PKP2 that was considered definitive proof of ACM.ACM is a rare hereditary heart disease characterized by a progressive fibro-fatty replacement of the myocardium that can affect either the right or the left ventricle or both. It is mainly caused by variants in the desmosome genes with autosomal dominant transmission and incomplete penetrance. The disease shows a wide spectrum of clinical manifestations, including ventricular arrhythmias, HF and myocarditis. The latter is considered a ‘hot phase’ in the natural history of the disease and must therefore be distinguished from the isolated AM, which is frequently due to viral infections. Our case report is an example of how an AM, as the first manifestation of the disease, helped to reach a diagnosis of ACM through the genetic analysis. In fact, the multi-parametric investigation, which also included CMR and EMB, revealed controversial aspects that led us to perform the genetic test. The latter revealed a heterozygous pathogenic variant in the  Although two-thirds of cases recover spontaneously, the remaining patients develop LV dysfunction and arrhythmias. Based on post-mortem studies, AM explains 3% to 12% of all cases of SCD . To dateand MYH7 .“hot phases” of ACM which mimic a viral AM during disease progression [PKP2.Interestingly, AM episodes have been described in patients with ACM suggesting that inflammation may play a part in the pathogenesis of the disease. Chest discomfort and elevated troponin level represent the symptom and sign, respectively, of the gression . Furthergression . In this2A 65-year-old female with no family history of cardiomyopathy, with known hypertension and dyslipidemia presented to our hospital with persistent moderate-intensity chest pain and dyspnoea. Three weeks earlier she had an episode of high fever lasting a couple of days, which had resolved spontaneously, followed by the onset of mild-to-moderate dyspnoea. At admission, the patient was tachypnoeic and still symptomatic although apyretic. Blood pressure was 150/100 mmHg and SpO2 was 98%. Cardiovascular examination was unremarkable and respiratory examination revealed bi-basal crepitations without peripheral oedema and jugular vein distension. The initial ECG showed sinus tachycardia, low voltages, and mild ST-elevation in the infero-lateral leads. The ECHO showed akinesia of the apical and periapical segments with a severe reduction of LVEF (25%) and moderate mitral regurgitation. There was no pericardial effusion. The high-sensitivity troponin test detected significantly elevated troponin level.The patient was diagnosed with ST elevation myocardial infarction and was urgently transported to the catheterization laboratory. The coronary angiography showed no stenosis of the epicardial vessel, and the patient was subsequently transferred to the ICU.At ICU admission, diuretic, nitro-glycerine, and inotropic therapy with dobutamine was initially administered. Dobutamine was subsequently stopped due to the appearance of PVC and NSVT. Nitrates were also discontinued due to the appearance of hypotension. Pharmacological therapy was optimised by starting a cycle of levosimendan with vasopressor support by noradrenaline. In addition, the patient had febrile rises for which empiric broad-spectrum antibiotic therapy was administered. Troponin I continued to rise and remained critically elevated  for several days. The remaining blood tests showed neutrophilic leukocytosis and elevated PCR (5.7 mg/L). B-type natriuretic peptide level was 1511 pg/mL. The subsequent ECHO confirmed severely depressed LVEF (25%), with akinesia of the apex and para-apical segments and showed increased parietal thickness as from intramyocardial oedema. A minimal pericardial effusion was also detected.2), focally organized in small clusters of 2–3 cells, without evidence of myocytes damage. There was mild interstitial oedema, with a modest increase of fibrous tissue, and focal myocardial fibro-adipose infiltration, limited to one of the myocardial fragments  with a concomitant reduction of RVEF (46%), albeit of a lower degree A. The imragments . During ragments . A CMR pragments  B,C. ConPKP2 was validated using NGS. The genotype analysis revealed a heterozygous variant in the PKP2. The frameshift variant NM_004572.3: c.148_151del, (p.Thr50Serfs*61), located on exon 1 of the PKP2 gene, alters the plakophylin 2 protein at the 50 amino acid by introducing a premature termination codon with prediction of either an absent or truncated protein. According to ACMG criteria , the variant was classified as likely pathogenic. The segregation study of the PKP2 variant identified in the proband was performed in her two healthy sons. Both of them, free from cardiac disease history, resulted carriers of the variant. They were asymptomatic and without suggestive signs of ACM.The proband was referred for genetic counselling and analysis to the Medical Genetic Unit, Sant'Andrea Hospital, Rome. Genomic DNA was extracted from the peripheral blood using the DNeasy Blood & Tissue Kit and QIAamp DNA Blood Mini Kit , according to the manufacturer's instructions. The genetic tests were performed after obtaining ethical approval and written informed consent of the proband. The genetic analysis was performed using a TruSight Cardio Panel  according to the manufacturer's instructions. The panel includes 174 genes related to cardiac diseases, and all core genes associated with ACM. The targeted regions underwent paired-end sequencing (2 × 150 bp cycles) on the MiniSeq platforms. For variant identification, we used a developed pipeline according to the Genome Analysis Toolkit (GATK) best practices for germline variant identification ,10. Raw PKP2 variant, a VUS within the ACTN2 was detected in the probamd: the missense variant c.1072C > T, located on exon 10 of the ACTN2, causing the substitution of the amino acid proline at position 358 by the amino acid serine in the protein actinin alpha 2. The variant is absent in the main general population consultation sites (GnomAD Genomes and Exomes), in the dbSNP, ClinVar, CardioClassifier, Atlas of Cardiac Genetic Variation databases, and in the scientific literature. The main prediction sites interrogated to evaluate the impact of the variant on the structure/function of the protein resulted in conflicting results. Therefore, according to ACMG criteria, the variant was classified as VUS.In addition to the 3The role of inflammation in ACM is not fully understood. In fact, it is unknown whether inflammation is a primary event leading to myocardial damage and arrhythmias or is a secondary response to cardiomyocytes death. Among other hypotheses, it has been proposed that an inflammatory, infective, or autoimmune trigger causes the onset and progression of the disease. Alternatively, the myocarditis-like episodes may represent an acute phase of ACM. Further research is needed to fully understand the molecular basis of the inflammatory process in ACM ,12,13.Clinically, patients may present with signs of AM, such as chest pain, elevated troponin level, ECG abnormalities, or myocarditis-like pattern on CMR.DSP [A recent study performed in a cohort of 12 young females who presented with myocarditis syndrome  reported that they were later diagnosed with ACM. These patients displayed distinct clinical and genetic characteristics, such as female predominance, LV involvement, and specific gene variants . Lopez-ADSP .DSP were identified in 3% of cases versus 0.4% of controls , even in the absence of family history [Recently, 336 patients with AM underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes. As a result, genetic variants associated with DCM and ACM were identified in 8% of patients with AM. Notably, truncating variants of  history ,15,16.PKP2 identified in our proband is rare in major general population reference sites (GnomAD Genomes ƒ = 0.0000263). It is noted in dbSNP databases (rs397516997) ClinVar (Variant ID: 54195) as pathogenic and in Cardio Classifier as likely pathogenic (PM2) (PP5). This variant has been previously described in multiple individuals from unrelated families with ARVC, but also in healthy family members, suggesting an incomplete penetrance [The frameshift variant LRG_3981t1: c.148_151del on netrance ,18.PKP2, for which loss of function is a known mechanism of disease, are usually considered deleterious and are associated with autosomal dominant ARVD type 9 (MIM # 609040). The plakophilin 2 protein mediates the attachment to intracellular filaments and membrane proteins, anchoring desmoplakin and the intermediate filament to the desmosome structure.Functional studies demonstrated that this variant is responsible for reduced levels of mRNA and plakophilin 2 protein ,20. NullThe loss of function or haploinsufficiency of the plakophilin 2, or of other proteins involved in the desmosome plaque structure, may cause a structural and mechanical failure due to the instability of the DIFC . RecentlPKP2 have an earlier onset of ARVC, compared to carriers of missense mutations, with a risk of endpoint events  lower than DSP carriers [PKP2 variants carriers had also an earlier onset of symptoms and arrhythmias with a higher proportion of T wave inversion in V1–3 leads than subjects with negative genotypes [PKP2:c.148_151del may present with a variety of symptoms, including palpitations, syncope, chest pain, and HF. However, AM has never been associated with this variant. Other PKP2 pathogenic variants have been identified in patients with AM (either single or recurrent episodes) in the absence of a previous diagnosis of cardiomyopathy [Usually, carriers of null variants in carriers ,18. PKP2enotypes . Individmyopathy ,24.A peculiar aspect of our patients is that she had a fulminant AM with severe depression of LVEF and hypotension as the first manifestation of ACM. In the aforementioned studies, the majority of patients carrying mutations in the desmosomal genes had preserved EF during the myocarditis phase with district a/hypokinesias, although they had a higher arrhythmic risk and an extended LGE at CMR . The onsOur case report suggests that common diagnostic procedures such as ECG, Holter monitoring, echocardiography and CMR may be insufficient to distinguish between AM and ACM. The histological finding of a fibro-adipose replacement in the myocardium is certainly very important but, given the high rate of complications related to EMB, is not frequently performed. In these cases, the genetic analysis can provide straightforward insights. However, the genetic analysis cannot be performed in all patients due to its high cost and limited availability in most healthcare facilities. Therefore, the opportunity of genetic testing must be driven by specific features, called “red flags”, usually obtained from the above-mentioned diagnostic procedures. The most suggestive “red flags” reported in the literature are: the low voltages in the infero-lateral leads with T-wave inversion, an extensive late gadolinium enhancement at CMR (“ring-like pattern”), presence of ventricular arrhythmias, HF and recurrent AM ,26,27. OIn conclusion, a clinically suspected AM can be the initial manifestation of a hereditary cardiomyopathy, particularly of ACM. The genetic background should be investigated in patients with suspected AM to identify factors that may affect disease progression and to perform a precise diagnosis of cardiomyopathy for a specific medical treatment and follow up.This is an observational retrospective patient report that did not involve any research-based intervention. All interventions were intended to diagnose and treat the patient. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of S. Andrea Hospital .Written informed consent for the present study was obtained from the patient's parents.RM, CM, FF, MF, SP: data curation and investigation; CS, AG, GDA, CG:: methodology and analysis; SR, MP, CA, AP, VV: supervision and writing. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. All authors confirm the absence of previous similar or simultaneous publications.None.


