Male Births Research Articles

Trends of Sex Ratio at Birth and its Association with Sociodemographic Factors Among Asian American Subgroups in the US from 2016 to 2021

Background Concerns about stigmatization and barriers to access to reproductive health among Asian American women have been raised. Methods To explore the characteristics of associated factors of non-natural sex ratio at birth (SRB), we analyzed the National Vital Statistics System Natality Data from 2016 to 2021 (N=1,668,875). We defined Asian Americans as people with ancestors from Asia, including Asian Indian, Chinese, Filipino, Vietnamese, Korean, and Japanese. Additionally, we stratified data according to the Asian-American subgroup. Per each group, we estimated changes in the male-to-female SRB over time. We performed logistic regression for male birth, adjusting for birth order and sociodemographic factors. Results Most Asian-American subgroups demonstrated SRBs within natural ranges for the first and second child, whereas, from the third child, SRBs skewed and differed by Asian-Americans. For respective Asian countries with skewed SRBs, Asian-American subgroups had lower SRBs than those. After adjustments, the third child had 8.0% greater odds (for male birth in the ratio scale) than the first in Asian Indians (95% CI 5.7, 10.4) and 6.9% greater odds in Chinese (95% CI 4.4, 9.5). Foreign-born mothers had 3.6% greater odds than U.S.-borns in Asian Indians (95% CI 2.0, 5.2) and 5.2% greater odds in Chinese (95% CI 3.5-6.9). Among the Filipinos, mothers with high school degrees had 2.2% lower odds than mothers with college degrees (95% CI 0.2, 4.1), while Japanese mothers with lower education categories had greater odds. Unmarried Asian Indians had 2.9% decreased odds than married (95% CI 0.0, 5.7), and unmarried Koreans showed 5.6% increased odds (95% CI 0.6, 10.9). Discussion We found differential associations of SRB with sociodemographic factors and birth order by subgroup. Conclusion Future demographic analyses of SRBs must disaggregate Asian populations into subgroups. Policy actions need to consider the specific backgrounds of different Asian-American subgroups while empowering women in all Asian-American communities.

Emerging concepts in male contraception: a narrative review of novel, hormonal and non-hormonal options.

Access to reliable contraception is a pillar of modern society. The burden of unintended pregnancy has fallen disproportionately on the mother throughout human history; however, recent legal developments surrounding abortion have sparked a renewed interest in male factor contraceptives beyond surgical sterilization and condoms. Modern efforts to develop reversible male birth control date back nearly a century and initially focused on altering the hypothalamic-pituitary-testes axis. These hormonal contraceptives faced multiple barriers, including systemic side effects, challenging dosing regimens, unfavorable routes of delivery, and the public stigma surrounding steroid use. Novel hormonal agents are seeking to overcome these barriers by limiting the side effects and simplifying use. Non-hormonal contraceptives are agents that target various stages of spermatogenesis; such as inhibitors of retinoic acid, Sertoli cell-germ cell interactions, sperm ion channels, and other small molecular targets. The identification of reproductive tract-specific genes associated with male infertility has led to more targeted drug development, made possible by advances in CRISPR and proteolysis targeting chimeras (PROTACs). Despite multiple human trials, no male birth control agents have garnered regulatory approval in the United States or abroad. This narrative review examines current and emerging male contraceptives, including hormonal and non-hormonal agents.

Neonatal Posterior Urethral Valves as a cause of Acute Abdominal Distention

Introduction: An 18-day-old term, male presented to the emergency department (ED) for 1-2 days of progressive abdominal distention. Case Report: Over the past week the infant had been spitting more, but it was non-bilious and non-projectile. He had no fevers. On examination, he was ill appearing with a distended abdomen. A flat-plate of his abdomen was obtained that was concerning for possible partial small bowel obstruction, which led to extensive imaging with an upper and lower gastro-intestinal contrast studies that were negative. Ultimately, an ultrasound was performed that revealed marked bladder distention with hydronephrosis. A urinary catheter was placed to relieve his bladder obstruction. Avoiding cystourethrogram confirmed a diagnosis of posterior urethral valves. Conclusion: Posterior urethral valves (PUVs) as a cause of abdominal distention in the neonate is a rare presentation. PUVs have an incidence of 1/4000 male births; of which 1/3rd are detected in-utero, 1/3rd in the first year of life. Most infants with PUVs will present with a urinary tract infection, others present with failure to thrive, poor urine stream and or grunting while urinating. The neonate with acute abdominal distention warrants a thorough and expedited evaluation for possible acute surgical etiologies, such as midgut volvulus due to malrotation. Early identification of bladder obstruction by point of care ultrasound would have helped focus the evaluation and lead to earlier relief of his bladder obstruction. PUVs should be considered on all male infants with urinary tract infection, failure to thrive, poor urinary stream or abdominal distention.

