of-hospital cardiac arrest (OHCA), it may be easier for clinicians to diagnose acidosis for IHCA. In our study, about 65% (1099 out of 1698) of screened patients had early intra-arrest blood gas analysis, revealing that 10.8% of them were experiencing severe metabolic acidaemia. Nonetheless, not only severe metabolic acidaemia, blood pH ≤ 7.18 itself was identified to be a significant predictor for IHCA outcomes. That is, severe acidosis (blood pH ≤ 7.18)23, irrespective of the type of acidosis, was more influential on outcomes than pure severe metabolic acidaemia.Few studies investigated the effects of SB use during CPR for IHCA17, SB use may thus become an epiphenomenon of severe acidosis and could have introduced the bias of “confounding by indication,” leading to worse outcomes associated with SB use27. When the confounding effects of blood pH were accounted for, the SB use itself was no longer associated with IHCA outcomes, as shown in the Primary Model in the Table Since severe acidosis was both a negative prognostic factor and a potential indication for SB administrationFurthermore, we attempted to investigate whether the effects of SB would be dependent on intra-arrest blood pH. As shown in Table When we examined the two interaction terms, SB use × blood pH ≤ 7.18 (OR 0.29) and non-SB use × blood pH ≤ 7.18 (OR 0.20), we noticed that SB administration actually increased the chances of neurological recovery for patients with blood pH ≤ 7.18 OR 0.24). The increase in ORs between SB use × blood pH ≤ 7.18 and non-SB use × blood pH ≤ 7.18 was caused by the administration of SB, which suggested that for patients with blood pH ≤ 7.18, SB might improve neurological outcomes. Nonetheless, the effect estimates of SB use × blood pH ≤ 7.18 and non-SB use × blood pH ≤ 7.18 were so close that this result could only indicate a tendency of improvement by SB use rather than a definite conclusion. However, this result may encourage future investigators to examine whether SB use could improve the outcomes of patients with blood pH ≤ 7.18. In contrast, for patients with blood pH > 7.18  was significantly higher than that in the non-SB group (17 min). Andersen et al.11 indicated that, if a medication was more likely to be administered when CPR efforts continued longer, this would tend to bias the results toward a harmful effect since CPR duration was strongly associated with worse outcomes31. This bias might be mitigated to some extent by considering both CPR duration and timing of intervention in the analysis. As shown in Table Guidelines for CPR published in the year 2000SB group 0 min was28. Vukmir et al.26 demonstrated that overall, there was no difference in survival between the SB and placebo groups. Nonetheless, survival rates were significantly higher in the SB group than in the placebo group in the subgroup with prolonged arrest (> 15 min)26. According to the 3-phase cardiac arrest model32, CPR duration longer than 20 min may fall into the metabolic phase, during which interventions other than prompt defibrillation or high-quality CPR should be employed, such as SB. Beyond its metabolic effects, SB was also a volume expander, which might be beneficial during circulatory phase. Nonetheless, since we did not collect the hemodynamic data during CPR, the circulatory effects of SB during CPR should be further examined. Furthermore, despite the fact that our results showed that SB use in prolonged CPR might be effective, it should be remembered that SB is administered after other effective interventions have been performed28.The definition of “prolonged CPR” was not clearly defined in the 2000 guidelines for CPRIn summary, SB tended to be used in a subgroup with inherently poor outcomes. By carefully dealing with the bias of “confounding by indication” and “resuscitation time bias,” our results seemed to corroborate SB use in certain conditions. However, because of the retrospective study design, the results should be viewed as hypothesis-generating, laying the foundation for further clinical trials.33. However, this could only be resolved by a prospective study adopting a certified method to obtain arterial blood gas. Third, the SB dosage was not accounted for in the analysis. A dose–response effect, if present, could have offered stronger evidence for the effect of SB use on outcomes. Fourth, the exact timing of obtaining blood gas samples was not recorded in the previously established IHCA database13 and therefore, we could not verify whether the timing of obtaining blood gas samples was prior to the timing of SB use. Nonetheless, since the clinicians in NTUH were instructed to obtain blood gas analysis as soon as possible in the beginning of CPR, the interval between the timing of blood gas analysis and SB use may be quite small (maximum: 10 min), which may not cause significant changes in blood gas analysis data. Finally, we studied only patients with intra-arrest blood gas data available. As shown in Supplemental Table First, because of the inherent limitation of the retrospective study design, only an association, rather than a causal relationship, could be investigated between independent and outcome variables. The effects of unmeasured confounders could have introduced bias into the results. Second, it was difficult to ascertain whether blood gas was retrieved from an arterial or a venous origin. It was reported that venous pH may be consistent with arterial pHOur results suggested that SB should not be empirically administered for IHCA patients with blood pH > 7.18. Also, for patients receiving CPR longer than 20 min, SB might be administered, given other effective interventions had been performed.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.