Data from the National Health and Nutrition Examination Survey (NHANES) were used to assess the association between the triglyceride-glucose (TyG) index and hearing impairment (HI).We used eight survey cycles from NHANES 2001–2012 and 2015–2018 to conduct this cross-sectional study. HI was designed as an dependent variable, and the TyG index was selected as an exposure factor (independent variable). The correlation between the two variables was assessed using multiple logistic regression. In order to assess whether there was a non-linear relationship between the TyG index and HI, the TyG index was distributed and a test for trend was conducted (P for trend), followed by smooth curve fitting  and generalized additive model (GAM) regression. We also performed a subgroup analysis to identify sensitive groups whose responses were clearly associated with independent variables.10,906 participants were finally included in the study, and those with a higher TyG index had a higher frequency of hearing impairment. There was a linear positive correlation between the TyG index and HI. For the low-frequency HI, however, this positive correlation was not statistically significant ; however, it was more stable for the high-frequency HI . Additionally, as the TyG index increased, this positive association increased as well (P for trend = 0.05). The HPTA test showed a positive association with more severe HI (simultaneous) as the independent variable increased , and this association was even more significant with increasing severity (P for trend 0.05). According to the subgroup analysis, the positive association between TyG index and high-frequency HI was more significant in females, 40–69 years old, without hypertension or diabetes, and when strict high-frequency HI was significant in males, females, 40–69 years old, with hypertension and diabetes.Participants with a higher TyG index may have a higher risk of HI. TyG index and HI risk showed a linear relationship, which became even more significant when HPTA was included. Ageing, genetic mutations, noise exposure, therapeutic drug exposure with ototoxic side effects, and chronic disease degradation processes are the most important risk factors . It has A hyperinsulinemic normoglycaemic clamp (HEC) is the gold standard for measuring insulin, but this is difficult in a non-study setting . In prev22.1Throughout this study, data were drawn from the NHANES database. To obtain large data sets representative of the US population, the NHANES survey used a complex multistage probability sampling design. There were six sections to the survey, including sociodemographic information, dietary intake and habits, health behaviors, medical history, and physiological and laboratory examinations. The Research Ethics Review Board of the National Center for Health Statistics (NCHS) reviewed and standardized the NHANES protocols each year in compliance with the Human Research Subjects Protection Policy of the US Department of Health and Human Services (HHS). The consent of all participants was obtained in a verbal and written manner. The NHANES freed up all the data without further permission or ethical review.This study analyzed eight NHANES survey cycles  to determine the number of hearing tests performed. This survey was filled out by 81,176 respondents. Since hearing was only tested in people aged 20–69 years, we first excluded those outside of this age group . Subsequently, we removed participants who were missing information on their hearing data (n=24351) and TyG index (n=662). Meanwhile, we removed participants whose 1kHZ hearing test results differed by more than 10dB between the two tests (n=8). In the self-report questionnaire, we removed participants with missing information on various diseases, including hypertension, diabetes, coronary heart disease, asthma and cancer (n=101). Finally, participants with a small amount of missing information were also removed; these included AUQ20  (n=11), education (n=1), marital status (n=3), activity information (n=7), blood uric acid (n=1) and BMI (n=91). After excluding missing data, a total of 10,906 were included in the final study, with the specific exclusion criteria shown in 2.2A triglyceride-glucose index (TyG) was designed as an exposure variable. TyG = ln [fasting triglycerides (mg/dl) *fasting glucose (mg/dl)/2]. An automated biochemistry analyzer was used to determine triglyceride levels and fasting glucose levels enzymatically. Using the Roche Cobas 6000 chemistry analyzer and the Roche Modular P, serum triglyceride concentrations were measured. Using a standardized protocol supplied by the NCHS, audiometry was performed on all eight cycles by trained examiners in a soundproof room at the mobile examination center. Both the beginning and the end of the field tests used the same audiometer calibrated to the same specification. Each ear’s G-conductivity threshold was measured over a range of 10 kHz to 120 kHz at 0.5, 1, 2, 3, 4, 6, and 8 kHz. A 1 kHz frequency was tested twice in each ear, and if the results differed by more than 10 dB, the participant was excluded . LPTA l. A more www.cdc.gov/nchs/nhanes/, you can find detailed measurements of all study variables.Based on previous research –24, a mu2.3www.empowerstats.com; X&Y Solutions, Inc., Boston, MA, USA) as well as R 4.0.2 . Those numerical variables that had more missing values were converted to categorical variables, with the lowest quantile as the reference group, and evaluated from the median to the interquartile range.It is recommended that all statistical analyses be conducted using the NHANES sampling weights, stratifications, and clusterings provided in the study. To determine the weight associated with the variable to be studied in the maximum population, it is first necessary to specify the variable to be studied in the population. According to the weit selection guidelines, in this study, fasting triglyceride data were used, and the sub-weights corresponding to fasting triglycerides (WTSAF2YR) were divided by 8 for the final weight . By usin33.1The baseline demographic characteristics of the included participants were shown in 3.2It was observed that the TyG index was positively associated with the increased prevalence of high-frequency HI. Based upon the fully adjusted model (model 3) of the study, this strong association with high-frequency HI remained stable , showing that an increase in TyG led to an increase in the risk of high-frequency HI by 12%. To analyze sensitivity, we converted the TyG index from a continuous variable to a categorical variable (tertiles). A 25% increase in tertile 3 was observed when compared with the lowest TyG index tertile (tertile 1) , as shown in 3.3The relationship between the TyG index and the prevalence of HI was further explored using a generalized additive model and smooth curve fitting. Our results indicate a linear positive correlation between the TyG index and the prevalence of HI, with both low-frequency and high-frequency HI 3.3.4Subgroup analyses were conducted to examine the robustness of the association between the TyG index and high-frequency HI prevalence. Results: females , age <40 years , age 40-69 years , non-hypertension , non-diabetics  Table 3.3.5TyG index was still associated with a higher prevalence of severe high frequency HI among those with PTAs greater than 15 dB in both ears  when using a stricter definition of HI Table 2.4According to Seo M., mild high-frequency hearing impairment may be associated with HOMA-IR in the Korean population , and theDiabetes mellitus is a well established risk factor for HI, but the exact mechanism by which diabetes mellitus causes the development of HI remains unclear . ResearcDiabetes mellitus is a well established risk factor for HI, but the exact mechanism by which diabetes mellitus causes the development of HI remains unclear . ResearcWe found a positive correlation between IR and high-frequency HI (including strict HI) in this study, as well as sensitive populations that require further attention. In the HPTA test, the most sensitive population for HI in both ears was female participants between 20 and 39 years of age, while the most sensitive population for HI in both ears in the HPTA was males between 40 and 69 years of age. In previous studies, researchers found that there was a difference in the probability of HI occurring in each ear before and after a certain age group between males and females . For peoConsidering the sample size, this is the first cross-sectional study to demonstrate a positive relationship between the TyG index and HI. However, our study has several limitations. In the first place, cross-sectional studies cannot be used to prove causality, and prospective studies are required to further confirm the findings. Second, as a cross-sectional study, we included as many confounding factors as possible and adjusted them in the model to better prove the independent effect between independent and variable variables, but there are still other potential confounding factors. Moreover, although NHANES participants are representative, the proportion of HI in both ears is still low, and fewer individuals have severe HI, so the current conclusions may not be appropriate for this group. Finally, due to the lack of validation of gold standard hyperinsulinemic-hyperglycaemic clamp test data, our current results would still need to be validated by subsequent studies.5TyG index correlates linearly with HI, particularly among high-frequency HI participants, which applies to unilateral and bilateral HI. Women aged 20-39, without diabetes or hypertension, were more likely to be associated with unilateral HI based on TyG, whereas men aged 40-69 years, with diabetes and hypertension, may be more likely to develop bilateral HI if their TyG index is higher.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.https://www.cdc.gov/nchs/nhanes/irba98.htm), and all participants of the study provided informed written consent. The NHANES database is open to the public and therefore the ethical review of this study was exempt.The NCHS Research Ethics Review Committee approved the NHANES survey protocol (Data analysis and manuscript writing: LL. Study design and statistical advice: LL, MQ and JJ. Manuscript editing: MQ, JJ and WW. Validation and review: WW, LL, MQ and JJ. Quality control: WW. All authors contributed to the article and approved the submitted version.


