Radical cystectomy (RC) is historically considered the gold standard treatment for muscle invasive and high‐risk non‐muscle invasive bladder cancer. However, this technique leaves the majority of patients of both sexes with poor sexual and urinary function. Organ‐sparing cystectomy (OSC) techniques are emerging as an alternative to the standard procedure to preserve these functions, without compromising the oncological outcomes. We present a systematic review and meta‐analysis of the published literature.MEDLINE, Embase and Web of Science were systematically searched for eligible studies on 6 April 2021. Primary outcomes studied were both oncological outcomes, specifically overall recurrence, and functional outcomes, specifically sexual function, and daytime and nighttime continence. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated. The PROSPERO registration reference number was CRD42018118897.From 13 894 identified abstracts, 19 studies  were eligible for inclusion in this review. These studies included patients who underwent either whole prostate, prostate capsule, seminal vesicle, nerve, uterus, ovary, vagina and fallopian tube sparing techniques. Four studies included only female patients.p = 0.34). Thirteen studies reported on male sexual function. In men, OSC had significantly greater odds of retaining potency . Fourteen studies  reported urinary outcomes. In men, OSC demonstrated greater odds of daytime  and nighttime continence .Thirteen studies reported oncological outcomes, and overall recurrence rate was similar between the two groups (five studies; OR 0.73; 95% CI 0.38–1.40, In carefully selected patients, OSC allows the potential to provide better sexual and urinary function without compromising oncological outcomes. There remains, however, a paucity of OSC studies in females. Further studies are required to make recommendations based on robust clinical evidence. These techniques aim to maintain similar oncological outcomes to RC but with improvement in sexual and urinary outcomes. In males, prostate‐sparing cystectomy was first described in 2002 and involves sparing the prostate gland, seminal vesicles, vas deferens and neurovascular bundles.In females, organ‐sparing techniques are less well described. These have included sparing of the uterus, fallopian tubes, ovaries and anterior wall of the vagina.Given the relative paucity of organ‐preserving cystectomies, there is a lack of consensus in regard to the benefit of these techniques in the holistic management of bladder cancer patients. The aim of this systematic review is to provide an update of results on the role of organ‐preserving techniques in the management of bladder cancer patients of either sex suitable for OSC.22.1The protocol for this review has been published online in the PROSPERO database (CRD42018118897).Three reviewers  screened the article titles identified from the database search for potentially eligible articles. Once eligible articles had been identified, further abstract screening was commenced with the final list of papers undergoing a full text screen. Those shortlisted had their full manuscript assessed against eligibility criteria Figure . Any dis2.2All study designs comparing the relevant interventions were considered for inclusion. Case series involving OSC were included if they involved over 50 patients. Studies reported in English, or any other language with an accessible English translation, involving human participants since 2000 were included.2.3The participants of interest were patients, male or female, with bladder cancer undergoing cystectomy for curative intent in the primary setting. The patients with bladder cancer, either muscle‐invasive (MIBC) or high‐risk non‐muscle‐invasive (NMIBC), and any stage up to T4 Nx/N1M0 undergoing cystectomy were included. Adjuvant treatments were permissible.2.4The intervention of interest was pelvic OSC. For men, this included prostate‐sparing, capsule‐sparing, seminal vesicle‐sparing and neurovascular bundle‐sparing cystectomies. In women, this included uterus‐sparing, ovary‐sparing, vagina‐sparing cystectomy and neurovascular bundle‐sparing cystectomy. The comparator was standard RC, where pelvic organ sparing was not attempted.We also included studies that compared individual organ‐sparing techniques, without a comparison to standard RC, for example, a study comparing capsule‐sparing cystectomy and seminal vesicle‐sparing cystectomy. As mentioned, we also included case series of a single technique if over 50 patients were included.2.5Primary outcomes of interest were both oncological and functional. The oncological outcomes were assessed by reported positive surgical margins, local recurrence or metastatic disease (including site and time of diagnosis), summated overall recurrence, recurrence‐free survival, progression‐free survival disease‐free survival and overall survival after 2 years. The data regarding adjuvant treatments and proportion of orthotopic neobladders were also collected.The primary functional outcome was sexual function after surgery, as compared to preoperative status. In males, sexual function (potency) was assessed from subjective reporting on erectile function and questionnaires such as International Index of Erectile Function‐5 (IIEF‐5). We also planned to analyse fertility data, ability to achieve orgasm, and adjuvant treatments. For female patients, we extracted data pertaining to vaginal length, ability to have penetrative sex and the use of hormone‐replacement therapy.The secondary outcomes were measures of urinary function, including day and night continence (as measured by questionnaires), number of pads used and self‐reported outcomes. Urodynamic study data were also extracted in patients who underwent orthotopic neobladder formation or other functional assessments.2.6This was dependent on the study design. The Cochrane Risk of Bias 2.0 tool was used to assess randomised‐controlled trials (RCTs),2.7Because of the nature of the intervention, male and female patients were assessed separately. We also performed subgroup analysis according to the type of OSC, the modality  and according to differences in how functional outcomes were measured, for example, using questionnaires, subjective reports or other measures.2.8p value of <0.05. Meta‐analysis was performed using Cochrane RevMan . The quality of our effect estimates was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) rating system.A qualitative synthesis was performed, with discussion of possible explanations, and a subsequent summation in the conclusion. Meta‐analysis was performed to compare local, metastatic, and overall recurrence rates; potency; and day and night continence at 12 months. Odds radios (OR) with 95% confidence intervals (95% CI) were calculated. In the presence of heterogeneity (I2 > 50%), a random‐effect model was used. Otherwise, a fixed‐effect model was used. Statistical significance was defined by 33.1Our search identified 13 894 articles of which 1214 had their abstracts screened. A total of 1173 abstracts were excluded leaving 41 full text articles. Based upon our eligibility criteria, a further 22 articles were excluded, leaving a total of 19 studies included from the database searches. A further two articles were included from searching references of included articles, leaving 21 studies included in the present reviewTable The patient selection and inclusion criteria varied between the identified papers, and this information is summarised in Table In total, 1886 male patients were included across 17 studies. Eight studies reported on nerve‐sparing cystectomy,There were a total of 305 female patients included across five studies3.2Table p > 0.05).p = 0.074); although, the time‐point was not reported.Table p = 0.5)Table In total, only four studies included comparative data suitable for meta‐analysis of oncological outcomes, which were divided into subgroups: local recurrence and metastatic disease. All three of the studies used in the meta‐analysis of local recurrence were male only.p = 0.41). The meta‐analysis of metastatic disease featured two studies and showed similar rates of metastatic recurrence between OSC and RC .p = 0.12)The meta‐analysis of local recurrence rates featured three studies, two analysing prostate‐sparing techniques and the other nerve‐sparing technique.3.3Male sexual function was evaluated in 13 studies, as highlighted in Table p < 0.00001)  Figure .p < 0.01). The patients undergoing a seminal vesicle‐sparing cystectomy had an 84.2% potency rate (p = 0.06). The third study reported a significantly greater potency rate of 66.7% in prostate‐sparing cystectomy compared to 13.8% in nerve‐sparing cystectomy (p < 0.001)Three studies compared different organ‐sparing techniques with regards to potency rates. The first two studies analysed capsule‐sparing and nerve‐sparing cystectomies.e p = 0.0. The thiIn total, seven studies reported on the use of adjuvant treatments to aid sexual rehabilitation. The percentage of patients who required treatment to restore sexual function ranged from 1 to 100%, as defined by the trialists.As there was only one paper studying sexual outcomes in female patients, no meta‐analysis could be performed. This study compared the postoperative sexual function in 13 females undergoing either a nerve‐sparing or RC using the Female Sexual Function Index questionnaire.3.4Fourteen studies analysed continence rates using several methods, including questionnaires such as the BCI, and number of pads. Twelve studies reported 100% of patients having orthotopic neobladder formation.p < 0.00001)   Figure . Similar) Figure .Only one study analysed continence in female patients, observing continence rates of 60.9% in nerve‐sparing cystectomy patients compared to 25% in standard RC patients. The study used self‐impression to measure continence and did not indicate whether this was daytime or nighttime continencep = 0.1).p < 0.001)Three studies examined the difference in continence rates between various types of OSC.Only one study performed urodynamic assessment, showing better urodynamic outcomes in male patients who had nerve‐sparing cystectomy compared to RC. The study observed a significantly longer functional urethral length of 34.8 mm in the nerve‐sparing cystectomy group, compared to a length of 30.1 mm in the RC group. Furthermore, the study reported a greater maximum urethral pressure of 82.8 cm H20 in the nerve‐sparing cystectomy group, compared to 77.9 cm H20 in the RC group.3.5The data regarding the risk of bias assessment is detailed in Tables 3.644.1Overall, 21 studies were included, comprising 3 RCTs, 14 cohort studies and 4 case series. The studies described prostate‐, capsule‐, seminal vesicle‐, nerve‐, uterus‐, ovary‐, vagina‐ and fallopian tube‐sparing techniques. Of these studies, only four involved women.p = 0.12). Fourteen studies reported on sexual function, including one female cohort study. The meta‐analysis for men showed significantly greater odds of potency preservation after OSC compared to radical . Fourteen studies analysed urinary outcomes, including one female case series. In meta‐analysis for men, OSC was associated with significantly higher daytime  and nighttime continence  , they may help guide bladder cancer risk stratification and the use of organ‐sparing techniques. Recent systematic review analysed the use of MRI as part of the Vesical Imaging Reporting and Data System (VI‐RADS), which can be used to distinguish MIBC from NMIBC using multiparametric MRI, concluding that its use confers good performance and reproducibility.4.4The rationale behind improved functional outcomes following OSC is that the sparing of nerves or various pelvic organs allows the preservation of neurovascular bundles that control potency and continence. Erectile function in males is dependent on parasympathetic innervation via the cavernous nerves, which travel to the penis via the pelvic and prostatic plexus and have a close anatomical relationship to the bladder, seminal vesicles, prostate and urethral sphincter.Given both surgical options involve bladder reconstruction, it is important to analyse whether OSC has favourable postoperative urodynamics compared to standard RC. However, this was difficult in this review because only one study included postoperative urodynamic assessment results.4.5OSC is an emerging technique in the treatment of bladder cancer. This systematic review provides an up‐to‐date analysis of this technique in both sexes from three important perspectives: oncological, sexual and urinary. However, this review does present with some limitations.Firstly, the quality of the studies included were rated as either low or very low Table . There wSecondly, the reporting of outcomes between studies was inconsistent. In terms of oncological outcomes, there was incomplete reporting of overall survival, local and metastatic recurrence. Regarding functional outcomes, different methods were used to measure the same outcome, as evidenced through the use of both the IIEF‐5, which measured multiple domains associated with sexual function and the EHS, which relied solely on self‐reported erection strength.There were inconsistencies with what each study defined as either continence or potency based upon the scoring questionnaires. For example, some papers classed patients as potent when able to achieve an erection with the use of medication such as alprostadil,The studies in this review showed a lack of standardised follow‐up duration. This may impact the present analysis of results because the data were recorded at different times. Furthermore, the lack of long‐term follow‐up limits the use of the meta‐analysis in predicting any lasting effects of OSC.There is a significant lack of female studies. This is likely because of the greater prevalence of bladder cancer amongst males when compared with females.This review has also not discussed further complications of the surgery, for instance, the rate of bleeding, infection, bowel obstruction and urethral strictures. Analysing the rates of these complications, in the context of OSC and RC, can further provide a more detailed comparison of these two techniques, especially given the morbid nature of cystectomy.4.6Based on the low quality evidence in this review, there is potential for OSC to be considered where possible, instead of RC, when deciding the surgical management of carefully selected bladder cancer patients in order to preserve sexual and urinary function. Surgical planning may be aided by the use of preoperative imaging tools such as VI‐RADS.Future OSC RCTs, especially comparing oncological outcomes with standardised outcome reporting and long‐term follow‐ups, as well as female studies, are needed to add to the evidence base.Research comparing single versus multi‐organ sparing cystectomy and comparing different types of OSC will be beneficial.5There is a potential advantage to OSC regarding sexual and urinary function with equivalent oncological outcomes in carefully selected men when compared to RC. Our results would benefit from more standardised functional outcome reporting, further study of oncological outcomes in robust RCTs and higher quality OSC studies in women.This work was supported and funded by King's College London [JISC].All authors declare no conflicts of interest as per the ICMJE COI.All Authors contributed to the above review.


