Prevalence and risk factors associated with diabetes mellitus among middle-aged women in southern Brazil: a population-based study.

OBJECTIVES: To investigate prevalence and clinical factors associated with diabetes among middle-aged women. METHODS: In this cross-sectional population-based study, clinical and laboratory examinations were collected from 298 women. Participants wore a digital pedometer for 7 days to assess habitual physical activity. Abdominal computed tomography scans were performed to measure total fat area and visceral fat area. RESULTS: Mean age was 57.1 years (SD, 5.4 y); 78.7% of women were postmenopausal. The prevalence of diabetes was 17.1%. Women with diabetes were older (P = 0.02); worked fewer hours per week in the past month (P = 0.04); had an earlier age at menarche (P = 0.03); were more frequently inactive (P = 0.01); had higher body mass index (P = 0.01), higher waist circumference (P < 0.01), higher visceral (P < 0.01), and higher total fat (P < 0.01) but not subcutaneous fat (P = 0.14); and had higher systolic blood pressure (BP) (P < 0.01). There was a prevalence of 19.5% of current smoking, 32.5% of alcohol use, and 16.1% of current hormone therapy use, prevalence similar among the groups of women. There was a higher prevalence of metabolic syndrome (P < 0.01) and statin use (P < 0.01) in women with diabetes. A higher prevalence ratio of diabetes was associated with physical inactivity (prevalence ratio, 2.137; 95% CI, 1.056-4.325; P < 0.03). The odds of having diabetes increased by 12% for each year of earlier menarche and by 1.4% for each millimeter of mercury increase in systolic BP. CONCLUSION: The prevalence of diabetes was 17.1%. Age, physical inactivity, early age at menarche, and systolic BP were independently associated with higher prevalence of diabetes in this unselected population of middle-aged women.

Effects of different insulin sensitisers in the management of polycystic ovary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. CONCLUSIONS: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

Potassium levels in women with polycystic ovary syndrome using spironolactone for long-term.

OBJECTIVE: Spironolactone (SPL) has been used to manage hyperandrogenic manifestations in women with polycystic ovary syndrome (PCOS), but data on the risk of hyperkalemia in this population are scarce. The aim of this study was to evaluate the incidence of hyperkalemia in women with PCOS using SPL in the long term. DESIGN: Single-centre retrospective study. PATIENTS: Inclusion and analysis of 98 treatment periods in 78 women with PCOS (20 of whom were duplicates, returning after treatment interruption for a mean of 38 months) who received SPL for a minimum of 12 months and had at least three measurements of potassium levels over time. MEASUREMENTS: Clinical and hormonal profiles before and during SPL treatment. RESULTS: Mean age was 29.1 (SD: 9.6) years, and body mass index was 32.2 (SD: 8.1) kg/m². Nine patients had diabetes, and 22 had prediabetes. SPL was used in combination with combined oral contraceptive pills in 55 participants and progestin-only pills/long-acting reversible contraception in 28; metformin was added in 35, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 15. Median SPL dose was 100 (range: 50-150) mg. A total of 327 serum potassium measurements were obtained (84 pre-exposure and 243 postexposure). Four potassium measurements were above the reference range before exposure and 19 during exposure. All potassium measurements above the reference range during follow-up were classified as mild hyperkalemia (5.1-5.5 mEq/L). CONCLUSIONS: The present findings suggest that women with PCOS, without kidney or heart disease, using SPL combined with hormonal contraception for managing clinical hyperandrogenism have a low incidence of hyperkalemia and well-tolerated minor adverse effects.

[Intraocular pressure elevation and intravitreal steroid implant injection: State of the art in 2023. Recommendations of the French Glaucoma Society and French Ophthalmology Society [French version]]. / Hypertonie oculaire et injection intravitréenne d'implant de corticoïde, état de l'art en 2023. Recommandations françaises SFG/SFO [version française].