Objective To assess the “July effect” and the risk of postpartum hemorrhage (PPH) and its risk factors across the U.S. teaching hospitals. Method This study used the 2018 Nationwide Inpatient Sample (NIS) and included 2,056,359 of 2,879,924 single live-birth hospitalizations with low-risk pregnancies across the U.S. teaching hospitals. The International Classification of Diseases, Tenth Revision (ICD-10) from the American Academy of Professional Coders (AAPC) medical coding was used to identify PPH and other study variables. Multivariable logistic regression models were used to compare the adjusted odds of PPH risk in the first and second quarters of the academic year vs. the second half of the academic year. Results Postpartum hemorrhage occurred in approximately 4.19% of the sample. We observed an increase in the adjusted odds of PPH during July through September (adjusted odds ratios (AOR), 1.05; confidence interval (CI), 1.02–1.10) and October through December  compared to the second half of the academic year (January to June). Conclusions This study showed a significant “July effect” concerning PPH. However, given the mixed results concerning maternal outcomes at the time of childbirth other than PPH, more research is needed to investigate the “July effect” on the outcomes of the third stage of labor. This study’s findings have important implications for patient safety interventions concerning MCH. Postpartum hemorrhage (PPH) is an obstetric emergency and one of the contributing factors to maternal morbidity and mortality ,2. ReseaPPH has also been associated with poor obstetric practice and clinical management of postpartum hemorrhage. Delayed diagnosis of severe hemorrhage, poor team communication, limited access to timely and quality care, delayed transfusion, and inadequate access to resources such as blood products have been shown to be contributing factors that can increase the risk of severe PPH ,9,10.Active management of the third stage of labor is critical in reducing PPH occurrence but is influenced by many factors, including standard guidelines and protocols, quick service accessibility, availability of resources (equipment and staff), and quality of care services ,10,11,12Researchers suggested that the arrival of new and inexperienced residents and interns may increase adverse patient outcomes ,14,15. JThis retrospective cohort study used the 2018 National Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project’s (HCUP) databases. NIS is a hospital inpatient stay database derived from hospitals’ billing data from statewide data organizations across the U.S. The NIS database includes all patient discharges from community hospitals in the U.S.; however, since 2012, it has not included rehabilitation hospitals or long-term acute care hospitals. The NIS data provides the opportunity to create national and regional estimates by analyzing weighted data to produce accurate, unbiased results and demonstrate larger universe data . It inclA sample of women aged ≤19–54 in the third stage of labor with an index for postpartum hemorrhage (PPH) was selected using the NIS data from 1 January 2018 to 30 December 2018 across the U.S. teaching hospitals. This study included women with low-risk clinical conditions associated with maternal hemorrhage and excluded cases with previous c-sections, women with intrapartum hemorrhage, placental abruption, placenta previa, and high-risk cases in obstetrics because of their high-risk clinical conditions associated with maternal hemorrhage.The International Classification of Diseases, Tenth Revision (ICD-10) from the American Academy of Professional Coders (AAPC) for medical coding was used and identified codes O61, O63, O70, O71, O72, and O86 for failed induction of labor, prolonged labor, perineal laceration during delivery, other obstetric trauma, postpartum hemorrhage (PPH), and puerperal infections, respectively. Other codes, including O0993, O432, O43213, O43223, O43233, O468X3, O458X3, O4693, O610, O611, O618, O619, O63, O630, O702, O703, O710, O719, O8611, O8612, O8619, Z3800, and Z3801, were selected for further analysis  .The main dependent variable of interest for this study was PPH, and the corresponding ICD-10 code was identified as O72. The independent variable included the “July effect”, which was operationalized by categorizing the variable month  into three groups: (1) January to June ; (2) July to September (the first quarter of the academic year); and (3) October to December (the second quarter of the academic year).Covariates included the assessed region of the teaching hospital location, maternal age, race, or ethnicity, and variables that increase the risks of PPH, including failed induction of labor, prolonged labor, puerperal infections, other obstetric trauma, and perineal laceration during delivery. Maternal age was categorized as ≤19, 20–34, and 35–54 years of age. Maternal race and ethnicity were defined based on HCUP coding as follows: (1) White, (2) Black, (3) Hispanic, (4) Asian or Pacific Islander, (5) Native American, and (6) Other .We performed all analyses with STATA software version 16.1 . Five muThis study was exempted by Georgia Southern University’s institutional review board (IRB) from full board review as it uses de-identified secondary data.In 2018, there were 2,879,924 single live-birth hospitalizations with low-risk clinical conditions associated with maternal hemorrhage among women ages ≤19–54 across the U.S. teaching hospitals. Of these, 48.74% were performed in the months of January through June, 26.27% from July through September, and 24.99% from October through December. Approximately 4.2% of the women had postpartum hemorrhage (PPH). In the sample population, women’s races included White 49.80%, Black 15.84%, Hispanic 21.81%, Asian or Pacific Islander 6.96%, Native-American 0.54%, and other 5.05%. The age group of ≤19 accounted for approximately 5.19%, the age group of 20–34 accounted for almost 94.60%, and the age group of 35–54 accounted for only 0.21%.We performed five multivariable logistic regressions to test the association of PPH risk and each of its risk factors separately with the month of delivery (to indicate the “July effect”) while holding regions of teaching hospitals, race, and age constant see . ResultsResults for regions of teaching hospital locations showed that compared to Northeastern teaching hospitals, women who delivered at Midwest teaching hospitals had lower adjusted odds of puerperal infection  but higher adjusted odds of PPH  and other obstetric trauma . Women who delivered at teaching hospitals located in the South region had lower adjusted odds of PPH , failed induction of labor , and puerperal infections  compared to those who delivered at Northeastern hospitals. Women who delivered at West teaching hospitals had higher adjusted odds of PPH  and other obstetric trauma  but lower adjusted odds of puerperal infections  compared to Northeastern teaching hospitals.Results for race and age as control variables found that all races compared to White women had significantly higher adjusted odds of PPH and puerperal infections, and the adjusted odds were the highest for Native Americans . However, different results were observed for race and other factors that increase the risk of PPH. For instance, results showed that compared to being White, being Black and Hispanic decreased the adjusted odds of failed induction of labor  and perineal laceration  and, being Asian or Pacific Islander, increased adjusted odds of failed induction of labor, puerperal infections, and perineal laceration .Results also showed that each one-year increase in age decreased the adjusted odds of PPH risk, puerperal infections, perineal laceration, and other obstetric trauma by 13%, 53%, 11%, and 49%, respectively see .p < 0.0001) than the first quarter of the academic year: 1.05 (1.02–1.10) (p = 0.004).A multivariable logistic regression was performed to estimate adjusted odds ratios for PPH risk with the month of delivery (to indicate the “July effect”) while holding race, age, failed induction of labor, other obstetric trauma, perineal laceration during delivery, and puerperal infection constant . CompareCompared to Northeastern teaching hospitals, women who delivered in South teaching hospitals had lower adjusted odds of postpartum hemorrhage , while women who delivered in Midwest and West teaching hospitals had higher adjusted odds of PPH [ and , respectively.Results indicated that, compared to White women, all other race groups had increased adjusted odds of PPH, but the adjusted odds were the highest for Native Americans compared to other races . Each one-year increase in age decreased the adjusted odds of PPH .Compared to its absence, the presence of PPH risk factors, including perineal laceration, other obstetric trauma, puerperal infections, and failed induction of labor, was associated with increased adjusted odds of PPH of 1.98 (CI = 1.78–2.18), 2.61 (CI = 2.46–2.83), 5.44 (CI = 4.75–6.23), and 1.97 (CI = 1.76–2.23), respectively. The odds were the highest for puerperal infections (AOR = 5.44).p < 0.0001) than the first quarter of the academic year (July–September) (p < 0.004). There is no explanation for these differences. However, researchers suggested that one probability could be that in the second quarter of the academic year, trainees have more autonomy and less supervision in their decision-making regarding the status of patient care compared to the first quarter of the academic year and that sometimes can also lead to an increase in adverse patient health outcomes [This study used the 2018 National Inpatient Sample (NIS) from the HCUP database to compare the risk of PPH and its risk factors in the first and second quarters with the second half of the academic year to assess the effect of the “July effect” in teaching hospitals across the U.S. The analysis showed increased adjusted odds of PPH in the first and second quarters of the academic year compared with the second half of the academic year. The adjusted odds were the highest for the second quarter of the academic year (October–December) (outcomes . This stAlthough this project provided support for an association between the “July effect” and the increased risk of PPH, most literature on obstetric and gynecologic surgery reviewed by this study found no significant associations between the “July effect” and the third stage of labor outcomes ,24,25,26It should be noted that the method used by this study to assess the “July effect” on the