Changes in hippocampal volume during a preceding 10-year period do not correlate with cognitive performance and hippocampal blood‒brain barrier permeability in cognitively normal late-middle-aged men

Hippocampal blood–brain barrier (BBB) permeability may increase in normal healthy ageing and contribute to neurodegenerative disease. To examine this hypothesis, we investigated the correlation between blood–brain barrier (BBB) permeability, regional brain volume, memory functions and health and lifestyle factors in The Metropolit 1953 Danish Male Birth Cohort. We used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a gadolinium-based contrast agent to assess BBB permeability in 77 participants in the cohort. BBB permeability was measured as Ki values in the hippocampus, thalamus and white matter. Over a 10-year period, we observed progressive atrophy of both the left and right hippocampus (p = 0.001). There was no significant correlation between current BBB permeability and hippocampal volume, prior atrophy or cognition. The hippocampus volume ratio was associated with better visual and verbal memory scores (p < 0.01). Regional BBB differences revealed higher Ki values in the hippocampus and white matter than in the thalamus (p < 0.001). Participants diagnosed with type II diabetes had significantly higher BBB permeability in the white matter (p = 0.015) and thalamus (p = 0.016), which was associated with a higher Fazekas score (p = 0.024). We do not find evidence that BBB integrity is correlated with age-related hippocampal atrophy or cognitive functions. The association between diabetes, white matter hyperintensities and increased BBB permeability is consistent with the idea that cerebrovascular disease compromises BBB integrity. Our findings suggest that the hippocampus is particularly prone to age-related atrophy, which may explain some of the cognitive changes that accompany older age, but this prior atrophy is not correlated with current BBB permeability.

An increase in the developmental tempo affects the secular trend in height in male Austrian conscripts birth cohorts 1951-2002.

Using population-based data on height in Austria from birth cohort 1951 to 2002, we aim to evaluate the secular trends in height and developmental tempo among Austrian young men. Data were obtained from the Austrian conscription medical examination. We included 1 205 112 conscripts (18-<20 years) who were born between 1951 and 2002 and 853 645 conscripts (17-<19 years) who were born between 1961 and 2002. Height was measured during the medical examination and was used to evaluate the secular trends of mean height over time. Furthermore, the mean difference in height between conscripts of 17- and 18 years old were compared across birth cohorts. The mean height of conscripts aged 17 years increased by 2.2cm (p< .0001) in between 1961 and 2002. The mean height of conscripts aged 18 years increased by 4.3cm (p< .0001) between 1951 and 2002. However, the increase in mean height has slowed down since the 1970 s. The difference in mean height between 17 and 18 years old widened from about 0.1cm in 1961 to 0.3cm around 1970 and then steadily narrowed again to 0.1cm at the end of the study period. The increasing trend in height slows at the end of the 20th century, the developmental tempo at the population level, however, continued to increase. The difference in mean height between 17 and 18 years old narrowed, which may indicate that young men reached their final height earlier.

Severe cyclones and sex-specific birth outcomes in Queensland, Australia: An interrupted time-series analysis.