These are the recommendations of French glaucoma and retina experts on the management of ocular hypertension (OHT) observed in 1/3 of cases after intravitreal steroid implant injections. They are an update to the recommendations first published in 2017. There are two implants on the French market: the dexamethasone (DEXi) and fluocinolone acetonide (FAci) implants. It is important to know the pressure status before injecting a patient with a steroid implant. Monitoring of the IOP adapted to the specific drug is necessary throughout follow-up and reinjections. Real-life studies have made it possible to optimize the management algorithm by significantly increasing the safety of use of these implants. A corticosteroid test with DEXi is necessary before switching to FAci to optimize the pressure tolerance of the latter. In addition to topical glaucoma medications, SLT laser can be considered in the therapeutic arsenal for the management of steroid-induced OHT and future injections.

Ocular hypertension and intravitreal steroids injections, update in 2023. French guidelines of the French glaucoma society and the French ophthalmology society.

These guidelines are a consensus of French glaucoma and retina experts on the management of ocular hypertension (OHT) observed in a third of the cases after corticosteroid implant intravitreal injections. They update the first guidelines published in 2017. Two implants are marketed in France: the dexamethasone implant (DEXi) and the fluocinolone acetonide implant (FAci). It is essential to assess the pressure status before injecting a patient with a corticosteroid implant. A molecule-specific monitoring of the intraocular pressure is needed throughout the follow-up and at the time of reinjections. Real-life studies have allowed optimizing the management algorithm by significantly increasing the safety of these implants. Corticosteroid testing with DEXi should be performed before switching to FAci to optimize pressure tolerance of FAci. Beyond topical hypotensive treatments, selective laser trabeculoplasty may be considered in the therapeutic arsenal for the management of steroid-induced OHT and subsequent injections.

Improved clinical utility of preimplantation genetic testing through the integration of ploidy and common pathogenic microdeletions analyses.