increased adjusted odds of PPH was different from methods used in the cited literature. For instance, studies either compared the obstetric outcomes in the first quarter with the second quarter  or for eThe study’s limitations included its inability to establish a causal effect due to its observational, cross-sectional design. Due to the limitations of the available data, information was unavailable on whether residents, interns, or other birth attendants were specifically involved in each discharge. Contextual information about residents and the residency programs was also not assessed, including the status of the changeover system and supervision of training skills and experience. Research should examine longitudinal data to provide more evidence for the July effect.Despite medical advances, PPH remains one of the challenges of obstetric care services. Therefore, management of PPH regarding patient safety needs to be carried out throughout the pregnancy and with careful and intentional management during the third stage of labor. Risk factors for PPH should be assessed during prenatal care and the high-risk case process. All the initial assessment and patient resuscitation has to be conducted within the first 15 min of a PPH occurrence. A multidisciplinary team must be vigilant in the event of a PPH occurrence . EssentiWhile this study does not establish a causal effect of the “July effect” on patient outcomes, the findings show an increased risk of PPH in the first half of the academic year. These findings have implications for improving the teaching and care environments in teaching hospitals. Though it should be noted that not all trainees at the same level demonstrate the same knowledge and skills, medical schools must warrant that new interns and residents are trained and prepared with new protocols and practices before taking on new roles in the clinical setting, and that should be continued through the changeover . The finOverall, the root causes of PPH conditions should be investigated to determine deficiencies in the system and identify whether they are related to maternal risk factors or to PPH management by considering the availability of resources, including skilled birth attendants, multi-professional team collaboration, and medical services such as blood products and medications, and how they can be improved . This st


Multimorbidity causes substantial disease and economic burdens on individuals and the health care system.This study aimed to explore the disease burden of multimorbidity and the potential correlations among chronic noncommunicable diseases (NCDs) in a rural population in Henan, China.A cross-sectional analysis was performed using the baseline survey of the Henan Rural Cohort Study. Multimorbidity was defined as the simultaneous occurrence of at least two NCDs in a participant. This study examined the multimorbidity pattern of 6 NCDs, including hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, stroke, and hyperuricemia.P<.05). The analysis of the mean age at diagnosis suggested a cascade of interrelated NCDs and their accumulation over time. Compared with participants without 2 conditional NCDs, participants with 1 conditional NCD would have higher odds of another NCD , and those with 2 conditional NCDs would elevate the odds of the third NCD to 1.4-3.5 .From July 2015 to September 2017, a total of 38,807 participants  were included in this study. The overall population prevalence of multimorbidity was 28.1% , and the multimorbidity of hypertension and dyslipidemia was the most common . Aging, higher BMI, and unfavorable lifestyles were significantly associated with a higher risk of multimorbidity (multinomial logistic regression, all Our findings indicate a plausible tendency for the coexistence and accumulation of NCDs in a rural population in Henan, China. Early prevention of multimorbidity is essential to reduce the NCD burden in the rural population. Multimorbidity is the coexistence of multiple disease conditions over time. Many of these conditions shared similar age-associated structural, physiologic, and biological changes in predispose patients with multimorbidity, resulting in compound risks and adversities -4. The oIn China, this prevalence ranged from 6.4% to 76.5%, as reported in 2015 . PreviouThe United States has emphasized the importance of timely diagnosis of multiple NCDs to support the development of effective clinical guidelines for multimorbidity . In addiOur study aimed to explore the disease burden of multimorbidity and determine the pattern of NCD accumulation among rural adults in Henan, China. We recruited 39,259 participants aged 18-79 years in Henan province for this study.The baseline survey of the Henan Rural Cohort Study enrolled a total of 39,259 participants aged from 18 to 79 years between July 2015 and September 2017 in the counties of Yuzhou, Xinxiang, Tongxu, Yima, and Suiping in Henan Province by using the stratified cluster sampling method. Detail description of the cohort had been previously published . In thisThis study was approved by the Zhengzhou University Life Science Ethics Committee . Informed consent was signed by all participants.Information was collected through face-to-face interviews using a standardized questionnaire. Demographic characteristics included age , gender2), normal (18.5-23.9 kg/m2), overweight (24.0-27.9 kg/m2), and obesity (≥28.0 kg/m2) ). Compared with the healthy individuals, participant groups with 1, 2, or 3 or more NCDs were more likely to be older and women and have lower education and income, higher BMI, poorer marital status, a higher-salt diet, and lower physical activity level . They were also less likely to have a high-fat diet and adequate fruit and vegetable intake than healthy individuals .Among all participants, 33.5%  were living with 1 NCD, among which dyslipidemia was the most common . In contrast, 18.8%  of participants were living with 2 NCDs, and the most frequent cluster of NCDs was dyslipidemia and hypertension . Moreover, 9.3%  of participants were living with 3 or more NCDs, and the cluster of dyslipidemia, hypertension, and hyperuricemia  was the most common in participants .P<.001; Overall, the prevalence of multimorbidity (2 or ≥3 NCDs) was 28.1% , and it was significantly higher in participants who were aged over 60 years , men , educated in elementary school or below , living alone , had low physical activity , and obese , those who are living alone (P<.001 and P=.007), those who are overweight and obese , former drinkers , current drinkers (P=.006 and P=.047), and those with a history of family hypertension and diabetes  were at a significantly higher risk of multimorbidity . Although women  and participants with moderate and high physical activity , high-fat diet (P=.004 and P=.008), and who are underweight  were less likely to report multimorbidity , individuals who currently smoke were less likely to report multimorbidity  were diagnosed with hyperuricemia at a mean age of 54.0 years, followed by dyslipidemia , hypertension , CHD , T2DM , and stroke . In addition, we observed additional connections between NCD pairs .P<.001). Individuals with 2 conditional NCDs (hyperuricemia and dyslipidemia) would further elevate their odds of hypertension to 2.1  would have significantly higher odds of hypertension . Individuals with 2 conditional NCDs  would further elevate their odds of CHD to 1.4-1.7  would have significantly higher odds of CHD , and individuals with these 2 conditional NCDs (dyslipidemia and hypertension combination or dyslipidemia and CHD combination) would further elevate their odds of T2DM to 2.7-3.1  would have a significantly higher odd of T2DM . Individuals with these 2 conditional NCDs (6 NCD combinations) would further elevate their odds of a stroke to 2.3-3.5  would have significantly higher odds of stroke  and increased with age, unfavorable lifestyles, and a higher BMI among Henan rural adults. The multimorbidity of dyslipidemia and hypertension was the most prevalent in study participants of all age groups. In addition, the onset of NCDs was associated, and a later NCD is often predictable by 1 or more preceding NCDs. The tendency of NCD accumulation indicates that compared with participants without conditional NCDs, participants with 1 existing NCD are more likely to develop a second NCD, whereas participants with 2 NCDs have an even greater likelihood to develop a third NCD.Our study finding demonstrated a lower multimorbidity prevalence than previous studies . A youngOur study found that unfavorable lifestyles and a higher BMI were associated with a higher risk of multimorbidity. Our finding is supported by evidence in other settings. A multinational cohort study found that a prediagnostic healthy lifestyle, such as a healthy diet, lower BMI, and higher physical activity, could reduce the risk of multimorbidity . A pooleOur study suggested a tendency for NCD accumulation among the participants. The clustering of dyslipidemia and hypertension was the most prevalent multimorbidity observed in our study, consistent with previous studies ,51. A JaOur findings have important implications for research and public health policy for multimorbidity. This study indicates that multimorbidity is an important health concern in rural Henan. In light of the WHO Sustainable Development Goals for preventing and controlling NCDs , existinThis study has several limitations. First, the causal relationship between NCDs may not be reliable on account of the data being from the baseline survey of a prospective cohort study in Henan Province. Therefore, prospective studies are needed to confirm the results of this study. Second, we define hypertension, dyslipidemia, hyperuricemia, and T2DM by self-report with laboratory measurements, whereas CHD and stroke are defined only by self-report, which might underestimate their prevalence. Finally, although several potential confounders are controlled, there may be other unknown confounders affecting the results of this study.In conclusion, our study indicates that multimorbidity is an important health issue in rural Henan. Older age, unfavorable lifestyles, and a higher BMI are associated with a higher risk of multimorbidity. In addition, our findings highlight a plausible explanation for the coexistence and accumulation of NCDs. Care for multimorbidity is complex, and concerted efforts and early interventions to prevent the occurrence of multimorbidity are essential to improve health in the rural population in Henan, China.