A male is less adaptable to biological stressors than a female fetus with consequent higher morbidity and mortality. Adverse birth outcomes increase and male livebirths decrease after environmental disasters, economic crises, and terrorist events. We hypothesized the ratio of male to female livebirths would decrease in areas affected by severe tropical cyclones (TCs) in Queensland, Australia. Additionally, in male livebirths, there would be an increase in preterm and low birthweight births. Lastly, we hypothesized that the pregnancy stage at which exposure occurred would modify the association between TC exposure and observed outcomes. Interrupted time series analysis was used to analyze Queensland administrative birth records from July 2007 to June 2018 for significant changes in the sex ratio at birth, measured as the proportion of male livebirths. Adjusted generalized linear models were fitted to births in areas affected by two category five TCs: cyclones Yasi (February 2011) and Marcia (February 2015). To explore male mortality and morbidity risk, additional analysis was conducted on the proportion of male stillborn, low birthweight, and preterm births. The association between estimated pregnancy stage during the TC and the proportion of male births was also analyzed. Contrary to our hypothesis, increases in the proportion of male livebirths were observed following early-pregnancy exposure to cyclone Yasi and mid-pregnancy exposure to Marcia, although the latter was not statistically significant. No significant changes were observed in proportions of male stillborn, low birthweight, and preterm births. This study found a significant association between severe TCs and sex ratio at birth. The stage of pregnancy at which maternal stressors were experienced modified this association. Among people exposed in early to mid-pregnancy, the proportion of male births was higher. This may be because of differential loss of females in utero. Studying sex differences in birth outcomes provides insight into in utero vulnerabilities associated with environmental stressors. Climate change is increasing the intensity and frequency of natural disasters. Understanding fetal vulnerability to environmental stressors will provide crucial information supporting early life health interventions that mitigate the immediate and long-term effects.

Autologous bone marrow-derived MSCs engineered to express oFVIII-FLAG engraft in adult sheep and produce an effective increase in plasma FVIII levels.

Hemophilia A (HA) is the most common X-linked bleeding disorder, occurring in 1 in 5,000 live male births and affecting >1 million individuals worldwide. Although advances in protein-based HA therapeutics have improved health outcomes, current standard-of-care requires infusion 2-3 times per week for life, and 30% of patients develop inhibitors, significantly increasing morbidity and mortality. There are thus unmet medical needs requiring novel approaches to treat HA. We tested, in a highly translational large animal (sheep) model, whether the unique immunological and biological properties of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) could enable them to serve as cellular delivery vehicles to provide long-term expression of FVIII, avoiding the need for frequent infusions. We show that autologous BM-MSCs can be isolated, transduced with a lentivector to produce high levels of ovine (o)FVIII, extensively expanded, and transplanted into adult animals safely. The transplanted cells engraft in multiple organs, and they stably produce and secrete sufficient quantities of FVIII to yield elevated plasma FVIII levels for at least 15 weeks. These studies thus highlight the promise of cellular-based gene delivery approaches for treating HA.

Loss of WNT4 in the gubernaculum causes unilateral cryptorchidism and fertility defects.

Undescended testis (UDT) affects 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. To improve our understanding of the etiology of infertility in UDT, we generated a novel murine model of left unilateral UDT. Gubernaculum-specific Wnt4 knockout (KO) mice (Wnt4-cKO) were generated using retinoic acid receptor β2-cre mice and were found to have a smaller left-unilateral UDT. Wnt4-cKO mice with abdominal UDT had an increase in serum follicle-stimulating hormone and luteinizing hormone and an absence of germ cells in the undescended testicle. Wnt4-cKO mice with inguinal UDT had normal hormonal profiles, and 50% of these mice had no sperm in the left epididymis. Wnt4-cKO mice had fertility defects and produced 52% fewer litters and 78% fewer pups than control mice. Wnt4-cKO testes demonstrated increased expression of estrogen receptor α and SOX9, upregulation of female gonadal genes, and a decrease in male gonadal genes in both CDT and UDT. Several WNT4 variants were identified in boys with UDT. The presence of UDT and fertility defects in Wnt4-cKO mice highlights the crucial role of WNT4 in testicular development.

Duchenne muscular dystrophy: case series of rare inherited muscular disorder

Duchenne muscular dystrophy (DMD) is a rare muscular disorder caused by mutation of gene encoding dystrophin protein which required for maintaining muscle stability during contraction. DMD occurs in 1 in 5000 male live births and characterized by progressive muscular weakness associated with motor development delay, loss of independent ambulation, respiratory failure, and cardiomyopathy. We present a case series of 3 DMD patients who were diagnosed at Prof. dr. I.G.N.G. Ngoerah general hospital, Denpasar over a period of four years (2019-2022). Clinical manifestation of patients includes progressive weakness of lower extremities and difficulty to stand up from sitting position. Physical examination revealed pseudohypertrophy of calf, winged scapula, positive Gower’s sign, and waddling gait in all three cases. Supporting examination showed an increase of alanine transaminase and aspartate transaminase 5.6 times and 6.1 times the upper limit of normal, respectively. Definitive diagnosis of all patient was made based on immunohistochemistry staining which revealed an absent of dystrophin protein around muscle membrane.