The detection of prostate cancer requires histological confirmation in biopsy core. Currently, number of unnecessary prostate biopsies are being performed in the United States. This is due to the absence of appropriate biopsy decision‐making protocol.To develop and validate a 4K score/multiparametric magnetic resonance imaging (mpMRI)‐based nomogram to predict prostate cancer (PCa), clinically significant prostate cancer (csPCa), and unfavorable prostate cancer (uPCa).Retrospective, single‐center study evaluating a cohort of 574 men with 4K score test >7% or suspicious digital rectal examination (DRE) or Prostate Imaging Reporting and Data System (PI‐RADS) scores 3, 4, or 5 on mpMRI that underwent systematic and/or mpMRI/ultrasound fusion–targeted prostate biopsy between 2016 and 2020. External cohort included 622 men. csPCa and uPCa were defined as Gleason score ≥3 + 4 and ≥4 + 3 on biopsy, respectively. Multivariable logistic regression analysis was performed to build nomogram for predicting PCa, csPCa, and uPCa. Validation was performed by plotting the area under the curve (AUC) and comparing nomogram‐predicted probabilities with actual rates of PCa, csPCa, and uPCa probabilities in the external cohort.4K score, a PI‐RADS ≥4, prostate volume and prior negative biopsy were significant predictors of PCa, csPCa, and uPCa. AUCs were 0.84, 0.88, and 0.86 for the prediction of PCa, csPCa, and uPCa, respectively. The predicted and actual rates of PCa, csPCa, and uPCa showed agreement across all percentage probability ranges in the validation cohort. Using the prediction model at threshold of 30, 30% of overall biopsies, 41% of benign biopsies, and 19% of diagnosed indolent PCa could be avoided, while missing 9% of csPCa.This novel nomogram would reduce unnecessary prostate biopsies and decrease detection of clinically insignificant PCa. The 4K score test has repeatedly been shown to predict prostate cancer (PCa) biopsy outcome in men with elevated PSAs while also significantly reducing the number of unnecessary biopsies.Although the mpMRI and the 4K score test are both used in American clinical practice for the evaluation of prostate cancer, there are no reports on the impact of using these tests in combination. We hypothesize that both of these tests will provide independent and complementary value, and when combined, will improve the detection of clinically significant disease compared to either test alone.22.1We retrospectively reviewed our institution's prostate biopsy database to extract relevant patient records. A total of 1100 patients underwent 4K score test between January 2016 and April 2020. Of these, 584 (53%) underwent systematic or combined systematic and MRI/transrectal ultrasound (TRUS) fusion biopsy by a single expert surgeon (A.K.T. ) with 20 years of experience. Indications of biopsy were 4K score test of >7%, suspicious DRE, PI‐RADS scores of 3, 4 or 5 on mpMRI, or combination of any of the above. Men who have contraindication for prebiopsy mpMRI (n = 10) were excluded. In total, 574 men were used to build the model (development cohort). For validation, we used a cohort of 622 men that underwent systematic or combined systematic and MRI/TRUS fusion biopsy for similar indications  at the University of Miami.All men underwent standardized 3‐Tesla mpMRI prior to prostate biopsy. All mpMRI examinations were compliant with the American College of Radiology recommendations for technical specifications. All mpMRI results were evaluated according to PI‐RADS Version 2 (PI‐RADS V2) by clinical radiologists with experience in prostate imaging.All biopsies were performed using a spring‐loaded biopsy gun and 18‐gauge needles. For targeted biopsies, Artemis MRI/TRUS fusion device  was used and extra 2‐4 cores taken from each lesion in addition to standard 12 cores biopsy. An experienced genitourinary pathologist (K.H. III) reviewed all biopsy samples.2.2The outcome for predicting PCa was defined as a Gleason score of ≥3 + 3 on biopsy, and men with this outcome were considered cases. Men with negative biopsy were considered controls. The outcome for predicting csPCa was defined as a Gleason score of ≥3 + 4 on biopsy; men with this outcome were considered cases, and the remaining men with negative biopsy and men with Gleason