Concurrent bronchoscopy using radial probe and convex endobronchial ultrasound (RP‐ and CP‐EBUS) is used to simultaneously evaluate both peripheral lung lesions for the histological diagnosis of the primary tumor and mediastinal lymph nodes for mediastinal staging. So far, little is known about the combined procedure with RP‐ and CP‐EBUS.Between January 2020 and March 2021, the bronchoscopy database was reviewed to identify the clinical outcomes of the combined procedure with RP‐ and CP‐EBUS. Patients who underwent transbronchial biopsy using RP‐EBUS alone were classified as the RP‐EBUS group, while those who underwent a combined procedure with RP‐ and CP‐EBUS were classified as the combination group.p < 0.001). CP‐EBUS increased the diagnostic yield of the bronchoscopic procedure in the combination group by 9.3%. Although the mean procedure time was significantly longer, and the mean doses of midazolam and fentanyl were significantly higher in the combination group (p < 0.001), there were no differences in the overall complication rates between the two study groups .The overall diagnostic yield of the bronchoscopic procedure in the combination group was significantly higher than the RP‐EBUS group (90.7% vs. 70.0%, Combined bronchoscopy using RP‐ and CP‐EBUS is feasible and safe. In addition to mediastinal staging, CP‐EBUS increased the overall diagnostic yield of the bronchoscopic procedure by 9.3%. The combined procedure with radial probe TBLB and convex probe endobronchial ultrasound is feasible and safe. The combined procedure increased the overall diagnostic yield of bronchoscopy, besides concurrent diagnosis and mediastinal staging. Endobronchial ultrasound (EBUS) techniques expand the view of bronchoscopy beyond the central airway using convex probe EBUS (CP‐EBUS), and allow the investigation of peripheral lung lesions (PLLs), where conventional bronchoscopy is not possible, using radial probe EBUS (RP‐EBUS).The introduction of low‐dose computed tomography (CT) screening for lung cancer in high‐risk individuals has increased the detection rate of small PLLs.Between January 2020 and March 2021, the bronchoscopy database at Pusan National University Hospital, Republic of Korea, was used to identify the clinical outcomes of the combined procedure with RP‐ and CP‐EBUS. During the study period, 617 patients received RP‐EBUS‐TBB to evaluate PLLs. Two of these patients were excluded because PET was performed at another hospital, and could not be analyzed by nuclear radiologists. Another 12 patients were excluded because RP‐EBUS‐TBB was performed for a rebiopsy to detect genetic mutations in the lung cancer.PLLs were defined as any lung lesion existing beyond the segmental bronchus in the axial plane of the thin‐section CT scan.All procedures were performed under conscious sedation with intravenous midazolam and fentanyl. RP‐EBUS‐TBB was performed according to Kurimoto's standard technique, with or without virtual bronchoscopy navigation .When mediastinal LN sampling using CP‐EBUS was required, based on the CT scan or PET, it was followed by a RP‐EBUS‐TBB procedure. Using an ultrasound bronchoscope , CP‐EBUS‐TBNA was performed at the mediastinal LNs with a clinical suspicion of metastasis. A representative case of the combined procedure with RP‐ and CP‐EBUS is shown in Figure When bronchoscopy procedures using RP‐EBUS, with or without CP‐EBUS, failed to confirm the diagnosis, an additional surgical biopsy, percutaneous needle aspiration, or repeat bronchoscopy was performed after obtaining consent. Benign lesions, not otherwise specified, were defined as inflammatory cells only or a benign pathology, such as anthracotic pigmentation, on the biopsy specimen, with no changes on CT over at least 12 months of follow‐up.t‐test or Wilcoxon rank‐sum test for continuous variables. The diagnostic yield of the EBUS procedure was calculated by dividing the number of successful diagnoses by the total number of procedures. SPSS Statistics for Windows version 22.0 (IBM Corp.) was used for statistical analyses.All results are reported as numbers (percentages) for categorical variables and as the mean ± standard deviation for continuous variables. Data were compared using the chi‐squared or Fisher's exact test for categorical variables, and independent p < 0.001; mean age: 68.1 vs. 70.4 years, p = 0.021). Compared to the RP‐EBUS group, the combination group had larger mean PLL diameters , a greater proportion had a positive bronchus sign , and a greater proportion had solid PLLs  on thin‐section CT.The RP‐EBUS and combination groups consisted of 506 (83.9%) and 97 16.1%) participants, respectively. The baseline characteristics of the two study groups are shown in Table 6.1% partp = 0.021). The overall diagnostic yields of bronchoscopic procedure in the RP‐EBUS and combination groups were 70.0 and 90.7%, respectively (p < 0.001) . The mean doses of midazolam and fentanyl, administered for conscious sedation, were significantly lower in the RP‐EBUS than the combination group . However, there were no differences in the overall complication rates between the RP‐EBUS and combination groups  , 32 (33.0%), and nine (9.3%) participants, respectively , respectively. In total, 19 patients underwent thoracoscopic surgery with LN dissection, and four of the 32 LNs, aspirated using CP‐EBUS, were found to be false‐negatives. Unexpected N2 LN metastasis was found in the surgical specimen in one patient. In group B, three patients were diagnosed with SCLC, two with limited stage SCLC and one with extensive stage SCLC.In group C, nine patients were diagnosed using CP‐EBUS‐TBNA only, and all RP‐EBUS‐TBB results were found to be false‐negative. Among the seven NSCLC patients in group C, the number of aspirated N1, N2, and N3 LNs were two, eight, and one, respectively. All patients were eventually diagnosed with clinical stage III NSCLC. Thoracoscopic surgery was performed in five patients, and there were no false‐negative or ‐positive results in the eight LNs examined using CP‐EBUS.In the combination group, 41 NSCLC patients (54.7%) underwent surgery. Using the surgical specimen as the reference, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CP‐EBUS‐TBNA were determined to be 86.2, 100, 100, 87.5, and 93.0%, respectively.In the present study, we demonstrated that a combined procedure with RP‐ and CP‐EBUS was feasible for both histological diagnoses of primary tumors and mediastinal staging for suspected lung cancer. Our results demonstrate that CP‐EBUS‐TBNA, performed after RP‐EBUS‐TBB, improves the diagnostic yield of bronchoscopy. In addition, there was no difference in complication rates between the RP‐EBUS and combination groups (1.4% vs. 1.0%). To the best of our knowledge, this is the first study to investigate the clinical use and safety of the combined procedure with RP‐ and CP‐EBUS.Adenocarcinoma is known for early spread to adjacent LNs; the risk of occult LN metastases is reported to be more than twice as high as other histologies.In addition to mediastinal staging, our results show that CP‐EBUS‐TBNA, performed after RP‐EBUS‐TBB, increased the diagnostic yield of bronchoscopy. Previous studies reported that the diagnostic yield of RP‐EBUS‐TBB was 70%–80%,Previous studies have reported that the sensitivity and specificity of CP‐EBUS‐TBNA were 89–99% and 100%, respectively.Çağlayan et al.This study has some limitations. First, it was a retrospective study conducted at a single institute. Although the bronchoscopy database collected information for consecutive patients, potential selection bias could have influenced our results. In particular, there were significant differences in the baseline characteristics of the two groups. Second, RP‐EBUS‐TBB was performed conventionally, without the assistance of advanced bronchoscopy modalities, such as robotic bronchoscopy and cone‐beam CT, which could increase the diagnostic yield of the procedure. Third, the number of patients in the combination group, subgroup C was relatively small; thus, the findings may not be generalizable. Multicenter prospective studies with a larger number of participants are required to verify our findings.In conclusion, the combined procedure with RP‐ and CP‐EBUS is feasible and safe. In addition to mediastinal staging, additional CP‐EBUS‐TBNA increased the overall diagnostic yield of bronchoscopic procedures by 9.3%.All authors declare that they have no conflicts of interest relevant to this study.