Genome Editing of Factor IX Paralogs in Zebrafish Demonstrates Subfunctionalization of Procoagulant Function

Hemophilia is an inherited monogenic bleeding disorder affecting ~400,000 individuals worldwide, with 20% of cases due to deficiency of factor IX (FIX, hemophilia B), affecting 1 in 30,000 male births. Although there are many exciting new treatments for this disorder, there are still unknown features of FIX. This includes potential distribution from plasma to tissue, which may affect some therapies. The zebrafish is a unique model to study coagulation disorders due to its high fecundity, external development, and optical transparency, as well as a high degree of genetic and functional conservation with the mammalian hemostatic system. Due to an ancestral gene duplication event in zebrafish, 30-40% of the zebrafish genome is duplicated, including the FIX gene (f9), resulting in the paralogs f9a and f9b. Such paralogs may arise due to subfunctionalization of the ancestral gene, raising the possibility that this could identify roles for mammalian FIX that have not previously been discovered. Here we utilize CRISPR/Cas9 genome editing to produce large deletions in f9a and f9b using guide RNAs that delete the intervening regions between exons 2 and 8, uncovering evidence for subfunctionalization. Assessment of hemostasis in 3 day post fertilization (dpf) mutant larvae using laser-mediated endothelial injury unexpectedly revealed that single and double f9a and f9b homozygous mutants exhibited normal thrombus formation. Upon crossing these mutants into an antithrombin (at3) deficient background (which exhibits spontaneous venous thrombosis), loss of F9b (f9b-/-;at3-/- mutants) prevented intravascular thrombosis development. f9a-/-;at3-/- double mutants were indistinguishable from f9a+/+;at3-/- siblings, both showing spontaneous thrombosis. These results demonstrated subfunctionalization of F9 activities, which could be due to differential functions or tissue-specific expression. The latter was investigated using whole mount in situ hybridization in wild-type larvae, revealing that f9a and f9b are both expressed in the liver. To evaluate function, microinjection of zebrafish f9a and f9b cDNAs regulated by a ubiquitous promoter was performed in one-cell stage f9b-/-;at3-/- zebrafish embryos. Analysis at 3 dpf found that only F9b could restore spontaneous thrombosis, confirming functional differences between F9a and F9b. Alignment of human FIX to F9a and F9b indicated conservation of functional domain sequences (signal sequence, propeptide, Gla, Egf1, Egf2, activation peptide, and protease). These domains were individually swapped between the f9a and f9b plasmids. Except for Egf1, all individual domains of F9a exchanged into F9b were able to restore thrombus formation in f9b-/-;at3-/- mutants. Replacement of F9b Egf1 with a F9aQ59G modified Egf1 domain (F9b has a glycine at this orthologous position), resulted in normal function. In summary, these data show clear evidence for subfunctionalization of F9 in zebrafish larvae, with F9b retaining procoagulant function. F9a possesses an active protease domain, but variation in Egf1 prevents it from contributing to canonical circulating FIX activity. We hypothesize that the alternative role for F9a might represent a previously unknown activity or tissue localization of human FIX. This putative role would also be deficient in hemophilia B patients and/or may be lacking in current therapies. An additional possibility is that this represents another means for regulation of FIX. In both cases, further study could lead to novel therapeutic ideas for patients with hemophilia B.

Selection in utero against male twins in the United States early in the COVID-19 pandemic.