STUDY QUESTION: Can chromosomal abnormalities beyond copy-number aneuploidies (i.e. ploidy level and microdeletions (MDs)) be detected using a preimplantation genetic testing (PGT) platform? SUMMARY ANSWER: The proposed integrated approach accurately assesses ploidy level and the most common pathogenic microdeletions causative of genomic disorders, expanding the clinical utility of PGT. WHAT IS KNOWN ALREADY: Standard methodologies employed in preimplantation genetic testing for aneuploidy (PGT-A) identify chromosomal aneuploidies but cannot determine ploidy level nor the presence of recurrent pathogenic MDs responsible for genomic disorders. Transferring embryos carrying these abnormalities can result in miscarriage, molar pregnancy, and intellectual disabilities and developmental delay in offspring. The development of a testing strategy that integrates their assessment can resolve current limitations and add valuable information regarding the genetic constitution of embryos, which is not evaluated in PGT providing new level of clinical utility and valuable knowledge for further understanding of the genomic causes of implantation failure and early pregnancy loss. To the best of our knowledge, MDs have never been studied in preimplantation human embryos up to date. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis including blastocyst biopsies collected between February 2018 and November 2021 at multiple collaborating IVF clinics from prospective parents of European ancestry below the age of 45, using autologous gametes and undergoing ICSI for all oocytes. Ploidy level determination was validated using 164 embryonic samples of known ploidy status (147 diploids, 9 triploids, and 8 haploids). Detection of nine common MD syndromes (-4p=Wolf-Hirschhorn, -8q=Langer-Giedion, -1p=1p36 deletion, -22q=DiGeorge, -5p=Cri-du-Chat, -15q=Prader-Willi/Angelman, -11q=Jacobsen, -17p=Smith-Magenis) was developed and tested using 28 positive controls and 97 negative controls. Later, the methodology was blindly applied in the analysis of: (i) 100 two pronuclei (2PN)-derived blastocysts that were previously defined as uniformly euploid by standard PGT-A; (ii) 99 euploid embryos whose transfer resulted in pregnancy loss. PARTICIPANTS/MATERIALS, SETTING, METHODS: The methodology is based on targeted next-generation sequencing of selected polymorphisms across the genome and enriched within critical regions of included MD syndromes. Sequencing data (i.e. allelic frequencies) were analyzed by a probabilistic model which estimated the likelihood of ploidy level and MD presence, accounting for both sequencing noise and population genetics patterns (i.e. linkage disequilibrium, LD, correlations) observed in 2504 whole-genome sequencing data from the 1000 Genome Project database. Analysis of phased parental haplotypes obtained by single-nucleotide polymorphism (SNP)-array genotyping was performed to confirm the presence of MD. MAIN RESULTS AND THE ROLE OF CHANCE: In the analytical validation phase, this strategy showed extremely high accuracy both in ploidy classification (100%, CI: 98.1-100%) and in the identification of six out of eight MDs (99.2%, CI: 98.5-99.8%). To improve MD detection based on loss of heterozygosity (LOH), common haploblocks were analyzed based on haplotype frequency and LOH occurrence in a reference population, thus developing two further mathematical models. As a result, chr1p36 and chr4p16.3 regions were excluded from MD identification due to their poor reliability, whilst a clinical workflow which incorporated parental DNA information was developed to enhance the identification of MDs. During the clinical application phase, one case of triploidy was detected among 2PN-derived blastocysts (i) and one pathogenic MD (-22q11.21) was retrospectively identified among the biopsy specimens of transferred embryos that resulted in miscarriage (ii). For the latter case, family-based analysis revealed the same MD in different sibling embryos (n = 2/5) from non-carrier parents, suggesting the presence of germline mosaicism in the female partner. When embryos are selected for transfer based on their genetic constitution, this strategy can identify embryos with ploidy abnormalities and/or MDs beyond aneuploidies, with an estimated incidence of 1.5% (n = 3/202, 95% CI: 0.5-4.5%) among euploid embryos. LIMITATIONS, REASONS FOR CAUTION: Epidemiological studies will be required to accurately assess the incidence of ploidy alterations and MDs in preimplantation embryos and particularly in euploid miscarriages. Despite the high accuracy of the assay developed, the use of parental DNA to support diagnostic calling can further increase the precision of the assay. WIDER IMPLICATIONS OF THE FINDINGS: This novel assay significantly expands the clinical utility of PGT-A by integrating the most common pathogenic MDs (both de novo and inherited ones) responsible for genomic disorders, which are usually evaluated at a later stage through invasive prenatal testing. From a basic research standpoint, this approach will help to elucidate fundamental biological and clinical questions related to the genetics of implantation failure and pregnancy loss of otherwise euploid embryos. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. S.C., M.F., F.C., P.Z., I.P., L.G., C.P., M.P., D.B., J.J.-A., D.B.-J., J.M.-V., and C.R. are employees of Igenomix and C.S. is the head of the scientific board of Igenomix. A.C. and L.P. are employees of JUNO GENETICS. Igenomix and JUNO GENETICS are companies providing reproductive genetic services. TRIAL REGISTRATION NUMBER: N/A.

Estradiol Replacement as a Potential Enhancer of Working Memory and Neuroplasticity in Hypogonadal Trans Women.

INTRODUCTION: The cognitive effects of cross-sex hormone therapy (CSHT) are not well understood. In cisgender individuals, sex hormone therapy can impact neurotransmitter levels and structural anatomy. Similarly, in gender-diverse persons, CSHT has been associated with neural adaptations, such as growth in brain structures resembling those observed in cisgender individuals of the same sex. Hormone-related changes in learning and memory, as seen in menopause, are associated with physiological hypogonadism or a decline in hormones, such as estradiol. The present study examined the effect of estradiol administration in humans on glutamate concentration in brain regions involved in semantic and working memory (i.e., the dorsolateral prefrontal cortex [DLPFC], the posterior hippocampus, and the pregenual anterior cingulate cortex) and its relationship with memory. METHODS: Eighteen trans women (male biological sex assigned at birth) ceased CSHT for 30 days for a washout phase (t1) upon study enrollment to reach a hypogonadal state. Working and semantic memory, cognition, hormonal assays, and brain imaging were assessed. Participants resumed CSHT for 60 days for a replacement phase (t2), after which the same evaluations from t1 were repeated. RESULTS: Estradiol increased among trans women after 60 days of resumed CSHT with significant improvements in semantic memory compared to the hypogonadal phase. Working memory recall was significantly and positively correlated to glutamate in the DLPFC during the reinstatement phase, although the relationship was not moderated by levels of estradiol. DISCUSSION: These results may have clinical implications for the therapeutic effects of estradiol replacement, serving as a protective factor against cognitive decline and impairment for trans women post-gonadectomy.