score 3 + 3 on biopsy were considered controls. The outcome for predicting uPCa was defined as a Gleason score of ≥4 + 3 on biopsy; men with this outcome were considered cases, while the remaining men with negative biopsy, Gleason score 3 + 3, 3 + 4, were considered controls.U test. Categorical variables were reported as rates and were tested with a chi‐square test, as appropriate. The prediction model included the following variables: age, family history of prostate cancer, history of negative prior biopsy, 4K score test, DRE findings, mpMRI prostate volume, and highest PI‐RADS score. We are aware that 4K score test incorporates clinical parameters like age, family history, DRE, and prior biopsy history. Therefore, we calculated matrix of correlation coefficients between 4K score test and these predictors. We also ran variance inflation factor analysis (the inflation in the variances of the parameter estimates due to collinearities among predictors) to evaluate the potential presence of substantial multicollinearity between these predictors in our model.Descriptive statistics for the two groups were calculated. Continuous variables were reported as median and interquartile range (IQR) and compared using a Mann–Whitney Analysis of correlation coefficients between predictors as well as variance inflation index of predictors did not indicate presence of strong collinearity between 4K and other predictors in our model. There were no strong correlations (>0.8) between 4K score test and other predictors. PI‐RADS scores of 1 and 2 were grouped for the purpose of analysis. Multivariable binary logistic regression analysis was performed for presence of PCa, csPCa, and uPCa in the development cohort. The nomogram predicting PCa, csPCa, and uPCa was built based on coefficients of the logit function.P < .05.Nomogram validation was performed in the external cohort in two stages. First, receiver‐operating characteristics (ROCs) were plotted for presence of PCa, csPCa, and uPCa using the same variables that were used to build the nomogram. Second, calibration graphs were plotted by grouping sorted nomogram‐predicted probabilities from the development cohort into deciles and then comparing the mean prediction of each group with the observed proportion of men from the validation cohort with PCa or csPCa or uPCa. Using nomogram‐derived probability cut‐offs, we calculated the number of biopsies that could be avoided without missing PCa, csPCa, or uPCa in the validation cohort. Decision curve analysis (DCA) was performed to evaluate the performance of the prediction models in the validation cohort. Statistical analyses were performed using STATA 12  and SAS 9.4 . All tests were two‐tailed with a significance level of 3Of the total 574 men in the development cohort, 232 (40%) were diagnosed with PCa, while the remaining 342 men (60%) were not having PCa. Median age was 66 years  and 64 years  for PCa and benign biopsies, respectively; median PSA was 6.1 ng/mL , 5.3 ng/mL ; and median 4K score test was 28 , 9  for men with PCa and men with benign biopsy, respectively. Of the 232 men with PCa, 89 (38%), 65 (28%), 27 (12%), 30 (13%), and 21 (9%) had Gleason scores of 3 + 3, 3 + 4, 4 + 3, 4 + 4, and 4 + 5/5 + 4/5 + 5, respectively. Of the 622 men in the validation cohort, 328 (53%) did not have prostate cancer on biopsy. Of the remaining 294 who had cancer in the validation cohort, 121 (41%), 77 (26%), 29 (10%), 29 (10%), and 38 (13%) had Gleason scores of 3 + 3, 3 + 4, 4 + 3, 4 + 4, and 4 + 5/5 + 4/5 + 5, respectively (Table 3.1P < .05), while family history of PCa was significant in predicting PCa and uPCa; PI‐RADS score 3 was found significant predictor for PCa  for predicting PCa, csPCa, and unfavorable PCa in the validation cohort were 0.84. 0.88, and 0.86, respectively Figure . 