Sjögren’s syndrome (SS) is a systemic autoimmune disease that affects about 0.04-0.1% of the general population. SS diagnosis depends on symptoms, clinical signs, autoimmune serology, and even invasive histopathological examination. This study explored biomarkers for SS diagnosis.We downloaded three datasets of SS patients’ and healthy pepole’s whole blood  from the Gene Expression Omnibus (GEO) database. We used machine learning algorithm to mine possible diagnostic biomarkers for SS patients. Additionally, we assessed the biomarkers’ diagnostic value using the receiver operating characteristic (ROC) curve. Moreover, we confirmed the expression of the biomarkers through the reverse transcription quantitative polymerase chain reaction (RT-qPCR) using our own Chinese cohort. Eventually, the proportions of 22 immune cells in SS patients were calculated by CIBERSORT, and connections between the expression of the biomarkers and immune cell ratios were studied.We obtained 43 DEGs that were mainly involved in immune-related pathways. Next, 11 candidate biomarkers were selected and validated by the validation cohort data set. Besides, the area under curves (AUC) of XAF1, STAT1, IFI27, HES4, TTC21A, and OTOF in the discovery and validation datasets were 0.903 and 0.877, respectively. Subsequently, eight genes, including HES4, IFI27, LY6E, OTOF, STAT1, TTC21A, XAF1, and ZCCHC2, were selected as prospective biomarkers and verified by RT-qPCR. Finally, we revealed the most relevant immune cells with the expression of HES4, IFI27, LY6E, OTOF, TTC21A, XAF1, and ZCCHC2.In this paper, we identified seven key biomarkers that have potential value for diagnosing Chinese SS patients. It mCurrently, the diagnosis of SS is a combination of symptoms, clinical signs, histopathology, and autoimmune serology , 15. ComAs is well known, the immunopathogenesis of SS involves the activation of T and B lymphocytes , 20. ManSS = 522, nnormal = 46). Next, we identified the differentially expressed genes (DEGs) between SS and controls. Subsequently, we screened the diagnostic biomarkers of SS through three machine learning algorithms. Following that, we validated the expression of the identified diagnostic biomarkers by using the validation data , and investigated the logistic regression model by the receiver operating characteristic (ROC) curve. Beyond that, we used our own Chinese cohort  to validate the expression of the candidate biomarkers. Furthermore, we applied the algorithm of CIBERSORT to calculate the ratio of 22 immune cells in blood samples of SS patients and healthy people. Finally, we investigated the connection between the expression of the identified biomarkers and the ratios of immune cells in blood samples of SS patients. A workflow chart summarizing our work is shown in Herein, we downloaded three expression matrix files of SS patients’ and healthy people’s blood samples from the Gene Expression Omnibus (GEO) database. Then, we merged the three expression matrix files into one metadata, and took about 80% of the samples as the discovery cohort , in which about 80% of the samples were used as the discovery data set  and the rest as the verification data set .Three expression matrix files  of SS blood samples were obtained from GEO database. The GSE51092 data set contained 190 SS and 32 healthy controls, the GSE66795 data set contained 131 SS and 29 healthy controls, and the GSE140161 data set contained 351 SS. After batch corrections using the R package “SVA”, the three files GSE51092, GSE66795, and GSE140161 were performed principal component analysis (PCA), which contained the SS patients and healthy controls. Then, the three files were combined into a metadata cohort  and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted to analyze the functions of the DEGs in the DAVID database online. The gene set enrichment analysis (GSEA) was used to pick the most important pathway between SS and controls. The gene set “c2.cp.kegg.v7.0.symbols.gmt” was selected as the reference gene set from the Molecular Signatures Database (MSigDB).2.3The least absolute shrinkage and selection operator (LASSO) logistic regression, support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF) were used to screen the potential SS diagnostic markers. To prevent overfitting the data set, the LASSO analysis was performed using the R package “glmnet”, and based on support vector machine, the SVM-RFE was used to find the optimum variables. The candidate diagnostic markers selected by the three algorithms were overlapped, and the resulting intersection genes were further studied. Then, the candidate diagnostic biomarkers’ expressions were verified in the verification data set.2.4To investigate the diagnostic capability of the candidate markers, ROC curves were plotted according to the discovery data set and the validation data set. Combined ROC curves were also produced to assess the combined diagnostic utility of candidate markers.2.5In total, the whole blood of 14 SS samples and 10 control samples was obtained from Shenzhen People’s Hospital. All participants volunteered to enter this research. Patients who were included in the study were confirmed SS patients according to ACR-EULAR classification criteria, and the clinical manifestations of them were sorted out in When the whole blood samples were obtained, the peripheral blood mononuclear cells (PBMCs) were collected after being diluted with an equal volume of phosphate-buffered saline (PBS) and Ficoll and centrifuged at 2000 rpm for 20 min, and the red blood cell was lysed with red blood cell lysis buffer . Finally, the PBMCs were mixed with 1mL Trizol  and stored at -80 °C.According to the manufacturer’s instructions, total RNA was extracted from PBMCs. The transScript all-in-one first-strand cDNA synthesis superMix for qPCR  kit  was utilized for the reverse transcription of mRNA. Following that, the RT-qPCR tests were undertaken by the PerfectStart Green qPCR SuperMix kit . The list of primers is showed in After the RT-qPCR validation, SLE biomarkers screened from the public database that we have previously published were compared, in order to further confirm the diagnostic value and specificity of the diagnostic markers we screened in SS patients.2.6The CIBERSORT algorithm was used for the immune cell analysis of the expression matrix of SS patients and healthy people. We edited an R language script to run CIBERSORT. CIBERSORT is used to estimate the cell composition of a single sample. The script reads the mixed gene expression data to be analyzed from the file system, normalizes and fits the mixed expression data using support vector machine, and then outputs the estimated relative content of each cell subset in the mixture after loading the necessary packages and functions. The script includes three functions: CoreAlg, doPerm, and CIBERSORT. The CoreAlg function defines the core algorithm, which accepts one cell type gene expression data and one mixed gene expression data, uses the support vector machine model to train and normalize the mixed data, and returns the relative content of each cell subset based on the model in the mixed cells. The main function is CIBERSORT, which accepts two file locations (unit-type gene expression data and mixed gene expression data), the number of permutations, and a Boolean value indicating whether quantization normalization is applied. The R package “vioplot” was adapted to visualize the ratios of 22 immune cells in SS and control groups . The “corrplot” package was used to draw the heat map, which presented the quantitative correlation between different immune cells in SS patients. Additionally, the R package “ggplot2” was applied to investigate the relationship between the expression of the diagnostic markers and the ratios of immune cells using the Pearson method.33.1After batch corrections using the R package “SVA”, we performed PCA on three datasets  from GEO , macrophages M1, activated dendritic cells, activated NK cells, and naïve B cells, and negatively correlated with the ratios of CD4 naive T cells, CD4 memory resting T cells, resting NK cells, macrophages M0, and CD4 memory activated T cells . However, a larger cohort may be required for further validation in future research. Due to the small sample size, there was a quite difference in age between SS and healthy control. The biomarkers we validated were somewhat impacted by the age mismatch. Previous studies have also shown that the levels of some indicators vary in different age groups. The elderly-onset of SS was associated with lower frequency of SS-related inflammatory arthritis, anti-Ro/SSA and anti-La/SSB positivity, and lower levels of RF, C3, and C4  to screen biomarkers and verify the screening markers. The results showed that the expression trends of biomarkers screened in the discovery data set were consistent with those in the validation data set, indicating that our screening strategy was reliable. In addition, HES4, IFI27, LY6E, OTOF, TTC21A, XAF1, and ZCCHC2 were found to be more suitable biomarkers for SS in the Chinese population after validation in our own Chinese cohort  as prospective SS biomarkers, which were more suitable for Chinese populations. In addition, we observed quantitative changes in six different types of immune cells in SS patients. Finally, we explored the relationship between the expression of the seven genes and the proportion of different immune cells. Our study provides potential biomarkers for Chinese SS patients and elucidates the relationship between gene expression and ratios of immune cells.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study.WZ conceived and designed the project. YZ performed the literature search and wrote the manuscript. SL provided data analysis support. XH and DL contributed to clinical sample collection. JL and LL performed the literature search. ZZ and WC performed the experiments. DT and YD supervised the study. All authors contributed to the article and approved the submitted version.