We aim to contribute to the literature reporting tests of selection in utero. The theory of reproductive suppression predicts that natural selection would conserve mechanisms, referred to collectively as selection in utero, that spontaneously abort fetuses unlikely to thrive as infants in the prevailing environment. Tests of this prediction include reports that women give birth to fewer than expected male twins, historically among the frailest of infants, during stressful times. The onset of the COVID-19 pandemic in the United States in Spring 2020 demonstrably stressed the population. We test the hypothesis that conception cohorts in gestation at the onset of the pandemic in the United States yielded fewer than expected live male twin births. We retrieved deidentified data on the universe of live births in the United States from the National Center for Health Statistics birth certificate records. We applied Box-Jenkins time-series methods to the twin secondary sex ratio computed for 77 monthly conception cohorts spanning August 2013 to December 2019 to detect outlying cohorts in gestation at the onset of the pandemic. The twin secondary sex ratio fell below expected values in three conception cohorts (i.e., July, September, and October 2019, all p< .05) exposed in utero to the onset of the pandemic. Our results add to prior findings consistent with selection in utero. The role of selection in utero in shaping the characteristics of live births cohorts, especially during the COVID-19 pandemic, warrants further scrutiny.

OR05-3 Utility of Genomic work-up for 46XY Disorder of Sex Development Patients with Severe Hypospadias

Abstract Background Hypospadias is a common human congenital anomaly occurring in ∼1: 200 to 1: 300 live male births in the USA, with an unexplained doubling in incidence over previous decades. Historically, 46XY Differences of Sex Development (DSD) patients, with severe hypospadias have lacked a genetic diagnosis. With the advent of commercially available DSD genomic panels, this is now changing (GeneDX. Neonatal 46 2021, In-vitae 2021). The goal of this study is to review the anatomical characteristics of severe hypospadias that can accurately define patients that have 46XY DSD and to determine the practical utility of performing a genomic workup in these rare 46XY DSD patients with severe hypospadias.Patients: 14 patients seen in disorders of sexual development clinic between 2018–2020 with severe hypospadias defined by an ectopic urethral meatus typically in the scrotum or perineum, an abnormally small glans penis size (&amp;lt;14 mm at maximal width in the first year of life), severe curvature and associated foreskin fusion or penoscrotal transposition were enrolled in the study. Methods Patients who met the criteria for 46XY disorder of sexual development and severe hypospadias were offered a genomic work-up in consultation with pediatric genetics. Patients were identified through chart review. Data extracted included karyotype, hypospadias phenotype including stretched penile length at diagnosis, age at genetic diagnosis/genomic workup, gene defect/ pathologic variant, gender identity, and clinical course.Main Outcome Measurements: The main outcome measured was the presence of a genetic mutation that can be linked to the disorder of sexual development. Secondary outcomes measured included gender identity, clinical course, and histological findings if a biopsy was obtained. Results Of the 14 patients that underwent genomic analysis, 8 had documented pathologic variants known to cause hypospadias. Pathologic genetic variants include defects in the AR (3), SRD5A2 (1), NR5A1 (2), WT1 (1), and ARTX (1). Five had no evidence of pathologic variants based on the Invitae and GeneDx commercial 46XY DSD panel (see Table 2 for genes tested). One had a genetic variant of unknown significance, FREM2. The patient with WT1 was consequently found to have a Wilms tumor and the patients with SRD5A2 are now undergoing adrenal insufficiency surveillance after their genetic testing. Conclusions Patients with 46XY DSD and severe hypospadias can benefit from genetic evaluation as their underlying disorders may unveil mutations that could have potentially life-altering consequences and change surveillance and monitoring. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.

OR25-2 RBFOX2 Copy Number Variation Disrupts Urethral Development Causing Hypospadias