Referring to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2018 pathological classification, we aim to reveal the significance of cellular/fibrocellular crescents in lupus nephritis (LN) patients.Patients with LN proven by renal biopsy at the First Affiliated Hospital of Wenzhou Medical University from December 2001 to November 2017 were identified, and eligible cases were divided into two groups according to the presence or absence of cellular/fibrocellular crescents in renal biopsy tissues.P = 0.006). In the group with proteinuria < 3.5 g/24 h, the prognosis of crescent group was significantly worse than of non-crescent group (P < 0.001), while in the group with proteinuria ≥ 3.5 g/24 h, there was no significant relationship between crescents and prognosis (p = 0.452). By multivariable Cox hazard analysis, positive anti-dsDNA, chronic index of renal biopsy tissue, cellular/fibrocellular crescents and its interaction with 24 h proteinuria were independent risk factors for poor prognosis of LN.A total of 401 LN patients were identified from our follow-up database, and 296 eligible LN patients were enrolled in the study. Of these patients, 146 patients in the group without cellular/fibrocellular crescents (non-crescent group) and 150 patients in the group with cellular/fibrocellular crescents (Crescent group). The median follow-up time of patients was 47 months, and a total of 54 patients progressed to the composite endpoint. Crescent group had higher serum creatinine, lower serum albumin, higher systemic lupus erythematosus (SLE) disease activity index, and higher activity index of renal tissue. The interaction between cellular/fibrocellular crescents and proteinuria at baseline was associated with the prognostic risk of LN (LN patients with cellular/fibrocellular crescents had more severe and active disease features, and cellular/fibrocellular crescents is a risk factor for poor prognosis of LN. There was an interaction between cellular/fibrocellular crescents and proteinuria in predicting poor prognosis, and among patients with low levels of proteinuria at the time of renal biopsy, those with crescents had a worse long-term prognosis than those without crescents.The online version contains supplementary material available at 10.1186/s40001-023-01022-9. Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus (SLE) and an important cause of disease progression and death. Studies have shown that 5 ~ 25% of proliferative LN patients die directly from kidney disease within 5 years of onset, and 10 ~ 30% of LN patients progress to end-stage renal disease (ESRD) . In thisThis study aimed to investigate the clinical and pathological characteristics of LN patients with or without cellular/fibrocellular crescents in renal tissue, and to analyze their relationship with the prognosis of LN.This study was a retrospective cohort study using data from the follow-up database of the First Affiliated Hospital of Wenzhou Medical University.A total of 401 biopsy proven LN patients at the First Affiliated Hospital of Wenzhou Medical University from December 2001 to November 2017 were identified. The diagnostic of SLE was based on EULAR/ACR 2019 classification criteria , and theBiopsy specimens were embedded in paraffin and sectioned, and stained with HE, PAS, Masson and direct immunofluorescence. All the biopsy specimens were processed by standard light and immunofluorescence, and 80–90% were examined by electron microscopy. Two pathologists each reviewed and reclassified the renal pathology data according to the ISN/RPS 2018 classification criteria without knowing of the patient's clinical data, and if there was a discrepancy between the two pathologists, biopsies were reviewed until consensus was reached.The crescent is defined as a lesion consisting of extracapillary hypercellularity, composed of a variable mixture of cells, which may contain fibrin and fibrous matrix and should involve ≥ 10% of the circumference of Bowman's capsule; cellular crescent defined as crescent composed of > 75% cells and fibrin and < 25% fibrous matrix; fibrocellular crescent defined as composed of 25 ~ 75% cells and fibrin and the remainder fibrous matrix; fibrous crescent defined as composed of > 75% fibrous matrix and < 25% cells and fibrin [2], blood pressure, mean arterial pressure (MBP) [diastolic + 1/3 (systolic–diastolic)], SLE disease activity index (SLEDAI) , serum The composite endpoint was defined as a decrease in eGFR of > 30%, ESRD or the need of dialysis and/or kidney transplantation, and death. The follow-up time was the time of the first endpoint event.t test was used for comparison between groups. The continuous variables with non-normal distribution were described by median [quartile], and Wilcoxon rank sum test was used for comparison between groups. The classified variables were described by the number of cases (%), and the comparison between groups was described by χ2 or Fisher exact test. Kaplan–Meier curve (log-ranch test) was performed to demonstrate the different survival of poor outcomes of LN patients. Linear mixed model was built to display the different change of eGFR over time. Cox regression models were constructed to analyze the effects of clinicopathological characteristics on poor outcomes, and the results were expressed as hazard ratio (HR) and corresponding 95% confidence interval (CI). Interactions between variables were evaluated and a multivariate Cox regression model was constructed and optimized using forward–backward stepwise methods. The receiver operating characteristic (ROC) analysis was used to assess the performance of the optimal Cox regression model. A two-sided p value of < 0.05 was considered statistically significant. The R software (version 4.1.2)  months, and 54 patients (18.2%) reached composite endpoint event (Table P < 0.001). Compared with non-crescent group, MBP (P < 0.001), serum creatinine (P < 0.001), WBC count (P = 0.019), 24-h proteinuria (P < 0.001), urinary ACR (P < 0.001), urine WBC count (P < 0.001), urine RBC count (P < 0.001), proportion of positive anti-dsDNA antibodies (P < 0.001), and SLEDA index (P < 0.001) were higher, while eGFR (P < 0.001), serum albumin (P = 0.001), hemoglobin (P < 0.001), complement C3 (P = 0.007), complement C4 (P = 0.015), and lupus anticoagulant ratio (P < 0.001) were lower in crescent group. The rest of the clinical indexes were not significantly different , interstitial inflammation (P < 0.001) and fibrinoid necrosis (P = 0.007) were higher in crescent group. AI score was higher in crescent group , with no significant difference in CI score  , while the proportion of class IV (76.0%) in crescent group was significantly higher than that of other pathological classifications. According to proposed modified NIH lupus nephritis activity and chronic scoring system, the scores of endocapillary hypercellularity , proportion (P = 0.028) and total dose (P = 0.017) of methylprednisolone pulse therapy, and total dose of cyclophosphamide (P < 0.001) were higher in the crescent group than that in the non-crescent group . However, eGFR in crescent group gradually increased during the first 24 months of follow-up and decreased thereafter.The changes of eGFR over time in both groups are shown in Fig. P = 0.099), but the median follow-up time of crescent group was shorter than that of non-crescent group . Long-term prognostic assessment of LN patients who were followed up for > 3 months revealed that the overall long-term prognosis was worse in crescent group (P = 0.005)  , but there was no significant correlation between crescents and prognosis in the groups with proteinuria ≥ 3.5 g/24 h  and antinuclear antibodies (P = 0.040) was higher, while serum albumin (P = 0.004) was lower, and the median follow-up time was shorter (P < 0.001) in the group with crescents, but in the group with proteinuria ≥ 3.5 g/24 h, there was no significant difference between the groups with or without crescent , interstitial inflammation (P < 0.001), fibrinoid necrosis (P = 0.052) and AI scores (P < 0.001) were higher in the crescent group. In the proteinuria ≥ 3.5 g/24 h group, the most common histological classification was class IV , with a higher AI score (P < 0.001) in the group with crescent, while the remaining pathological features were not significantly different between the groups with or without crescent  and cyclophosphamide (P < 0.001) was higher in the group with crescent, and patients with crescent received a higher dose (P = 0.026) and proportion (P = 0.038) of methylprednisolone pulse therapy. In the proteinuria ≥ 3.5 g/24 h group, there was no significant difference in treatment between groups with or without crescent , methylprednisolone pulse therapy (P = 0.055), cyclophosphamide (P < 0.001) at baseline and during the first 2 years of follow-up in the group with proteinuria ≥ 3.5 g/24 h were higher than those in the group with proteinuria < 3.5 g/24 h, and the median follow-up time was shorter . In crescent group, the proportion of class III and IV was higher in the group with proteinuria ≥ 3.5 g/24 h, but there was no significant difference in the treatment regimens and median follow-up time between the two groups with different levels of proteinuria , positive antinuclear antibody , positive anti-dsDNA antibody , AI score , CI score , crescent , and total glucocorticoid dosage at baseline and during the first 24 months of follow-up  were associated with the prognosis of LN patients.Univariate Cox regression model was constructed to analyze the relationship between clinical factors and the composite endpoint of LN Table . The resP = 0.003), CI score , crescent , and the interaction of crescent with 24-h proteinuria were independent risk factors for the composite endpoint of LN  was 0.82 (95%CI 0.71–0.93)  at baseline with crescents had worse long-term prognosis than those without crescents, whereas crescents in patients with high level proteinuria (≥ 3.5 g/24 h) had no significant effect on the long-term prognosis of LN. The difference in histological classification between the two groups is one of the reasons: in patients with low levels of proteinuria, patients with crescents had a higher proportion of class IV, while patients without crescents were dominantly class V. In patients with high levels of proteinuria, class IV was the dominant histological classification in both crescent or non-crescent group. Rezende et al. pointed out that proteinuria mainly reflects podocyte damage in LN, by comparing the podocyte biomarkers, they found that the expressions of synaptopodin (69.2%), WT1 (69.2%), GLEPP1 (53.9%) and nephrin (60.0%) were retained in the pure membranous LN group, while only synaptopodin (2.6%), WT1 (7.7%), GLEPP1 (2.9%) and nephrin (9.4%) were retained in the proliferative LN group. It is speculated that structural podocyte injury occurs in proliferative LN, while only functional podocyte injury occurs in pure membranous LN, which may explain the better prognosis of pure membranous LN . Our stuPrevious studies have shown that a high proportion of SLE patients with low-level proteinuria can be pathologically diagnosed as proliferative or membranous LN –20. Our Our study also found that CI of renal tissue was an independent risk factor for poor prognosis of LN, and the higher the CI, the worse the prognosis, which is consistent with previous studies , 22. In There are several limitations to this study. First, this was a retrospective, observational study with variation in patients’ conditions. There were differences in the treatment background of the patients, and some patients received treatment, such as immunosuppressants prior to biopsy. Second, the exclusion of some patients from the study cohort due to a follow-up period of < 3 months and loss of some patients during follow-up may have impact on the patients’ outcome. The impact of special types of LN  on clinical features and prognosis was not evaluated in this study, which need to be further studied in the future.In summary, our study found that LN patients with cellular/fibrocellular crescents in renal biopsy tissue had more severe and active disease manifestations. The presence of cellular/fibrocellular crescents was a risk factor for poor prognosis in LN patients, and there was a significant interaction between cellular/fibrocellular crescents and proteinuria in predicting poor prognosis. Among patients with low levels of proteinuria at the time of renal biopsy, those with cellular/fibrocellular crescents had a worse long-term prognosis than those without crescents. Meanwhile, we constructed a stable prognosis prediction model of LN to facilitate clinical practice in identifying poor prognosis in LN patients.Additional file 1: Drugs used to maintain remission.Additional file 2: Correlations between crescent and clinical and pathological parameters at the time of renal biopsy.Additional file 3: Treatment regimens of LN patients stratified by proteinuria.Additional file 4: Clinical characteristics of LN patients stratified by proteinuria grouped according to crescent.Additional file 5: Pathological characteristics of LN patients stratified by proteinuria grouped according to crescent.Additional file 6: Treatment regimens of LN patients stratified by proteinuria grouped according to crescent.