4K scorWe evaluated the nomogram's calibration by comparing predicted and actual probabilities of PCa, csPCa, and unfavorable PCa in the validation cohort. There was agreement between the predicted and actual rate of probabilities (0%‐100%) for PCa, csPCa, and unfavorable PCa as seen by points on the diagonal line in Figure DCA showed superior clinical risk prediction for 5%‐95% of nomogram‐derived probabilities for predicting PCa, csPCa, and uPCa than relying on 4K score test alone or PI‐RADS score alone. Figure .Using our model in the validation cohort, 10% of biopsies could be avoided without missing uPCa and with missing 1% csPCa, avoiding 17% of benign biopsies and avoiding 4% of clinically indolent PCa Figure . Additio4Multiparametric MRI and the 4K score test are both used in American clinical practice for the evaluation of prostate cancer. To our knowledge, this is the first study investigating the use of both the 4K score test and mpMRI in combination to detect PCa, csPCa, and uPCa. Our model confers three key benefits. (a) It reduces number of biopsies without compromising detection of csPCa and uPCa rates, (b) the model shows efficacy of 4K score test and mpMRI PI‐RADS score, for predicting PCa, csPCa, and uPCa, and (c) the model showed accuracy in predicting any PCa, csPCa, and uPCa in entirely different cohort across all ranges of probabilities.Combining both the 4Kscore and mpMRI in this newly developed model has the ability to guide prostate cancer diagnostics with more accuracy and further decrease number of unnecessary biopsies as well as the detection of non‐csPCa. By reducing the number of unneeded biopsies, patients can avoid the risk of biopsy‐related complications including pain, bleeding, and infections, and in 1%‐2% of biopsied men, life‐threatening urosepsis.Studies have shown that the 4K score can improve the diagnostic discrimination of csPCa, reducing the number of required prostate biopsies. It has been suggested it could play an important clinical role in the decision‐making process prior to proceeding with initial prostate biopsy in men with an elevated PSA level or abnormal digital rectal examination (DRE) or after a prior negative biopsy and persistently abnormal PSA levels.Probabilistic estimates and predictions are being used with increasing frequency in prostate cancer research to guide the decision‐making process. Huge data sets and increasingly sophisticated statistical software allow for individualized probability predictions. However, these predictions can be only helpful if they accurately reflect the correct underlying probabilities.Our study has some limitations. First, all biopsies were performed by a single experienced, high‐volume expert, which could affect reproducibility. Second, as mentioned in methodology, not all men who had 4K score test done were included in the analysis. Stringent biopsy criteria could also affect generalizability.5We have developed a 4K score/MRI‐based tool to assist clinicians in biopsy decision‐making and counselling of men at risk for PCa. Using our novel prediction model could significantly reduce the large number of biopsies that detect benign or clinically insignificant PCa, while missing only a small proportion of csPCa and uPCa. Our results demonstrate the importance of combining 4K score test, prior negative biopsy, prostate volume, and mpMRI PI‐RADS score ≥4 for predicting PCa, csPCa, and uPCa. This novel model could reduce unnecessary biopsies and decrease detection of clinically insignificant prostate cancer more effectively than mpMRI or 4K score alone. Thus, this model could have a significant impact on patient morbidity and social economic costs within prostate cancer diagnostics.The authors declare no conflicts of interest.Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Visualization, Writing‐original draft, Writing‐review and editing, V.W.; Data curation, Software, Writing‐review and editing, S.S.; Data curation, Formal analysis, Methodology, P.R.; Investigation, Resources, Writing‐review and editing, J.Y.; Investigation, Writing‐review and editing, A.L.;. Data curation, Investigation, Writing‐review and editing, S.P.; Investigation, Writing‐review and editing, U.F. and S.L.; Data curation, Investigation, L.L.; Data curation, Writing‐review and editing, K.H.; Validation, Writing‐review and editing, S.P.; Conceptualization, Writing‐original draft, Writing‐review and editing, P.W.; Conceptualization, Project administration, Resources, Supervision, Writing‐original draft, Writing‐review & editing, A.T.The study was conducted at the Icahn School of Medicine at Mount Sinai Health System (ISMMS) after approval from the Institutional Review Board (GCO 19‐1711). Informed patient consent waived for this study.