Abstract Despite the frequency of hypospadias (1: 125 live male births) often the etiology is not known. The Lamb Laboratory previously determined that RNA Binding Fox-1 Homolog 2 (RBFOX2) copy number variation (CNV) is associated with clinical cases of upper and lower tract genitourinary (GU) anomalies, including hypospadias. RBFOX2 encodes a RNA binding protein that regulates mRNA splicing. The hypothesis was tested that altered RBFOX2 gene dosage impacts the developing penis transcriptome via mRNA splicing, specifically the mesenchymal to epithelial transition critical for penile urethra formation, resulting in hypospadias.Searches, in publically available and local clinical databases, centered on hypospadias occurance with gene CNV: identified the RBFOX2 locus as a gene dosage sensitve region. To identify developmental pathways regulated by RBFOX2 in the GU system, Rbfox2 haploinsufficient and null mouse models were developed, and penises were collected for RNA-seq, in situ hybridization, and micro-CT analysis of urethral development. In situ hybridization together with re-analysis of published scRNA-seq datasets were employed to define the anatomical regions of Rbfox2-specific expression in the developing mouse penis [Amato &amp; Yao, PNAS 118(25): e2103856118, 2021; Armfield &amp; Cohn, Dev Biol 477: 145-154.2021].Publicly available clinical data identified 17 patients (0.068% n=24,896) with pathogenic RBFOX2 CNVs: 4 were noted to have hypospadias. Results from our cohort of non-syndromic GU birth defect patient samples identified 11 patients (2.4% n=450) with RBFOX2 CNVs: 21% of whom have hypospadias. RNA immunoprecipitation agianst RBFOX2 in human kidney cells validated mRNA transcipt targets previously identified in cardiac cells [Verma 2016]. Micro-CT analysis on fetal Rbfox2-haploinsufficient mice validated the modeled clinical phenotype. Combined in situhybridization and scRNA-seq spatial analysis on mouse samples revealed, after penile sex determination (E15.5), Rbfox2 expression becomes restricted to the penile urethral mesenchyme. Differential gene expression and transcript usage analysis on the Rbfox2-loss mouse penis transcriptome identified mis-expression of gene products associated the estrogen signalling pathway.Alterations in RBFOX2 gene dosage clinically correlate with upper and lower tract genitourinary anomalies, specifically hypospadias. Data from human cell lines and mouse models seemingly indicate the phenotype seems is partially the product of an RBFOX2 role in directing the mesenchymal to epithelial transition. Specifically our data support the a direct role of RBFOX2 in balancing the competing male and female pathways at the level of estrogen and androgen signaling pathways. We are currently using immunofluorescence experiments to define the changes in androgen-receptor, estrogen-receptor, and RBFOX2 patterning throughout perinatal penis development. Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.

The influence of childhood aspirations on the risk of developing psychotic disorders, substance use disorders, and dual diagnosis in adulthood based on the Metropolit 1953 Danish Male Birth Cohort.

Thestudy aims to investigate the association of aspiration for future occupation, socioeconomic position, and intellectual abilities with risk of dual diagnosis, psychosis, substance use disorder (SUD) in later life, and to explore if social and intellectual disadvantage modify any effect of childhood aspirations on outcomes. The study included 7177 Danish boys born in 1953. We investigated childhood aspirations (preference regarding future occupation), socioeconomic position (paternal social group), and intellectual abilities (Härnquist intelligence score) on outcomes with dual diagnosis, psychotic disorder, or SUD in Danish registers. Combinations of variables were used for a two-way and three-way analysis (high and low levels of exposure variables). Cox regression with age as the underlying time scale was used for analysis. The separate analysis showed no associations between childhood aspirations and outcomes. Boys with low intelligence scores had an increased risk of developing psychotic disorders (aHR 1.5, 95% CI 1.1-2.1) and SUD (aHR 1.8, 95% CI 1.5-2.1) compared to high intelligence scores. The interaction analyses showed that individuals with a combination of low intelligence score, high aspirations, and/or high paternal social group might have an increased risk of developing dual diagnosis, psychotic disorders, or SUD in later life. This result should be interpreted with caution as interaction variables were not overall significant with the outcome of dual diagnosis or psychotic disorder. The findings suggest that childhood abilities and social position could be associated with the development of psychotic disorders and SUD in later life, however, further studies are needed to address the temporality of the association to gain an understanding of the underlying mechanism of the association.

The state of health in Indonesia's provinces, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