Coronavirus disease 2019 (COVID‐19) vaccination is reportedly safe and effective. The histologic features of post‐COVID‐19 vaccination myocarditis are unknown. We present a case of a 77‐year‐old Japanese woman diagnosed with eosinophilic myocarditis using endomyocardial biopsy, 7 days after the second dose of BNT162b2 COVID‐19 vaccine. Steroid pulse therapy was effective. Myocarditis following COVID‐19 vaccination is a rare complication, and most cases are mild. However, the present case was a severe one in an elderly woman who responded remarkably to steroid pulse therapy. Eosinophilic myocarditis should be suspected in patients with heart failure after COVID‐19 vaccination. Her medical history was notable for dyslipidemia without heart disease, and there was no family history of cardiovascular disease.3On admission, her blood pressure was 100/67 mmHg; heart rate, 75 beats per minute, and oxygen saturation on room air, 98%. Her heart and lung sounds were normal, and she had no abdominal tenderness or lower extremity edema. Laboratory test results indicated renal dysfunction  and liver dysfunction .Her brain natriuretic peptide (BNP), troponin T, creatine kinase (CK), CK‐MB, and C‐reactive protein levels were elevated to 1661 pg/ml, 8.4 ng/ml, 532 U/L, 71 U/L, and 6.6 mg/L, respectively. The results of her COVID‐19 polymerase chain reaction testing were negative. Further, investigation results for parvovirus B19, mycoplasma, Epstein–Barr virus, adenovirus, influenza virus, and herpes simplex viruses 1 and 2 were also negative.Electrocardiography performed on admission showed a first‐degree atrioventricular block, low voltage in all the limb leads, and inverted T waves in leads V3–V6 Figure . Her cheOur differential diagnoses included acute coronary syndrome, heart failure, and cardiomyopathy.After admission, her blood pressure gradually decreased to 90/60 mmHg on Day 2. Additionally, her urine output decreased to 150 ml per 8 h, despite adequate infusion. Therefore, we performed an emergency cardiac catheterization. Swan–Ganz catheterization indicated a low output syndrome and mild pulmonary hypertension Table . We subs2  on Day 19 of admission showed no delayed gadolinium enhancement or abnormal T1 and T2 mapping Figure .On Day 26, we performed a second right ventricular endomyocardial biopsy and histologically confirmed that acute inflammation had subsided and tissue remodeling was ongoing. Some lymphocytic infiltration, hemosiderin deposition, and fibrosis were observed in the injured interstitium. Eosinophilic infiltration was not observed.On Day 28, the patient was discharged following improvement in the LVEF (66%), BNP (46 pg/ml), and troponin T (0.028 ng/ml) levels. At discharge, we prescribed carvedilol (2.5 mg per day), sacubitril/valsartan (100 mg per day), and prednisolone (15 mg per day) Figure .4Two months after discharge, the patient was asymptomatic with normal cardiac function. Prednisolone was tapered and discontinued at 3 months post‐discharge. Carvedilol (2.5 mg per day) and sacubitril/valsartan  were continued.5Myocarditis is most commonly caused by viral infections, although idiopathic, autoimmune, and hypersensitivity‐related myocarditis have also been reported.There have been several reports of myocarditis after mRNA COVID‐19 vaccination. Lee et al. reported that 14 US military personnel developed myocarditis after receiving mRNA COVID‐19 vaccines, which included both the mRNA‐1273  and BNT162b2‐mRNA  formulations.Cases of post‐vaccination myocarditis or pericarditis have been reported in the literature, particularly after smallpox vaccination,The pathophysiology of post‐vaccination myocarditis and pericarditis remains unclear. Furthermore, there has been only one reported case of eosinophilic myocarditis after tetanus toxoid immunization diagnosed by endomyocardial biopsy, and the report suggested an underlying mechanism of nonadaptive immune‐mediated injury or hypersensitivity reaction.Almost all previously reported cases of myocarditis after mRNA COVID‐19 vaccination were diagnosed using cardiac MRI, and only one patient underwent endomyocardial biopsy, although there was no pathological evidence of myocarditis.The optimal treatment for myocarditis after COVID‐19 vaccination is yet to be determined. According to previous reports, most patients with myocarditis after mRNA COVID‐19 vaccination have good outcomes.Very few patients with myocarditis after COVID‐19 vaccination underwent endomyocardial biopsy and steroid therapy. In this case, we were able to diagnose eosinophilic myocarditis using endomyocardial biopsy. However, it is difficult to prove an association between myocarditis and COVID‐19 vaccination, and this could be a limitation of our report. In addition to myocarditis, other adverse events of COVID‐19 vaccination have been reported, including optic neuropathy, Guillain–Barre syndrome, and thrombocytopenia.Further studies are needed to determine the exact mechanisms and optimum treatments for patients with myocarditis after COVID‐19 vaccination.6Eosinophilic myocarditis should be suspected in patients with heart failure after COVID‐19 vaccination, and endomyocardial biopsy is recommended for these patients.Kaishi Otsuka involved in writing the paper. Takashi Matsuo involved in drafting the article. Takuro Hamamoto involved in analysis and interpretation of data. Atsuki Fukae involved in revising the manuscript critically for important intellectual content. Takashi Isimatsu involved in acquisition of data. Koji Oku involved in conception and design of study. Masahiro Ito involved in providing pathological images and analyzing pathological findings.This report received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.The authors declare that they have no conflict of interest.We did not obtain IRB approval because this is a case report.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.Table S1Click here for additional data file.