Congenital hypothyroidism (CH) is the most common cause of preventable but irreversible mental retardation in children, although the risk has been widely abolished by national neonatal screening programs. The aim of this study was to determine, (a) the cause of CH, (b) the etiological cause of persistent CH and (c) to investigate the role of laboratory and clinical data in predicting persistent and transient CH.Patients diagnosed with CH, who started L-thyroxine treatment and were followed up for at least three years were included. Patient data were reviewed retrospectively. Serum thyroid hormones were measured four weeks after discontinuation of therapy at age three or earlier. Cases with a thyroid-stimulating hormone (TSH) value of >10 mIU/mL were accepted as permanent hypothyroidism, while cases with normal TSH values for six months after cessation were accepted as transient hypothyroidism.There were 232 treated cases, of whom 108 (46.6%) were female, and 169 (72.8%) were eventually diagnosed with transient CH. The best cut-off point for predicting permanent status was determined as LT4 cut-off dose ≥1.45 mcg/kg/day. The median (range) duration of L-thyroxine treatment in transient hypothyroid cases was 24 (range: 6–36) months, and treatment was discontinued before the age of three years in 64%.It has been shown that the most common etiologic cause of CH is transient hypothyroidism. The thyroxine dose at the time of discontinuation of treatment and free thyroxine and TSH levels at the time of diagnosis are essential determinants in distinguishing permanent/transient CH. Congenital hypothyroidism (CH) is defined as insufficient thyroid hormone production as a result of dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis present at birth . ThyroidWith screening programs in developed countries, babies with CH are diagnosed and treated without delay. However, CH continues to be a significant cause of mental retardation in countries that do not have a screening program . DependiDetermining the etiology of raised neonatal TSH is important in terms of the duration of the treatment . PermaneWhile the number of referrals from screening programs increased markedly as TSH threshold values decreased, the incidence of permanent CH did not change much ,10. For Medical records of patients diagnosed sequentially with CH in the pediatric endocrinology clinic between January 2011 and July 2020 were retrospectively reviewed. Cases diagnosed with CH in the newborn and infancy periods, started on LT4 treatment, and reached at least three years old were included. At the same time, patients who started treatment in other centers, whose thyroid function tests were known at the time of diagnosis and during follow-up, and who were followed up regularly in our clinic were also included in the study. Exclusion criteria were: (1) patients diagnosed at another center and undergoing LT4 replacement but lacking data on initial LT4 dose and/or pretreatment thyroid function tests; (2) patients not followed up regularly; and (3) follow-up of patients for less than 3 years.The age in days, sex, age at diagnosis, age at start of treatment, consanguinity between parents, gestational week at delivery, birth weight, family history of hypothyroidism, iodine exposure, maternal history of antithyroid drug use, free thyroxine (fT4) at diagnosis, free triiodothyronine (fT3), serum TSH levels (at diagnosis), and diagnostic thyroid ultrasonography (USG) results of the cases were recorded retrospectively from their files. Additionally, height SDS (standard deviation score), weight SDS, body mass index (BMI), BMI SDS, and head circumference SDS data were recorded during diagnosis and follow-up. The data of the initial and follow-up LT4 doses of the cases were recorded. The diagnosis of CH was made following the Consensus of the European Society of Pediatric Endocrinology, and LT4 treatment was started for the diagnosed patients . In patiPatients with TSH level <5.6 mIU/mL in the follow-up and thyroid gland in USG were discontinued at age three years or earlier. Cases with agenesis or ectopia detected on USG were accepted as permanent CH, and LT4 treatments were not discontinued. Serum thyroid hormones were measured 4–6 weeks after LT4 discontinuation in patients who were three years old or whose treatment was discontinued before, and patients with a TSH value >10 mIU/mL after being off-treatment were evaluated as permanent hypothyroidism and LT4 therapy was reinitiated in these patients. Patients whose fT4 and TSH values remained within normal limits for six months after LT4 withdrawal were considered transient hypothyroidism. Free T4 and TSH were measured again at the end of the second week in cases with normal fT4 and serum TSH <20 mIU/mL in the neonatal period. Cases whose TSH value decreased below 10 mIU/mL and LT4 treatment was not started were accepted as transient neonatal hyperthyrotropinemia.2 (m2). The evaluation of height, weight, head circumference, and BMI SDS was made according to the data prepared by Neyzi et al. for Turkish children [BMI was calculated using Bodyweight (kg)/Heightchildren . Obesitychildren . In all children . The fT4TSH, fT3, and fT4 levels were measured by 2-chamber 2-step enzymatic immunoassay methods using a Beckman Coulter DxI 800 device . Our laboratory uses the reference values provided in the Beckmann Coulter TSH and fT4 kits, which are TSH lower and upper limits 0.35–5.6 mIU/mL, and fT4 lower and upper limits were 0.61–1.32 ng/dL. The fT3 normal range was 1.9–4.2 pg/mL.Statistical evaluation was done using SPSS , version 17 . Whether the quantitative variables were normally distributed or not was tested with the one-sample Kolmogorov Smirnov test. The Mann-Whitney U test was used to compare data that were skewed, and the chi-square test was used to compare categorical data between groups. Descriptive statistics for the data are given as median (minimum-maximum) for skewed parameters and mean±SDS for normally-distributed parameters. A receiver operator characteristics (ROC) analysis was applied to determine the cut-off of the LT4 dose at the time of treatment discontinuation as a predictive criterion for distinguishing permanent and transient CH, and the sensitivity and specificity values were calculated for this threshold value. A p-value of <0.05 was considered significant.A total of 304 patients’ medical records were scanned. However, 41 patients were excluded due to insufficient data, leaving 263. Thirty-one of these followed-up patients were excluded due to transient hyperthyrotropinemia. The remaining 232 patients started on L-thyroxine (LT4) were analyzed. Flow diagram of the follow-up study is shown in Of the cases, 108 (46.6%) were female, and 124 were male. The mean fT3 level at the time of diagnosis was 3.3 ± 1.5 ng/dL, the fT4 level was 0.78 ± 0.4 ng/dL, and the mean serum TSH level was 54.6 ± 34.6 mIU/mL. There was no difference between the groups with permanent and transient CH in terms of sex, gestational week, birth weight, age at diagnosis (days), and age at onset of treatment (days). However, significant serum fT3, fT4, and TSH differences were found in patients with permanent and transient CH. Main characteristics of babies with permanent and transient CH are shown in th, 12th, 18th, 24th, 30th, and 36th months were lower in patients with transient CH than in permanent CH. Follow-up and treatment data of permanent and transient congenital hypothyroidism cases are shown in Mean LT4 doses at baseline, 6At the time of diagnosis, mean height SDS was significantly greater in patients with permanent CH than in transient CH. However, there was no significant difference at the end of three years. At the time of diagnosis, the head circumference SDS was higher in patients with permanent CH, but this difference disappeared at the end of one year. Height SDS, weight SDS, BMI SDS, and head circumference SDS in cases referred because of suspected congenital hypothyroidism are shown in As the best criterion for distinguishing between permanent and transient hypothyroidism, the threshold of the LT4 dose at the time of discontinuation was ≥1.45 mcg/kg/day by ROC analysis, the area under the curve (AUC) was 0.992  = 0.985–1.000), which was statistically significant (p < 0.001). The diagnostic sensitivity was 100% for this cut-off value, and the specificity was 90.4% as shown in Treatment of CH is easy, inexpensive, and highly effective . ThyroidAs a result of the screening program conducted in Turkey between 2008–2010, the frequency of CH was 1/650, and the female/male ratio was similar . In our In our clinic, 72.8% of the cases were diagnosed with transient CH and some cases taking LT4 improved before the age of three years. Notably, approximately 65% of transient CH cases discontinued LT4 replacement therapy before the age of three years at a median duration of 24 months. Kara et al. reported that in 70% of transient CH cases, the treatment was discontinued before the age of three and with a median age of 19 months . AlthougAmong the reasons why the frequency of transient CH differed between studies, factors such as differences in inclusion criteria (term/preterm), use of different TSH threshold values to define transient hypothyroidism, maternal iodine deficiency, iodine overload in the mother/baby (often iatrogenic), or the transmission of TSH-blocking antibodies to the fetus due to autoimmune thyroiditis in the mother may play important roles ,15,26,27The most common (61%–85%) cause of permanent CH is accepted to be thyroid dysgenesis ,27, whilIt is very important to distinguish permanency and transiency in CH cases, both to prevent unnecessary treatment for transient cases and to ensure that permanent hypothyroidism cases receive appropriate treatment. Various criteria have been investigated to predict transient and permanent hypothyroidism in cases where scintigraphy could be performed for etiological evaluation at the time of diagnosis or in cases with the ectopic thyroid gland in scintigraphy. Among these criteria, the most investigated are serum fT4, TSH levels, and LT4 dose at diagnosis and follow-up. Reports vary on this subject. Although it has been reported that fT4 at the time of diagnosis may be effective in determination in some studies and TSH in others, there are also studies stating that both are not determinative ,25,29,30Most studies reported that the LT4 dose of the permanent group was higher than the transient group at LT4 withdrawal ,17,20,24If CH is not treated, it causes irreversible mental retardation and reversible short stature . NeonataThe most important limitation of our study is that it was designed retrospectively. In addition, maternal and baby urinary iodine levels were not checked, which will probably have affected thyroid functions, especially given that our region is a known area of iodine deficiency. Furthermore, transplacental transmission of maternal thyroid autoantibodies and maternal drugs potentially affecting thyroid functions were not evaluated. Another limitation is the inclusion of patients diagnosed in other centers, although thyroid function tests are performed with a similar method and reference intervals are similar.In conclusion, the frequency of transient CH was 72.8%. Furthermore, LT4 dose at the time of discontinuation of treatment was shown to be predictive of the permanence of CH versus transient thyroid dysfunction while fT4 and TSH levels at the time of diagnosis were also significant among the predictive criteria in the differential diagnosis of transient and permanent CH.