SummaryBackgroundAnalysing trends and levels of the burden of disease at the national level can mask inequalities in health-related progress in lower administrative units such as provinces and districts. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to analyse health patterns in Indonesia at the provincial level between 1990 and 2019. Long-term analyses of disease burden provide insights on Indonesia's advance to universal health coverage and its ability to meet the United Nations Sustainable Development Goals by 2030.MethodsWe analysed GBD 2019 estimated cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), life expectancy at birth, healthy life expectancy, and risk factors for 286 causes of death, 369 causes of non-fatal health loss, and 87 risk factors by year, age, and sex for Indonesia and its 34 provinces from 1990 to 2019. To generate estimates for Indonesia at the national level, we used 138 location-years of data to estimate Indonesia-specific demographic indicators, 317 location-years of data for Indonesia-specific causes of death, 689 location-years of data for Indonesia-specific non-fatal outcomes, 250 location-years of data for Indonesia-specific risk factors, and 1641 location-years of data for Indonesia-specific covariates. For subnational estimates, we used the following source counts: 138 location-years of data to estimate Indonesia-specific demographic indicators; 5848 location-years of data for Indonesia-specific causes of death; 1534 location-years of data for Indonesia-specific non-fatal outcomes; 650 location-years of data for Indonesia-specific risk factors; and 16 016 location-years of data for Indonesia-specific covariates. We generated our GBD 2019 estimates for Indonesia by including 1 915 207 total source metadata rows, and we used 821 total citations.FindingsLife expectancy for males across Indonesia increased from 62·5 years (95% uncertainty interval 61·3–63·7) to 69·4 years (67·2–71·6) between 1990 and 2019, a positive change of 6·9 years. For females during the same period, life expectancy increased from 65·7 years (64·5–66·8) to 73·5 years (71·6–75·6), an increase of 7·8 years. There were large disparities in health outcomes among provinces. In 2019, Bali had the highest life expectancy at birth for males (74·4 years, 70·90–77·9) and North Kalimantan had the highest life expectancy at birth for females (77·7 years, 74·7–81·2), whereas Papua had the lowest life expectancy at birth for males (64·5 years, 60·9–68·2) and North Maluku had the lowest life expectancy at birth for females (64·0 years, 60·7–67·3). The difference in life expectancy for males between the highest-ranked and lowest-ranked provinces was 9·9 years and the difference in life expectacy for females between the highest-ranked and lowest-ranked provinces was 13·7 years. Age-standardised death, YLL, and YLD rates also varied widely among the provinces in 2019. High systolic blood pressure, tobacco, dietary risks, high fasting plasma glucose, and high BMI were the five leading risks contributing to health loss measured as DALYs in 2019.InterpretationOur findings highlight that Indonesia faces a double burden of communicable and non-communicable diseases that varies across provinces. From 1990 to 2019, Indonesia witnessed a decline in the infectious disease burden, although communicable diseases such as tuberculosis, diarrhoeal diseases, and lower respiratory infections have remained a main source of DALYs in Indonesia. During that same period, however, all-ages death and disability rates from non-communicable diseases and exposure to their risk factors accounted for larger shares of health loss. The differences in health outcomes between the highest-performing and lowest-performing provinces have also widened since 1990. Our findings support a comprehensive process to revisit current health policies, examine the root causes of variation in the burden of disease among provinces, and strengthen programmes and policies aimed at reducing disparities across the country.FundingThe Bill & Melinda Gates Foundation and the Government of Indonesia.TranslationFor the Bahasa Indonesia translation of the abstract see Supplementary Materials section.

A Holistic Approach on Duchenne Muscular Dystrophy by Ayurvedic Treatment Modalities along with Traction: A Case Report

Background &amp; Objectives- Duchenne muscular dystrophy (DMD) is individual and one of the most communal and serious condition come under childhood muscular dystrophies. The incidence of DMD is 1:3500 births of males. It is an X-linked recessive disorder that occurs due to deletion or alteration of dystrophin protein, which is encoded by DMD Gene on Xp21 chromosome. As per the view of Ayurveda, we can consider this disorder as chromosomal hereditary anomalies (Bheejabhagahaavyava dushti janya Adibalapravtrutta vyadhi). Main objective of this case report was reduce the complaints of patient and improve the quality of life. Method and Material- The present study is about the management of DMD as per Ayurveda perspective. An 11 years old male child, has complaints of difficulty in walking, frequent falls while walking, difficulty in sitting or squatting. On Ayurvedic management principles, the present case was managed with palliative care (Shaman) and bio-cleansing therapy (ShodhanChiktsa). Result- After treatment, there was a significant improvement in complaints with signs and symptoms. Interpretation and conclusion- Though we are unable to rule out the disposition of genes through Ayurveda treatment modalities such as internal medicines, 5 detoxification procedures (Panchakarma) procedures, traction etc. we can effectively prolong the deterioration and improve the quality of life with correction in diet and lifestyle as per Ayurveda principles.