To compare overall agreement between magnetic resonance imaging (MRI)–ultrasound (US) fusion biopsy (FB) and MRI cognitive fusion biopsy (CB) of the prostate and determine which factors affect agreement for prostate cancer (PCa) who underwent both modalities in a prospective within‐patient protocol.From August 2017 to January 2021, patients with at least one Prostate Imaging Reporting & Data System (PI‐RADS) 3 or higher lesion on multiparametric MRI underwent transrectal FB and CB in a prospective within‐patient protocol. CB was performed for each region of interest (ROI), followed by FB, followed by standard 12 core biopsy. Patients who were not on active surveillance were analysed. The primary endpoint was agreement for any PCa detection. McNemar's test and kappa statistic were used to analyse agreement. Chi‐square test, Fisher's exact test and Wilcoxon rank sum test were used to analyse disagreement across clinical and MRI spatial variables. A multivariable generalized mixed‐effect model was used to compare the interaction between select variables and fusion modality. Statistics were performed using SAS and R.k = 0.715). McNemar's test was insignificant (p = 0.285). Anterior location was the only variable associated with a significant variation in agreement, which was 70% for anterior lesions versus 89.7% for non‐anterior lesions (p = 0.035). Discordance did not vary significantly across other variables. In a mixed‐effect model, the interaction between anterior location and use of FB was insignificant (p = 0.411).Ninety patients and 98 lesions were included in the analysis. There was moderate agreement between FB and CB (In a within‐patient protocol of patients not on active surveillance, FB and CB performed similarly for PCa detection and with moderate agreement. Anterior location was associated with significantly higher disagreement, whereas other patient and lesion characteristics were not. Additional studies are needed to determine optimal biopsy technique for sampling anterior ROI. In patients with an elevated prostate‐specific antigen (PSA) and positive MRI, urologists who do not have access to FB technology must decide between proceeding with CB or referral to a centre with FB equipment. We are interested in determining if there are patient selection criteria that can optimally identify which technique to use. The primary objective of this study was to compare PCa detection rate between CB and FB and examine the effect of spatial parameters on performance of the two modalities side by side in patients who underwent both CB and FB.22.1This study was conducted after approval of the local Institutional Review Board. Eligible patients with Prostate Imaging Reporting & Data System 3 (PI‐RADS 3) or greater ROIs were enrolled. Patients with a prior MRI–ultrasound (US) FB or in‐bore MRI‐guided biopsy were excluded. Patients with PSA > 100 ng/ml or radiographic evidence of metastatic cancer, and those taking any type of androgen suppression were excluded. Patients who underwent any prior attempt at definitive local PCa therapy, radiation or otherwise, were also excluded. Patients were excluded from the analysis if they had already been diagnosed with PCa . Agreement and multivariable analyses were performed on a per ROI basis.2.2The majority of mpMRIs were performed at 3‐Tesla with an endorectal coil using the technical standards set forth by PI‐RADS v2. All mpMRI, including the few not performed at our institution, were interpreted by two diagnostic radiologists  with extensive mpMRI experience using PI‐RADS v2 criteria. Prostate and ROI contouring was performed using Dynacad software .2.3All biopsies were performed by three fellowship‐trained urologic oncologists  with extensive experience in fusion and standard TRUS biopsy. One of the surgeons performed FB prior to this study in training, while the other two surgeons had been performing FB for 2 years prior to initiation of the study. Informed consent was obtained, and biopsies were conducted per protocol, not as standard of care. The protocol is as follows. First, a TRUS was performed , and two cores from the targeted ROI on MRI were obtained using the CB technique, sampling either a TRUS‐visible hypoechoic ROI corresponding to the region identified by MRI or the general area specified by MRI if no hypoechoic ROI could be identified. Second, the MRI target ROI and prostate contour were co‐registered with the TRUS image using the UroNav FB device , and two cores were obtained from the ROI. If multiple ROIs were present, CB of all ROIs was performed first. FB followed in the standard fashion. Finally, a 12‐core standard sextant systematic biopsy was obtained.2.4Overall, cancer detection was the primary outcome and defined as any Gleason 3 + 3 or higher found in one or more cores for the ROI on biopsy final pathology. High‐grade cancer detection was a secondary outcome and defined as any Gleason 3 + 4 or higher found in one or more cores for the ROI on biopsy final pathology.2.5McNemar's test was used to analyse overall agreement of any PCa detection between CB and SB.p value of <0.05 was considered significant.Agreement was then assessed across specific pre‐biopsy clinical and MRI spatial parameters. These included clinical variables that are known or suspected to affect cancer detection rate, namely, age, ethnicity, family history of PCa, digital rectal exam (DRE) and previous biopsy. We also included MRI characteristics including PI‐RADS score, prostate volume, ROI maximum dimension, transverse dimension, anteroposterior dimension, craniocaudal dimension, and volume, and ROI location . Correlation between agreement for any cancer detection and each variable was tested using chi‐square test, Fisher's test or Wilcoxon rank sum test where appropriate. A Variables that significantly affected agreement were then selected for a separate secondary multivariable analysis to compare cancer detection rate between fusion modalities. A generalized mixed‐effect model was used. To compare CB and FB directly, all ROIs were counted twice within the same model. Individual ROIs had a unique identifier, and this was included as a random effect variable. Fusion modality used (CB or FB) was included as a fixed effect. Interactions between significant variables from the above subgroup analysis and fusion modality were tested. R (version 3.63) and SAS version 9.4 were used.33.1Ninety patients and 98 ROIs were included in the study. The median age was 68, and median PSA was 7 ng/ml. Sixty‐four percent of patients were diagnosed with any cancer, and 52% of patients were diagnosed with Gleason grade group 2 or higher. High‐grade cancer detection rate for both targeted biopsy techniques amongst all ROIs was 48%. High‐grade cancer detection rate amongst all ROIs was 40% for FB, and 43% for CB. Tables 3.2p = 0.285). Cohen's kappa coefficient for agreement for any cancer was 0.71 (‘moderate agreement’).Overall, concordance between FB and CB was 85.7% for all ROIs. FB detected cancer where CB did not in nine ROIs (9%). CB detected cancer where FB did not in five ROIs (5%) Table . McNemarhigh‐grade cancer where FB did not in eight ROIs (8%) (Table p = 0.579). Cohen's kappa coefficient for agreement for any cancer was 0.73 (‘moderate agreement’).Concordance for high‐grade cancer was 86.7%. FB detected high‐grade cancer where CB did not in five ROIs (5%). CB detected %) Table . McNemar3.3p = 0.035).Agreement was stratified by age, PSA, family history of PCa, DRE, ROI location of base, apex, or anterior, prostate volume, ROI maximum dimension, transverse dimension, anteroposterior dimension, craniocaudal dimension, and ROI volume Table . There w3.4p = 0.015). The odds ratio of any cancer detection in anterior lesions compared with non‐anterior lesions were 3.06  . All three of the urologists in the study were fellowship trained urologic oncologists experienced in TRUS‐guided biopsy . Applicability of these findings may be limited for general urology practices or with mpMRI obtained with different techniques and read by general radiologists, where there is known interobserver variability in interpretation.5Cognitive fusion has a similar cancer detection rate of all and high‐grade PCa as MRI‐US fusion via the transrectal approach in a within‐patient comparison, but with moderate agreement. Agreement did not significantly vary across most clinical and MRI variables except amongst anterior ROI locations. Anterior tumours continue to pose a challenge in PCa diagnosis using a transrectal approach. Utilization of cognitive fusion with standard template TRUS biopsy is a viable strategy for urologists without access to MRI‐US fusion technology. Given the limitations of transrectal biopsy for anterior ROIs, alternative biopsy strategies should be considered when the suspicion for PCa persists following negative targeted transrectal biopsy of anterior ROIs.Study concept and design: Mitch Hayes and Jen‐Jane Liu. Analysis and interpretation of data: Mitch Hayes, Luc Boileau, Jacob Grasseur, Solange Bassale, Nicholas Chakiryan. Drafting of the manuscript: Mitch Hayes and Jen‐Jane Liu. Critical revision of the manuscript for important intellectual content: Mitch Hayes, Matthew Wagner, Bryan Foster, Fergus Coakley, Sudhir Isharwal, Christopher Amling, Jen‐Jane Liu. Obtained funding: Jen‐Jane Liu.


Median hospital stays for children ranged from 2 days in the United States to 7.5 days in China. High‐risk adults with RSV (n = 6 studies) commonly (≥40% of adults) reported cough, sputum, dyspnea, and fever/feverishness. Median length of hospital stay in adults ranged from 6 to 15 days across studies. Caregivers and clinicians reported similar RSV S&S in young children, including upper and lower respiratory and systemic symptoms. In high‐risk and immunocompromised adults, the most frequent (in multiple publications) and commonly reported RSV S&S were primarily LRTI symptoms. RSV symptoms could last for weeks and are variable based on geography.Respiratory syncytial virus (RSV) is responsible for over 30 million lower respiratory tract infections (LRTIs) and 3 million hospitalizations worldwide each year. Despite the risk RSV poses to young children, older adults, and individuals with comorbidities or suppressed immunity, there is limited understanding of RSV symptom presentation across these at‐risk groups, and there is no vaccine for RSV. We conducted two systematic literature reviews (SLRs) of studies that document signs and symptoms (S&S) of RSV in (1) children aged ≤5 years and (2) immunocompromised adolescents and adults, and adults at high risk for severe RSV due to age or comorbidities. Symptom duration and hospital length of stay (LOS) were explored. Electronic database searches were performed following PRISMA guidelines. Studies captured RSV S&S across community and hospital settings. Clinicians and caregivers reported ( In 1998, the US Food and Drug Administration approved ribavirin, an antiviral agent, but ribavirin has minimal clinical benefit in RSV and is not routinely prescribed.Because of this lack of effective treatments and preventions, and the vulnerable populations RSV affects, a clear understanding of how RSV presents is important for identifying individuals most at risk for disease progression, identifying treatment targets, and evaluating treatment efficacy in each of these populations. To provide a comprehensive examination of the signs and symptoms (S&S) of RSV in the most at‐risk populations, two systematic literature reviews (SLRs) of patient‐reported S&S were conducted, one in young children and one in high‐risk adults (older adults or those with comorbidities) and immunocompromised adults and adolescents. Because young children are not able to report their symptoms, the literature review for this population focused on studies that included reports by clinicians and caregivers of children with RSV. This study can provide researchers and clinicians with the tools necessary to identify and adequately treat RSV infections based on the unique needs of each of these vulnerable populations.2We performed two separate systematic reviews of literature published in English‐language journals indexed in the MEDLINE, Embase, PsychINFO, and Cochrane Library medical databases: One review of the literature from 22 June 2011 to 22 June 2021 on caregiver‐ or clinician‐reported RSV S&S in children aged ≤5 years, and one review of the literature from 21 June 2011 to 21 June 2021 on self‐reported RSV S&S in adults at high risk for RSV‐related disease progression  and adults or adolescents who are immunocompromised. Additional searches of conference abstracts indexed in Embase and bibliographies of SLRs identified in the literature were performed. Included studies were limited to qualitative, focus group, and real‐world studies; clinical trials were included if they assessed patient‐reported S&S and if they included caregiver‐reported, questionnaire, measurement, or assessment terms in the title, abstract, or Medical Subject Headings (MeSH) or Emtree indexing. All sources were identified, screened, and included in this review on the basis of Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines,33.13.1.1We