We initiated the Fujian Tulou Pedigree-based Cohort (FTPC) as the integration of extended pedigrees and prospective cohort to clarify the genetic and environmental risk factors of cardiometabolic diseases.FTPC was carried out in Nanjing County, Fujian Province, China from August 2015 to December 2017 to recruit probands with the same surnames and then enroll their first-degree and more distant relatives. The participants were asked to complete questionnaire interview, physical examination, and blood collection. According to the local genealogical booklets and family registry, we reconstructed extended pedigrees to estimate the heritability of cardiometabolic traits. The follow-up of FTPC is scheduled every 5 years in the future.The baseline survey interviewed 2,727 individuals in two clans. A total of 1,563 adult subjects who completed all baseline examinations were used to reconstruct pedigrees and 452 extended pedigrees were finally identified, including one seven-generation pedigree, two five-generation pedigrees, 23 four-generation pedigrees, 186 three-generation pedigrees, and 240 two-generation pedigrees. The average age of the participants was 57.4 years, with 43.6% being males. The prevalence of hypertension, diabetes and dyslipidemia in FTPC were 49.2, 10.0, and 45.2%, respectively. Based on the pedigree structure, the heritability of systolic blood pressure, diastolic blood pressure, fast blood glucose, total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein was estimated at 0.379, 0.306, 0.386, 0.452, 0.568, 0.852, and 0.387, respectively.As an extended pedigree cohort in China, FTPC will provide an important source to study both genetic and environmental risk factors prospectively. In ChinProspective cohort studies provide a valuable advantage by allowing for the clarification of the temporal relationship between exposure and outcome in etiological studies. In contrast, traditional extended pedigree studies have been widely utilized to identify genetic determinants, offering improved control over population stratification in comparison to case–control designs , 6. MoreFujian Tulous represent a distinct style of rural dwellings found exclusively among the Hakka populations residing in the mountainous regions of southeastern Fujian province, China. These Tulous are characterized by their large, enclosed, and fortified earth buildings, typically exhibiting a rectangular or circular configuration. Notably, these structures feature remarkably thick load-bearing rammed earth walls, spanning three to five stories in height, capable of accommodating up to approximately 800 individuals . TypicalHerein, we initiated Fujian Tulou Pedigree-based Cohort (FTPC) to explore the genetic and environmental risk factors for cardiometabolic diseases. In this manuscript, we described the study design, enrollment methods, collection of research data, and baseline characteristics of FTPC. We also presented a heritability estimation of cardiometabolic traits based on the pedigrees.2.2.1.FTPC was an extended-pedigree-based prospective open cohort in the Tulou area of Nanjing County, Fujian Province. This study was designed to recruit any accessible multi-generation pedigrees. Probands were recruited according to their surname and then their first-degree and more distant relatives were invited to participate. A household was considered as a unit to be investigated and followed up prospectively.2.2.The study sites were carefully selected based on clan clustering, patterns of major cardiometabolic diseases and exposures, the stability of the population, and long-term local commitment to the project. Ultimately, six villages were selected for participant recruitment. Participants with surname Zhang were enrolled from Taxia Village, Qujiang Village, and Nanou Village. And participants with surname Chen were enrolled from Caoban Village, Tumei Village, and Beiling Village. About half of the local residents were enrolled in our study. From August 2015 to December 2017, the baseline investigation was conducted to enroll all eligible participants and their relatives in the six villages. For migrant workers or overseas nationals, a complementary investigation was carried out when they returned home during Spring Festivals or Tomb-sweeping Days. Adults over 18 years old were asked to complete a face-to-face questionnaire and a family registry. Participants were also asked to conduct a physical examination and provide a blood sample for long-term storage. At the end of each survey day, a blood sub-sample was sent to the local hospital laboratory to conduct the biochemical examination. Those under 18 years old were only required to provide basic demographic information by their guardians. The study was approved by the Ethics Committee of Peking University Health Science Center. Written informed consent was obtained from all participants.The inclusion criteria of the participants were as follows: (1) residents with surname Zhang or surname Chen who have accessible biological relatives and could provide complete genealogical information; (2) spouses of the probands; (3) volunteered to participate in the project and signed informed consent. Subjects with disabilities or other serious diseases were excluded if they were unable to complete the investigation.2.3.According to the genealogical booklets and on-site investigations, the family registry collected information about the participants and their relatives’ names, kinships, and dates of birth. Trained investigators were asked to interview relatives of the probands as many as possible. According to the family registration, pedigrees were reconstructed using R version 3.6.2.2.4.The questionnaire interview included the following information: (1) demographic information; (2) social-economic status ; (3) health-related behaviors ; (4) health status (disease history and medication history); (5) menstrual and obstetrical histories for women ; (6) psychological status assessments (adapted Kessler10) .Physical examinations included: (1) height; (2) body weight and body fat percentage; (3) waist circumference and hip circumference; (4) blood pressure and heart rate. These examinations were conducted twice per subject. If the difference between the two blood pressure measures was greater than 10 mmHg, a third measure would be conducted. The average of the last two measurements was recorded and used in the analysis.For each participant, a 15 mL fasting blood sample was collected to conduct biochemical examinations (2 mL EDTA anticoagulant sample) and future genotyping (8 mL EDTA anticoagulant sample and 5 mL coagulant sample). Biochemical examinations included: (1) blood lipids levels such as total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein; (2) liver function markers such as aspartate aminotransferase, alanine aminotransferase, glutamyl transpeptidase, total protein, albumin, globulin, and total bilirubin; (3) renal function markers such as uric acid, creatinine, and uric acid nitrogen; (4) fasting blood glucose.Hypertension was defined if the participant was under any following conditions: (1) self-reported hypertension diagnosed by secondary or higher-level hospitals; (2) taking antihypertension drugs; (3) systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg . Diabete2.5.The active follow-up interview is scheduled at a 5-year interval among all surviving participants. The information about any incident cases of stroke, coronary heart disease, cancer, and other non-communicable diseases will be collected through a passive linkage with records of local health surveillance system. The death events will be obtained from the Death Registry of the National Centers for Disease Control and Prevention. All participants will be followed up indefinitely until cause-specific mortality is observed. The first wave of follow-up has initiated on April 2023.2.6.FTPC adopted a unified manual for field investigation and standard criteria for the physical and biochemical examination. The collected data was checked regularly during the study period by the study coordinating centers. Most questionnaires were electronically collected with a logical verification to avoid systematic errors.2.7.In this study, baseline characteristics of participants in FTPC were present with means  and proportions for the continuous and categorical variables, respectively. Descriptive analysis was conducted in Stata version 13.1.2, age by sex, and age2 by sex. Lipid and blood pressure values were corrected for the use of lipid-lowering and antihypertensive medication using published constants   . p value3.3.1.From August 2015 to December 2017, 2,727 individuals were interviewed in clan Zhang and clan Chen . As showBased on physical and biochemical examinations, the prevalence of hypertension, diabetes, and dyslipidemia was estimated at 49.2, 10.0, and 45.2%, respectively, which were much higher than the self-reported prevalence . Despite3.2.Based on the pedigree registry, 452 pedigrees were reconstructed, including one seven-generation pedigree, two five-generation pedigrees, 23 four-generation pedigrees, 186 three-generation pedigrees, and 240 two-generation pedigrees . More th3.3.Based on the pedigree structure, we generated the heritability estimations for cardiometabolic traits . The her4.The rapidly rising prevalence of cardiometabolic diseases has made them the predominant disease burden in China, with the prevalence of hypertension alone increasing 2.5 times from 2002 to 2017 , 20. HowWe decided to establish our pedigree-based cohort in the Tulou area, which is an ideal region for recruiting extended pedigrees. As one Tulou is occupied by one large family clan, the family members generally live close and have homogeneous genetic backgrounds. Because of the remote location, traffic inconvenience, and native tradition, local residents in the Tulou area rarely move outside. Driven by the strong faith in clan culture, migrant workers always come back home and visit their relatives at regular intervals. These features make it possible to recruit more family members of a pedigree and follow them up for a long time. In this study, we successfully identified extended pedigrees of different family sizes and extracted various family relationships. These pedigrees will provide an important source to conduct any type of genetic epidemiological study. There is a unique Hakka culture in the Tulou area where local residents have distinctive living habits such as a preference for tea consumption and light food. The insight into the association between those living habits and cardiometabolic diseases may contribute to the understanding of modifiable risk factors and further intervention measurements. Besides that, by comparing the migrant workers and local residents, FTPC will provide the possibility to study the effect of migration and social determinants in the future.FTPC is based in a typical rural region in southern China with a heavy burden of cardiometabolic diseases. We adopt a means of snowball sampling to recruit participants for FTPC where probands are first identified and their relatives are then investigated. Such a sampling method will naturally result in a higher prevalence of cardiometabolic diseases because of the familial aggregation for these diseases. According to the baseline investigation, the prevalence of hypertension, diabetes, and dyslipidemia in FTPC is reported to be 49.2, 10.0, and 45.2%, respectively, which is even higher than that in urban areas of China , 27, 28.Our cohort has begun to make significant contributions to the estimation of heritability for cardiometabolic traits. Based on the pedigree structure, we obtained heritability estimations for SBP, DBP, and hypertension, ranging from 0.36 to 0.40. This finding suggests that the genetic component may have a similar effect on the variation of blood pressure and liability of hypertension, or there may be the same susceptible genes to determine the blood pressure values and hypertension. The heritability for SBP and DBP in FTPC is consistent with the estimation in Nigerian families but lower than the estimation from the previous meta-analysis of twin studies . CompareThis study has some limitations. More than half of the pedigrees in FTPC are two-generation pedigrees because of inadequate genealogical information. To address this limitation and expand our pedigrees, we have incorporated an additional village into our ongoing investigation. Our aim is to gather more comprehensive family information, enabling the connection of two-generation pedigrees and the enrollment of additional members from multi-generation pedigrees.Because of the difficulties in recruitment, investigation, and follow-up of the pedigrees, there are only several extended-pedigree-based studies in the world, such as Nigerian families and Oman families , 33. In twu@bjmu.edu.cn.The datasets presented in this article are not readily available because Data used in this study are available from the corresponding authors upon reasonable request. Requests to access the datasets should be directed to TW, The studies involving human participants were reviewed and approved by the Ethics Committee of Peking University Health Science Center. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by Special Fund for Health Scientific Research of Public Welfare (201502006), Fujian Provincial Health Technology Project (2020CXB009), Natural Science Foundation of Fujian Province, China (2021 J01352), and Peking University Outstanding Discipline Construction Project of Epidemiology and Biostatistics.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We concluded that medical cannabis in older adults has a number of serious adverse events, but was not associated with a decrease in functional status, as illustrated by ADL and IADL scores after six months of continuous treatment.The proportion of older adults using medical cannabis is rising. Therefore, we aimed to assess the effects of herbal medical cannabis on the functional status of older adults. We conducted a prospective observational study of patients aged 65 years or older that initiated cannabis treatment for different indications, mostly chronic non-cancer pain, during 2018–2020 in a specialized geriatric clinic. The outcomes assessed were activities of daily living (ADL), instrumental activities of daily living (IADL), pain intensity, geriatric depression scale, chronic medication use, and adverse events at six months. A cohort of 119 patients began cannabis treatment: the mean age was 79.3 ± 8.5 and 74 (62.2%) were female. Of the cohort, 43 (36.1%) experienced adverse effects due to cannabis use and 2 (1.7%) required medical attention. The mean ADL scores before and after treatment were 4.4 ± 1.8 and 4.5 ± 1.8, respectively ( While cannabis has historically been predominantly associated with recreational use among younger demographics, recent shifts in societal attitudes and evolving legalization efforts have sparked a surge of interest in exploring its potential effects on older populations ,2. MedicAmong older adults, cannabis exhibits its effectiveness across multiple dimensions, notably in mitigating pain, enhancing mood, refining sleep quality, and elevating overall quality of life. Furthermore, the therapeutic introduction of medical cannabis yields the advantageous outcome of facilitating decreases in opioid dosages or utilization, which is especially pertinent within the context of chronic pain management ,10,11. IFunctional status, which is a crucial aspect of geriatric care, plays a significant role in assessing overall well-being. As the global population continues to age, the focus on improving the quality of life of older adults becomes increasingly pertinent. Activities of Daily Living (ADLs), encompassing essential self-care tasks such as bathing, dressing, eating, and mobility, serve as critical indicators of an individual’s functional independence and overall well-being. With the rise in chronic conditions and age-related ailments, finding innovative therapeutic approaches that enhance older adults’ ability to perform ADLs is of paramount importance. Moreover, a decline in function can lead to heightened healthcare utilization, diminished quality of life, compromised independence, and an elevated risk of mortality. The Katz ADL scale and the Lawton instrumental activities of daily living (IADL) scale are well-known scales that assess functional status in older adults ,16.The impact of medications on IADL and ADL scores is a critical consideration in geriatric healthcare. Polypharmacy, often necessary to manage the multiple chronic conditions prevalent in older adults, has been associated with functional impairment . Some meWith advancing age, alterations in appetite and nutritional status pose significant challenges for older adults . The intWe previously published the treatment protocol and initial data about the cohort of older adults treated with cannabis in a specific clinic . The aimThe study was conducted in a specialized geriatric clinic aimed to provide medical cannabis therapy within a comprehensive geriatric platform. This was a prospective observational study that included all patients above the age of 65 years who began their cannabis treatment in the clinic during the years 2018–2020. There were no exclusion criteria. The recruitment for the study was stopped due to the emergence of the coronavirus disease-19 (COVID-19) pandemic. The patients were followed for six months from cannabis treatment initiation. The cannabis for patients was supplied by pharmacies in Israel according to the doctor’s prescription and not by the study personnel. The constituents of the cannabis products are reported to the Ministry of Health and include the content of THC and CBD in each product.Perception of the general effect of cannabis—global assessment using the Likert scale with seven options: significant improvement, moderate improvement, slight improvement, no change, slight deterioration, moderate deterioration, or significant deterioration.Changes in appetite—global assessment using the Likert scale with six options: significant increase, slight increase, no change, slight decrease, significant decrease, or change only immediately after cannabis consumption.Adverse effects—incidence, duration, severity, and the need to seek medical care for the reported adverse event.Changes in chronic drug regimens—drugs that were added, stopped, and changed in dosing.Stopping use of medical cannabis—patients that stopped using cannabis after six months were asked about the reasons for stopping treatment.Patients were invited to take part in the study and were requested to complete the study questionnaire during their initial appointment, prior to commencing cannabis treatment. Subsequently, they were asked to respond to the same set of study questions after undergoing six months of continuous cannabis treatment. The data collected before treatment included demographics, chronic medications, indication for cannabis use, type of cannabis selected, dosing, and route of administration. In addition, the patients responded to the following questionnaires before and after treatment: Geriatric Depression Scale (GDS) , Katz Act-test or paired Wilcoxon test to compare quantitative and ordinal variables, respectively. We used multivariable logistic regression to assess the factors associated with improvements in the different scores assessed in the study. The variables inserted in the model were those significant in univariable comparisons, the basic demographic characteristics, and the data about cannabis use. THC-rich strains were defined as strains with 10% THC content or higher. The definition of non-THC-rich strains included cannabidiol (CBD)-rich strains and patients treated with equal amounts of THC and CBD.Continuous variables with normal distribution were presented as means with standard deviation. Ordinary variables or continuous variables with non-normal distribution were presented as medians with an interquartile range (IQR). Categorical variables were presented as counts and percent of the total. Univariable comparisons were made using paired Student’s p-value of 0.05 or less (two-sided) was considered statistically significant. SPSS software , version 25.0, was used for statistical analysis.A We prospectively followed 119 patients between 2018–2020; the patients’ mean age was 79.3 ± 8.5, and 74 (62.2%) were female. p < 0.001). In contrast, 46 (56.8%) of the respondents did not have any change in their appetite, 14 (17.3%) had a decrease in their appetite, and 20 (24.7%) had an increase in their appetite  of the respondents reporting some degree of improvement . Similarappetite . After up = 0.27), and the mean IADL scores before and after treatment were 4.1 ± 2.6 and 4.7 ± 3, respectively . Among those who had an improvement in their IADL score, the median age was 78 (IQR 74–83.8).The assessment of daily activities by IADL and ADL showed different outcomes. The mean ADL scores before and after treatment were 4.4 ± 1.8 and 4.5 ± 1.8, respectively  4.5, 95% CI 1.03–19.4) and that male sex was associated with improvements in IADL scores . The type of cannabis strain and the number of times cannabis was used each day were not associated with improvements in the different scores .p = 0.008).After six months of cannabis treatment, 63 patients (52.9%) reported stopping the use of at least one chronic medication; of them, 28 (23.5%) stopped using opioid analgesics. Conversely, 24 patients (20.2%) added a new chronic medication, but only 4 (3.4%) added opioids . When coIn this prospective cohort study of older adults treated with medical cannabis, we have shown that cannabis treatment for six months was associated with improvements in IADL and GDS, as well as a reduction in pain and opioid use. No significant changes were found in ADL or in appetite following cannabis treatment.The effect of cannabis on scales of functional status in older adults was not assessed in previous studies. A study of younger patients, in which only 5% of the population was above 70 years of age, showed that cannabis improved areas of bodily pain, physical functioning, and social functioning, but limitations due to either physical or emotional problems were not changed . AnotherNeither the number of times cannabis was used daily nor the THC content of the cannabis were associated with changes in ADL or IADL scores in the multivariable analysis. The minimally important changes for both Katz ADL and Lawton IADL were determined to be around half a point . In our The main indication for cannabis use in our study was neuropathic pain. This is the most common indication for cannabis in Israel as well as in other countries ,30,31. IThe most common route of administration for cannabis in our study was tinctures (cannabis oil). This route of administration is the most preferred for older adults and differs from younger individuals, especially those without a previous experience in smoking tobacco . ConsumiThe composition of cannabis products was heterogenous among our study group. Most of the patients used either CBD-rich cannabis or cannabis with equal amounts of THC and CBD. This finding is in line with other studies exploring the use of cannabis in older adults , and canTwo distinct patterns can be seen in our results: on the one hand, one-quarter of the patients decided to discontinue the treatment with cannabis after six months; on the other hand, almost all other patients reported that cannabis led to improvement in their overall condition, and two-thirds reported either moderate or significant improvement. These high rates of satisfaction can be explained by the high expectations from cannabis and its perceived efficacy in the general population ,34. The The effectiveness of cannabis in addressing mood-related disorders and overall quality of life among older individuals has been substantiated through multiple investigations, including our own ,11,35. OThe reduction in the VAS pain score after cannabis treatment is significant, both statistically and clinically. Clinically significant pain alleviation is characterized by a reduction of 2 points on a 0-to-10 numerical pain rating scale or a noteworthy reduction of 30% in pain intensity ,38. We dOur findings also demonstrate the relatively favorable safety profile of cannabis therapy, as evidenced by the notably low incidence of adverse events necessitating medical intervention. In addition, less than 10% of the cohort defined the adverse effects as most severe. These observations align with the outcomes of our previous investigations involving older adult cohorts , as wellAs evidenced in our prior investigation , a notewCannabis has a known effect on appetite hormones ,45; neveOur study has several limitations. First, the observational nature of our study can only allow us to determine association and not causality. Second, the study was conducted as a before–after study without a control group. Third, not all participants used the same kind, same dose, and same composition of cannabis. Fourth, most of the patients in the study were treated with cannabis for pain, limiting generalizability for other common indications, such as malignancy.Medical cannabis in older adults can improve functional status and mood, as illustrated by better scores in IADL and GDS after six months of treatment. In addition, it is perceived as contributing to the general condition and reduces pain and the use of analgesics, including opioids. It is essential to gather additional evidence-based data, including data from double-blind randomized controlled trials, for this specific population.