P.04 New developments and data highlights in the international myotubular and centronuclear myopathy patient registry

The centronuclear myopathies are congenital neuromuscular conditions characterised by the central location of the nucleus in muscle cells and a highly variable clinical picture. The presumably most common form is the ultra-rare X-linked myotubular myopathy (XLMTM) with an estimated incidence of 1 in 50,000-100,000 male births and a usually severe phenotype. The myotubular and centronuclear myopathy patient registry has been collecting demographic, genetic and longitudinal clinical data on affected individuals (living and deceased) and female carriers of XLMTM from all over the world, since 2013. It facilitates translational research by providing data to answer research questions or inform clinical trial feasibility studies, supporting recruitment into clinical trials and other research studies, and offering an important communication and engagement tool for this patient population. Patients and caregivers provide longitudinal data via recurring online questionnaires available in multiple languages. New developments for 2022 include the addition of 2 new languages, increased frequency of data collection, and a feature allowing participants to nominate their doctor to verify their diagnosis and contribute clinical data to their record. This poster will present the impact of the new developments and highlight the latest registry data. On 28-03-2022 the registry contained 404 participants (258 male and 146 female), of which 42 were reported as deceased (39 male and 3 female) and 362 living (219 male and 143 female). Of the 143 living females, 74 were registered as female carriers of XLMTM and 69 as patients. 52 countries are represented, with the largest cohorts being UK & Ireland (105), United States (101), and Germany (34). Causative genes reported include <i>MTM1, DNM2, BIN1, RYR1, TTN</i>, and <i>SPEG</i>. The myotubular and centronuclear myopathy patient registry contains important data on a diverse and growing international cohort of individuals affected by this group of rare and ultra-rare conditions. It aims to support all areas of translational research including epidemiology, clinical trial planning and recruitment, outcome measure development, standards of care, and real-world data for regulatory decision-making.

Risk factors of deficit and non-deficit schizophrenia: Results from a cross-sectional study

AimIt has been observed that deficit and non-deficit schizophrenia (SCZ-D and SCZ-ND) might be characterized by different risk factors. Therefore, the present study aimed to assess as to whether previously reported risk factors of schizophrenia are specifically associated with SCZ-D and SCZ-ND. MethodThis study was based on a cohort of 118 stable outpatients with schizophrenia. A diagnosis of SCZ-D was established using the Schedule for the Deficit Syndrome (SDS). Risk factors were recorded using structured interview, the Operational Criteria for Psychotic Illness (OPCRIT) checklist and the Traumatic Experience Checklist (TEC). The following risk factors were explored: male sex, a history of schizophrenia in first-degree relatives, seasonality of birth, birth weight <3000g, delivery by cesarean section, a history of childhood trauma (emotional abuse, emotional neglect, physical abuse and sexual abuse) as well as substance abuse (other than nicotine) and cigarette smoking at psychosis onset. ResultsIndividuals with SCZ-D were more likely to be males as well as reported higher rates of birth weight <3000g and any categories of childhood trauma. In turn, substance abuse (other than nicotine) at psychosis onset was significantly more frequent in patients with SCZ-ND. Binary logistic regression, controlling for multiple comparisons, revealed similar findings, except for the association with any categories of childhood trauma that appeared to be not significant. ConclusionOur findings partially replicate differential patterns of risk factors for SCZ-D (male sex and birth weight <3000g) and SCZ-ND (substance abuse at psychosis onset), likely attributable to the effects of timing of exposure.

COMPARISON OF SECONDARY SEX-RATIO BETWEEN BENCHTOP AND TIME-LAPSE INCUBATOR DOES FROZEN/THAWED TRANSFER CYCLE HAVE A BETTER SEX-RATIO?

More than 10 million infants have been born worldwide using assisted reproduction technology in last three decades. The sex ratio at birth is also known as secondary sex ratio (SSR). According to WHO SSR ranges between 103-107 with an average of 105 male birth per 100 females, an increase in SSR has been reported in assisted reproduction (ART). Few studies suggested that different IVF laboratory procedures (transfer stage, cryopreservation, culture media, incubation conditions, standard IVF or ICSI etc.) can lead to biased SSR.

Genome-wide association study in patients with posterior urethral valves.

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.