identified 651 unique publications on pediatric RSV infections through our literature search. After two levels of manual screening following the PRISMA guidelines and our inclusion and exclusion criteria (see Table 3.1.2Studies on S&S of RSV in the pediatric population (25 studies) took place in both community and clinical settings, and S&S were reported by both caregivers (six studies)3.1.3Four studies presented S&S reported by caregivers of children with RSV initially and primarily treated in the outpatient setting Table .20, 23.1.4Four publications representing three studies presented S&S reported by caregivers of children hospitalized with RSV Figure 19, 31Saha et al3.1.5In the non‐hospitalized setting, eight studies captured clinician‐reported RSV S&S in children, primarily in infants.3.1.6In the hospital setting (not including patients in the ICUP < 0.001).Fever was also a commonly identified symptom of RSV by clinicians in the hospitalized pediatric population,Other trends were also identified based on clinician reports in the hospital setting. TachypneaIn 2 studies, clinicians reported RSV S&S for children in the ICU.3.1.7Four studies captured clinician reports of pediatric RSV S&S in a mixed setting , including children aged 0 to 4 years.3.1.8Hospital LOS was reported in 13 publications; three reported mean and median LOS,Some studies suggested factors potentially impacting LOS in pediatric populations. In a study conducted in the US,Thirteen studies reported RSV symptom duration,3.23.2.1Our search identified 234 unique studies of RSV infections in high‐risk or immunocompromised adults. Through the PRISMA‐guided screening process outlined in Figure 3.2.2Figure 3.2.32) < 95% (14%) were reported the least. Feeling unwell was reported in 91% of high‐risk adults, and disturbances in sleep and daily activities were reported in 72% and 75% of patients, respectively.Only one study presented S&S reported by patients with RSV treated in the community setting, which focused on European countries and included 1040 adults aged ≥60 years.3.2.4Two studies presented S&S reported by patients with RSV treated in the hospital setting; one was conducted in Canada3.2.5Three studies included patients in both hospital and outpatient settings.Two LRTI symptoms (cough [92.3%–97.8%] and shortness of breath [19%–55.6%]) were reported in all three studies.3.2.6Only two studies presented S&S in exclusively immunocompromised populationsOf the two studies, one was a retrospective analysis of adult lung transplant patients infected with RSV receiving oral or inhaled ribavirin. This study did not report proportions of patients experiencing each of the RSV S&S, but did report fever, cough, dyspnea, wheezing, rhinorrhea, pharyngitis, and headache as present in both treatment groups.3.2.7In addition to reporting S&S of RSV, six of the identified studies examined the hospital LOS and/or duration of RSV symptoms in high‐risk adults with RSV. Regarding hospital LOS, Belongia et alIn immunocompromised patients with RSV undergoing lung transplants, mean hospital LOS was 11 days  in the six patients receiving oral ribavirin and 5 days  in the 15 patients receiving inhaled ribavirin.4This comprehensive SLR captured S&S of RSV infection in pediatric populations, across a variety of ages and reported by both caregivers and clinicians, and high‐risk or immunocompromised adult populations. Across all reviewed ages (pediatric and adult), settings , and reporters , cough was the most commonly and frequently reported RSV symptom. Studies on the impact of RSV S&S on health‐related quality of life have also identified cough as not only one of the most prevalent symptoms of RSV but also one of the most burdensome symptoms in both children and adults.Among studies of caregiver‐ and clinician‐reported RSV S&S in children, regardless of setting or age group, RSV signs or symptoms that were commonly reported (≥40%) and also reported by at least three studies of each study type (caregiver‐reported or clinician‐reported) were cough, fever, and feeding abnormalities. While wheezing is also considered a prominent symptom of RSV in children,Symptom trends based on age or treatment setting in the pediatric population were overall not robust. The most salient trend identified in this review was related to fever. Both clinicians and caregivers more commonly reported fever in hospitalized children as their age increased.Overall, caregivers and clinicians reported similar S&S with similar frequency, despite the wide variety of RSV symptoms reported, indicating that caregivers may be acceptable reporters for their children, who are often unable to accurately report symptoms themselves.The studies of adults with RSV identified by this review focused primarily on adults over the age of 60 years. Four of the seven studies identified for the adult population included patients with comorbidities such as cardiovascular disease, lung disease, asthma, COPD, and diabetes, in addition to advanced age.Our review found that hospital LOS varied based on geography for both hospitalized adult and pediatric patients. Hospital LOS was examined in six studies of adult patients hospitalized for RSV across the globe. Across high‐risk and immunocompromised patients, mean LOS varied from 3.5 to 11 days in the US/AmericasReports of RSV symptom duration in children varied significantly, from 4 to 12 days, and depended on the method of evaluation, so no overall trends could be identified.A recent prospective cohort study of adults with respiratory tract infections across 12 countries that was published after our literature review was completed also found that LRTI symptoms are commonly associated with RSV infections in adults, particularly cough, wheezing, and shortness of breath.This study has some limitations. We identified common RSV S&S in multiple populations but did not capture the severity or burden of those symptoms on patients; less common S&S may be more burdensome. We limited our search to English‐language studies published between 2011 and 2021, so global studies in a non‐English language would have been missed in our search. We therefore may have overrepresented studies in English‐speaking countries. Despite the availability of studies on RSV S&S, data on the duration of symptoms or the LOS in hospitals was less readily available. Studies that did report symptom duration used different criteria for evaluating duration, so it is challenging to draw conclusions. However, duration of S&S and LOS were exploratory and were not part of the search terms for this study. An SLR focused on these outcomes may provide additional details. Although we initially included immunocompromised adolescents in our literature search strategy, the lack of data on S&S separately in this population in this SLR may have been caused by our requirement that included studies were either questionnaires or clinical trials to ensure that patients were being queried about the reported S&S. Observational studies in adults likely were also omitted. Due to the resulting limited number of studies in adult and adolescent populations, as well as the variation in the list of S&S reported, firm conclusions may not be drawn on the presentation of RSV in these populations.5Cough was reported in the majority of RSV patients across all age and risk groups assessed in this study. The most frequent commonly reported RSV S&S in the pediatric population were consistent across caregivers and clinicians and across settings . The most frequent commonly reported RSV S&S across settings in high‐risk and immunocompromised adult patients were primarily LRTI symptoms . Duration of RSV S&S in children was reported as up to 12 days in this review. In high‐risk and immunocompromised adults, RSV S&S were found to last several weeks (17–19 days in this SLR). Length of hospital stay for both children and adults varied by geography.Ann Colosia: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; writing‐original draft; writing‐review and editing. Jessica Costello: Conceptualization; data curation; formal analysis; investigation; methodology; writing‐review and editing. Kelly McQuarrie: Investigation; writing‐review and editing. Kelly Kato: Conceptualization; funding acquisition; methodology; project administration; supervision; writing‐review and editing. Kristi Bertzos: Conceptualization; formal analysis; investigation; methodology; project administration; writing‐review and editing.AC and JC are full time employees of RTI Health Solutions, an independent nonprofit research organization, which was retained by Janssen to conduct the research, which is the subject of this manuscript. Their compensation is unconnected to the studies on which they work. KB and KK are employees of Janssen and may hold shares and/or stock options in the company. KM was an employee of Janssen at the time the research was conducted and may hold shares and/or stock options in the company.https://publons.com/publon/10.1111/irv.13100.The peer review history for this article is available at Figure S1. Flow Diagram of Article Inclusion Following PRISMA Guidelines for the Pediatric Literature ReviewPRISMA = Preferred Reporting Items for Systematic Reviews and Meta‐Analyses.Figure S2. Flow Diagram of Article Inclusion Following PRISMA Guidelines for the Adult Literature ReviewPRISMA = Preferred Reporting Items for Systematic Reviews and Meta‐Analyses.Table S1. Summary of Eligible StudiesN/A = not applicable; S&S = signs and symptoms.Note: studies may be counted in more than one column, so the sum of columns 4–8 does not equal the total number of studies in column 3.a The study populations in Saha et al. and Broor et al. overlapped and are counted here as 1 study across 2 publications.Table S2. Common (≥ 40%) Caregiver‐Reported RSV S&S in Young Children✓ = reported in ≥ 40% of patients; < = reported in < 40% of patients; 0 = no cases; GI = gastrointestinal; LRTI = lower respiratory tract infection; NR = not reported; RSV = respiratory syncytial virus; S&S = signs and symptoms; URTI = upper respiratory tract infection; US = United States.20, Finland is not represented in the table; the only caregiver‐reported RSV sign or symptom presented was expiratory wheezing at home, which occurred in 28.4% of children aged ≤ 24 months treated in the outpatient setting.Note: Thomas et al.a Patients were included in this study if their parents suspected acute otitis media. b Reported as rhinorrhea. c None of the studies described vomiting, so whether vomiting was related to coughing or was a separate GI issue could not be determined. d Reported as poor feeding. e Reported as poor appetite.Table S3. Common (≥ 40%) Clinician‐Reported RSV S&S in Children in the Community Setting or a Mix of Settings✓ = reported in ≥ 40% of patients; < = reported in < 40% of patients; GI = gastrointestinal; LRTI = lower respiratory tract infection; NR = not reported; RSV = respiratory syncytial virus; S&S = signs and symptoms; URTI = upper respiratory tract infection; US = United States.a Reported as runny nose. b Reported as fever or feverishness. c Reported as documented fever. d Reported as decreased appetite.Table S4. Common (≥ 40%) Clinician‐Reported S&S in RSV‐Hospitalized Children✓ = reported in ≥ 40% of patients; < = reported in < 40% of patients; GI = gastrointestinal; LRTI = lower respiratory tract infection; NR = not reported; RSV = respiratory syncytial virus; S&S = signs and symptoms; URTI = upper respiratory tract infection; US = United States.a Data are for RSV‐positive patients only, not co‐infected patients. b Reported as rhinorrhea. c Reported as rhinorrhea or congestion. d Reported as shortness of breath.e Reported as wheezing on auscultation. f None of the studies described vomiting, so whether vomiting was related to coughing or was a separate GI issue could not be determined. g Reported as poor feeding. h Reported as feeding difficulties before admission. i Reported as reduced dietary intake. j Reported as poor appetite.Table S5. Duration of Any RSV Symptoms in the Pediatric PopulationED = emergency department; IQR = interquartile range; NR = not reported; RSV = respiratory syncytial virus; SD = standard deviation; SE = standard error; US = United States.a Belgium, Bulgaria, Chile, Colombia, Croatia, Czech Republic, Germany, Hungary, Israel, Latvia, Malaysia, Philippines, Poland, Slovakia, Spain, and Thailand.b In this study, most patients were kept in the hospital until complete recovery, although some patients were discharged before complete recovery for social reasons. Therefore, authors of this SLR assume that mean hospital length of stay (7.27 days [SD 4.458 days]) is only an approximation of the duration of symptoms during hospitalization.c All consecutive days in which the child had fever, rhinitis, or cough.d Mean duration of symptoms exceeded mean duration of hospital stay for each RSV severity group.e Timing of illness duration is not explicitly stated in the conference abstract, but the table appears to contain baseline information about the patients.f Timing not explicitly stated in this conference abstract.g Fever, cough, wheeze, difficulty breathing.Click here for additional data file.


Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.TransCon PTH is a sustained‐release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1‐34), and in development for hypoparathyroidism (HP). This phase 1, randomized, placebo‐controlled, single and multiple ascending dose  trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in healthy adults. SAD and MAD cohorts consisted of 10 subjects  who received up to seven single or six multiple ascending doses of TransCon PTH, respectively. TransCon PTH doses ranged from 3.5 to 124 μg PTH(1‐34) for the SAD cohorts and 3.5 to 24 μg PTH(1‐34)/day for the MAD cohorts. The primary PK endpoint was Free PTH. The PD endpoints included albumin adjusted serum calcium (sCa), fractional excretion of calcium (FECa), intact endogenous PTH(1‐84), bone turnover markers, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), serum phosphate (sP) and magnesium, and 1,25 dihydroxyvitamin D. TransCon PTH was generally well tolerated; there were no drug‐related serious adverse events (SAEs), and all AEs were transient in nature. Free PTH demonstrated an effective half‐life of approximately 60 hours and a dose‐dependent, sustained exposure with an infusion‐like profile within the calculated physiologic range for active PTH at steady‐state. Albumin‐adjusted sCa demonstrated a dose‐dependent, sustained response with complete control of FECa despite modest hypercalcemia at higher doses. Renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR) showed a dose‐dependent decrease, resulting in a dose‐dependent decrease in sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum bone‐specific alkaline phosphatase (BSAP) or P1NP, or the osteoclastic bone resorption marker, urine NTx, but modestly and transiently increased the osteoclast marker, serum CTx. These phase 1 data support TransCon PTH as a daily replacement therapy for HP providing physiological levels of PTH 24 hours per day and advancement into phase 2 clinical development. © 2020 The Authors.  Parathyroid hormone (PTH) is a product of endocrine secretion of the four parathyroid glands located at or near the posterior capsule of the superior and inferior lobes of the thyroid gland. It is synthesized by chief cells as a prohormone peptide, which is initially 115 amino acids in length, then cleaved to 90, and eventually secreted as 84 amino acids; ie, PTH(1‐84). Although PTH(1‐84) is the biologically active form, receptor activation requires only the 31 to 34 amino acid N‐terminus fragment; ie, PTH(1‐31 to 1‐34).Hypoparathyroidism (HP) is a rare disease of impaired PTH production with an estimated number of affected patients in the United States of 60,000 to 115,000.Standard‐of‐care (SoC) for chronic HP—specifically active vitamin D and calcium—only corrects hypocalcemia, targeting a serum calcium (sCa) just below or in the lower level of normal range to avoid worsening hypercalciuria, and is frequently associated with a sCa nadir prior to the next morning dose. SoC also does not restore PTH‐dependent renal calcium reabsorption, phosphate excretion, or normal bone turnover.Until recently, HP was the last remaining classic endocrine deficiency disorder for which the missing hormone was not available as a therapy.In 2015, rhPTH(1‐84)  received US Food and Drug Administration (FDA) approval as an adjunct to calcium and active vitamin D to control hypocalcemia in patients with HP who are not well controlled on conventional therapy. Although the availability of once‐daily rhPTH(1‐84) has advanced the field, it does not provide PTH with a continuous pharmacokinetics (PK) profile that closely resembles the normal tonic secretory dynamics of PTH. The rhPTH(1‐84) label states that the incidence of hypocalcemic episodes did not decrease  and did not reduce or normalize uCa excretion.TransCon PTH is a novel, long‐acting, essentially inactive prodrug designed to provide stable PTH levels in the physiological range for 24 hours per day, comparable to providing PTH1‐34) by continuous s.c. infusion. Similar to other transiently conjugated compounds such as TransCon Growth Hormone,‐34 by coThe purpose of this trial was to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of single and multiple doses of TransCon PTH in healthy adults.This was a phase 1, randomized, first‐in‐human, double‐blind, placebo‐controlled trial evaluating single and multiple ascending doses  of TransCon PTH. The trial was conducted at a single center, Nucleus Network, in Melbourne, Australia . Prior to trial initiation, independent ethics committee approvals and informed consent from participants were obtained.2 were eligible. Subjects with a history of malignancy, diabetes mellitus, PTH‐related or calcium‐related disorders, human immunodeficiency virus (HIV), hepatitis B or C, drug abuse, known hypersensitivity to components of the trial medication, or participation within 30 days in another trial were excluded. Pregnant or lactating females, subjects likely to be noncompliant, unable to complete the trial, or unable to follow the trial schedule were also excluded.Healthy adult males and females between the ages of 18 and 60 years with a body mass index between 18.5 and 27 kg/mn = 10/cohort; eight active and two placebo) and received a single or multiple dose(s) of TransCon PTH, respectively, via a syringe and 31G 8‐mm needle s.c. to the abdomen. Single TransCon PTH doses ranged from 3.5 to 124 μg PTH(1‐34) (containing PTH(1‐34) , identical to the first 34 amino acids of rhPTH). Multiple TransCon PTH doses administered daily for 10 days ranged from 3.5 to 24 μg PTH(1‐34)/day. Throughout drug administration and for 4 days following the final dose, subjects remained housed for laboratory tests and safety monitoring.Subjects attended a screening visit; those who met eligibility criteria were randomly assigned to a SAD or MAD cohort , intact endogenous PTH(1‐84), 1,25‐dihydroxyvitamin D, and urine samples were collected. In addition, a limited physical examination and electrocardiogram (ECG) were performed.Twice‐daily 12‐hour urine samples  were also collected. In MAD cohorts, serum samples collected from TransCon PTH‐treated and placebo‐treated subjects predose and postdose on day 14 were analyzed for anti‐PTH binding antibodies by BioAgilytix  using an electrochemiluminescence bridging assay. Samples were analyzed using a multitiered approach consisting of a screening assay and a confirmatory assay.Via regular vital sign checks, physical examinations, and safety laboratory tests, subjects were also monitored for adverse events (AEs) throughout the trial, including injection site reactions .Because of long prodrug circulation time, some PTH(1‐34) is metabolized by a single amino acid into PTH(1‐33), which shows equipotency at the PTH/PTHrP receptor. The primary PK endpoints therefore included Free PTH (defined as the sum of Free PTH(1‐34) and Free PTH(1‐33)) as well as TransCon PTH.The PD endpoints included albumin‐adjusted sCa, fractional excretion of calcium, sP, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), intact endogenous PTH(1‐84), osteoblastic bone formation markers , osteoclastic bone resorption markers (urine NTx and serum CTx), sMg, and 1,25‐dihydroxyvitamin D. PK samples were collected predose and at regular intervals postdose through 96 hours for the SAD cohorts and through day14 for the MAD cohorts.The PK samples were analyzed by PRA Health Sciences ; Free PTH was quantified using protein precipitation, liquid‐liquid extraction, and solid‐phase extraction followed by ultra high‐performance liquid chromatography with tandem mass spectrometry detection measuring the two peptides, PTH(1‐34) and PTH(1‐33), by collection of both transitions simultaneously. Free PTH was calculated only if samples contained quantifiable levels of both Free PTH(1‐34) and Free PTH(1‐33); ie, above 1.40 and 0.958 pg/mL for Free PTH(1‐34) and Free PTH(1‐33), respectively. No lower limit of quantification was calculated for Free PTH because the ratio between Free PTH(1‐34) and Free PTH(1‐33) is not constant. Safety and PD samples were collected and analyzed by a local laboratory .max was defined as the time to maximum observed concentration and Cmax was defined as the maximum observed concentration. Area under the curve (AUC) was calculated for the time from 0 to 24 and 96 hours postdose, respectively. Peak‐to‐trough was calculated as the ratio of Cmax to C24h at steady‐state. FECa was calculated based on time points when both serum and urine data were collected as follows:The PK parameters were calculated using Phoenix WinNonlin, version 6.4 . For Free PTH, tThe ratio, TMP/GFR is based on sP, urine phosphate (uP), serum creatinine (sCr), and urine creatinine (uCr) and was calculated as followsAll statistical analyses were performed using SAS 9.3 or higher . Summary statistics were reported for continuous data, including mean, standard deviation, standard error, median, minimum, and maximum, whereas number and percentage of subjects within treatment groups were reported for categorical data. For sP and TMP/GFR, a linear regression model was performed for the change from baseline, with dose and baseline as independent variables at near steady‐state. Near steady‐state was defined as the average of predose values on day 8, 9, and 10. Dose was defined as a continuous variable where placebo was considered zero.Overall, for the SAD cohorts, 56 subjects were randomized to TransCon PTH and 13 to placebo and received one dose of the study drug. Of these, 55 of 56 (98.2%) and 12 of 13 (92.3%) completed the trial, respectively. One subject administered TransCon PTH 32 μg PTH(1‐34) in SAD cohort 3 was withdrawn upon request for personal reasons 2 days early (day 3), whereas one subject administered placebo in SAD cohort 1 was withdrawn 1 day early (day 4) due to a serious adverse event (SAE), ie, bacteremia, assessed by the investigator to be unrelated to study drug.For the MAD cohorts, 50 subjects were randomized to TransCon PTH and 13 to placebo and received at least one dose of the study drug. Of these, 46 of 50 (92.0%) and 10 of 13 (76.9%) completed the trial, respectively. Four of 50 (8.0%) administered TransCon PTH and 3 of 13 (23.1%) administered placebo withdrew from the trial early. Two of 50 (4.0%) administered TransCon PTH (MAD cohort 3) were replaced after being incorrectly dosed (see Safety), one of 50 (2.0%) withdrew upon request for personal reasons, and one of 50 (2.0%) withdrew due to a family emergency. Two of 13 (15.4%) administered placebo withdrew for personal reasons, and 1 of 13 (7.7%) experienced an SAE, ie, catheter site phlebitis, assessed by the investigator to be unrelated to the study drug. The demographic characteristics of the SAD and MAD cohorts were similar to placebo (Table max) ranged from 4 to 8 hours postdose  and showed a dose‐dependent exposure over 96 hours. Plasma concentrations declined steadily after tmax, with mean effective half‐life ranging from 51 to 56 hours across TransCon PTH 72 to 124 μg PTH(1‐34) . For the MAD cohorts, median time to peak Free PTH concentrations (tmax) on day 10 ranged from 4 to 8 hours postdose. The mean effective half‐life after multiple dosings was approximately 60 hours. On day 10, Free PTH also demonstrated a dose‐dependent response, with minimal decline in concentrations over the 24 hours following the tenth and final dose; the peak‐to‐trough ratios of Free PTH were consistent across the dose range, with mean values ranging from 1.3 to 1.6, indicating an infusion‐like profile. By day 8, Free PTH concentration in cohorts administered TransCon PTH 16 to 24 μg PTH(1‐34)/day appeared to be approaching steady state. /day for day 1 to 8 because these concentrations were considered to be below the lower limit of quantification .) From examination of the albumin‐adjusted sCa and Free PTH concentration versus time profiles, the sCa response correlated with the Free PTH level. The PK of Free PTH is summarized in Table Mean plasma concentrations of Free PTH following a single dose and daily dosings of TransCon PTH for 10 days are shown in Fig. A). In the MAD cohorts, stable dose‐dependent albumin‐adjusted calcium levels were seen after about 1 week of dosing, which did not return to baseline for 3 to 5 days after the final dose on day 10, consistent with the approximately 60‐hour half‐life for TransCon PTH .Initial increases in mean serum albumin‐adjusted sCa were seen in TransCon PTH 32 μg PTH(1‐34) SAD and TransCon PTH 12 μg PTH(1‐34)/day MAD cohorts, respectively, with SAD cohorts dosed with TransCon PTH ≥32 μg PTH(1‐34) and MAD cohorts administered TransCon PTH ≥12 μg PTH(1‐34)/day, showing a sustained dose‐dependent response , mean ± SD albumin‐adjusted sCa increased from 9.43 ± 0.09 mg/dL at baseline to 10.97 ± 0.20 mg/dL on day 2. In the MAD TransCon PTH 24 μg PTH(1‐34)/day cohort (n = 8), adjusted sCa increased from 9.60 ± 0.06 mg/dL at baseline to 10.63 ± 0.22 mg/dL on day 11. However, despite mild hypercalcemia, FECa remained essentially within normal limits (approximately 0.4% to 2%) for both SAD (data not shown) and MAD cohorts  cohort (p = .0430) driven by a significant dose‐dependent decrease in TMP/GFR (p = .0022)  Figs.  and 6 anOf note, 1,25‐dihydroxyvitamin D levels did not change significantly in these normal healthy subjects (data not shown).Intact endogenous PTH(1‐84) showed a dose‐dependent suppression in both the SAD cohorts (data not shown) and MAD cohorts Fig. , as predCompared to placebo, neither the osteoblastic bone formation marker, BSAP Fig.  or P1NP B), CTx levels declined from day 8 to baseline by day 13.For the osteoclastic bone resorption marker, urine NTx, no consistent increase was seen over 10 days (data not shown). The osteoclastic bone resorption marker, serum CTx, increased modestly over 10 days of TransCon PTH administration compared to placebo Fig. . HoweverOnly one subject in the SAD cohorts and one subject in the MAD cohorts, both of whom were administered placebo, discontinued the trial due to an AE. Both discontinuations were due to an SAE, ie, bacteremia and phlebitis, respectively. No subjects administered TransCon PTH discontinued the trial due to an AE.In the SAD cohorts, 23 of 56 (41.1%) of subjects administered TransCon PTH and three of 13 (23.1%) administered placebo experienced at least one AE  administered TransCon PTH and nine of 13 (69.2%) administered placebo experienced at least one AE. More subjects administered TransCon PTH 24 μg PTH(1‐34)/day experienced at least one AE compared to the other treatment groups. Two subjects experienced SAEs, one administered TransCon PTH 12 μg PTH(1‐34)/day developed neutropenia in the setting of viral pharyngitis requiring brief hospitalization and one administered placebo developed catheter‐site phlebitis; neither SAE was assessed to be related to study drug and both resolved without sequelae.The most common treatment‐emergent AEs in the SAD cohorts administered TransCon PTH were dizziness (10.7%), headache (7.1%), and postural dizziness (5.4%). The most frequently reported treatment‐emergent AEs for subjects who received placebo were headache, hypotension, bacteremia, and dysmenorrhea . The most common treatment‐emergent AEs in the MAD cohorts administered TransCon PTH were headache (12%), dizziness (10%), palpitations and catheter site phlebitis (each 8%), postural dizziness and upper respiratory tract infections (each 6%), and presyncope and musculoskeletal pain (each 6%). The most frequently reported treatment‐emergent AEs for subjects who received placebo were headache, catheter site phlebitis, and catheter site pain (each 23.1%).All potential vasodilatory AEs  adjudicated as possibly related to the study drug are shown in Table One of three males in the TransCon PTH 24 μg PTH(1‐34)/day MAD cohort experienced symptomatic hypercalcemia (11.68 mg/dL) and discontinued dosing after the sixth dose; a second male subject was asymptomatic despite an albumin‐adjusted sCa of 11.76 mg/dL on day 11; none of the male subjects experienced vasodilatory AEs. As a result, TransCon PTH 20 μg PTH(1‐34)/day was identified as the maximum tolerable dose (MTD) in healthy volunteers. No MTD was observed in the SAD cohorts, even at the top dose of TransCon PTH 124 μg PTH(1‐34).TransCon PTH was generally well tolerated. Injection site erythema (likely due to PTH‐related s.c. vasodilation) not associated with pain, itching, swelling, induration, or other symptoms was observed but was not captured as an AE and did not impact compliance with dosing.No anti‐PTH antibodies were detected following s.c. administration of TransCon PTH. In addition, no safety concerns were detected on physical examination, by ECG, or in standard safety laboratory tests.In this first‐in‐human trial, TransCon PTH was generally well tolerated; there were no drug‐related SAEs or severe AEs, and all AEs were transient in nature and comparable to placebo. Free PTH showed an effective half‐life of approximately 60 hours and a dose‐dependent, sustained exposure with an infusion‐like profile within the lower half of the physiologic range for active PTH at steady‐state. Similarly, the albumin‐adjusted sCa showed a dose‐dependent, sustained response that correlated with the Free PTH profile, with control of FECa despite mild hypercalcemia in the higher dose cohorts. TransCon PTH also showed the expected decrease in TMP/GFR and sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum BSAP or P1NP, or in the osteoclastic bone resorption marker, urine NTx, but did modestly and transiently increase the osteoclastic bone resorption marker, serum CTx.Because of the short half‐life of calcitriol and currently available PTH‐based therapies, fluctuations in sCa, with mild hypocalcemia at trough and mild hypercalcemia at peak, may occur.The TransCon PTH PK and PD results mirror those of Winer and colleagues,Based on the approximate 60‐hour effective half‐life of Free PTH, eight to 12 daily doses of TransCon PTH are required to reach steady‐state, and accumulation was predicted. As a result, a single dose of TransCon PTH 32 μg PTH(1‐34) predicted the calcemic response of repeated TransCon PTH 12 μg PTH(1‐34)/day, and a single dose of TransCon PTH 100 μg PTH(1‐34) predicted the calcemic response of repeated TransCon PTH 20 to 24 μg PTH(1‐34)/day. The first MAD cohort to demonstrate an increase in sCa was administered TransCon PTH 12 μg PTH(1‐34)/day, which was associated with a Free PTH level of 5 pg/mL, in the lower end of the calculated normal range of PTH(1‐34). Higher doses of TransCon PTH resulted in dose‐dependent increases in both Free PTH and sCa, and as expected, suppression by negative feedback of intact endogenous PTH(1‐84) production, and all were associated with stable Free PTH levels within the lower half of the calculated normal range. These findings suggest the ability to individually titrate patients with HP into the normal calcemic range.TransCon PTH may also positively impact hypercalciuria, a major cause of morbidity in patients with HP. In a study by Syed and colleagues,In terms of bone turnover, SoC does not correct decreased osteoclast activity and diminished bone turnover associated with hypermineralized bone and increased bone mineral density (BMD) in HP. Because of their short half‐lives, currently available daily‐dosed PTH‐based therapies provide intermittent PTH exposure, stimulating osteoblastic bone formation as shown by increases in P1NP, BSAP, and trabecular BMD.The TransCon PTH bone turnover data are similar to the published literature, which illustrate that continuous PTH administration is not anabolic. Winer and colleaguesIn the subjects who received TransCon PTH 24 μg PTH(1‐34)/day, AEs reflected the known pharmacology of PTH, ie, vasodilatation , leading to orthostatic hypotension, lightheadedness, tachycardia, and syncope; similar AEs were seen in the placebo‐treated subjects in this cohort as well. Vasodilatory symptoms such as these have been seen previously with PTH‐based therapies.This trial had limitations. Although the trial was blinded, TransCon PTH was designed to increase PTH and therefore sCa levels; in later SAD and MAD cohorts administered higher doses, rises in sCa may have made it obvious to investigators which subjects were randomized to TransCon PTH versus placebo. As a phase 1 study, only healthy volunteers were included. Although calcium metabolism should not differ between populations, care should be exercised in extrapolating results to patients with HP who have underlying hormone and electrolyte abnormalities at baseline. No anti‐PTH binding antibodies were detected. However, assessments were made only 14 days after the first of 10 doses of TransCon PTH. Immunogenicity will be assessed with longer‐term dosing in future clinical trials. Finally, the trial was not blinded related to treatment dose; overreporting of side effects associated with the study drug may have occurred, especially in the higher‐dose cohorts.TransCon PTH demonstrated potent calcemic, renal calcium reabsorption, and potent phosphaturic effects, indicating control of sCa and phosphate as well as uCa, and no evidence of any anabolic effect. The results of this phase 1 trial support TransCon PTH as a replacement therapy for HP, providing physiological levels of PTH 24 hours per day, and advancement into phase 2 clinical development.DBK, EM, EK, SM, and DM are employees of Ascendis Pharma, Inc.; JAL is a former employee of Ascendis Pharma, Inc. SP is an employee of Ascendis Pharma A/S.