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

Impact of vascular liver disease on the menstrual cycle and metabolic status in premenopausal women.

BACKGROUND: Vascular liver disease (VLD) are rare liver diseases, which affect women at reproductive ages. Main complications are bleeding (portal hypertension, thrombopenia or anticoagulation related) and thromboembolism. Failure of liver function can occur. Thus endocrine abnormalities management and contraception are challenging. PURPOSE: to evaluate the impact on the menstrual cycles and related endocrine abnormalities in women with VLD and respective roles of liver function and portal hypertension. STUDY DESIGN: This was a single-center observational cohort study. Forty-seven premenopausal women with vascular liver disease were included for endocrine and gynecological assessments. Endocrine evaluation was performed at inclusion. Tolerance of contraception was followed up and assessed at 3 and 12 months. PARTICIPANTS, SETTING, METHODS: Forty-seven women (aged 16-50) followed in a Reference Center for Liver Vascular Disease between February 2009 and November 2016 were included and addressed for gynecological and endocrinological management. Twenty-five women had extrahepatic portal vein obstruction, 17 had Budd Chiari Syndrome and five had a porto-sinusoidal vascular disease. We explored gonadotropin at baseline and after GnRH, testosterone, sex hormone binding globulin (SHBG), androstenedione, GH axis and glucose metabolism. All women underwent pelvic ultrasonography. RESULTS: Vascular liver disease was associated with abnormal menstrual cycles in 53% of the women and clinical and/or biological hyperandrogenism and/or a polycystic ovary morphology was identified in 38%. Portal hypertension was correlated to higher testosterone levels (P = 0.04), whereas higher elevated levels SHBG in 28%, correlated with liver failure (P = 0.01). Sixteen had glucose intolerance profile or diabetes. IGF-1 levels were highly correlated with hepatic failure. Abnormal uterine bleeding occurred in 21% of women, 87% of which were due to gynecological pathologies revealed by anticoagulant treatment. Progestin contraception was well tolerated and helped to control bleeding. CONCLUSION AND IMPLICATIONS: endocrine abnormalities, prior described in association with cirrhosis, are also identified in patients with vascular liver disease, and require specific management. Glucose intolerance profile is frequent, further studies are needed to assess significant consequences on cardio-vascular system.

Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population.

STUDY QUESTION: What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents? SUMMARY ANSWER: The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population. WHAT IS KNOWN ALREADY: About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds the potential to significantly improve couple's genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring. STUDY DESIGN, SIZE, DURATION: A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples. PARTICIPANTS/MATERIALS, SETTING, METHODS: A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby. LIMITATIONS, REASONS FOR CAUTION: The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations. WIDER IMPLICATIONS OF THE FINDINGS: These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. A.C., M.F., S.C., M.P., L.G., and C.P. are employees of Igenomix Italy. C.S. is the head of the scientific board of Igenomix. TRIAL REGISTRATION NUMBER: N/A.

HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.

Association of TNF rs668920841 and INRA111 polymorphisms with caprine brucellosis: A case-control study of candidate genes involved in innate immunity.

Caprine brucellosis is an infectious, contagious zoonotic disease caused by Brucella melitensis. Multiple factors, including host genetics, can influence the outcome of the exposure to Brucella; and it is expected that genetic variants that affect the host innate immune response could have a key role in Brucella infection and pathogenesis. In this study, we evaluated if polymorphisms in innate immunity-related genes are associated with results of Brucella infection in goats. Nine polymorphisms within interferon gamma (IFNG), tumor necrosis factor (TNF), MyD88 innate immune signal transduction adaptor (MYD88), interleukin 10 (IL10) and IL-10 receptor subunit alpha (IL10RA) genes and two molecular markers (BMS2753 and INRA111) were resolved by PCR-capillary electrophoresis in samples from 81 seronegative and 61 seropositive goats for brucellosis. A heterozygous genotype at INRA111, a microsatellite near the VRK serine/threonine kinase 2 (VRK2) gene, was associated with absence of Brucella-specific antibodies in goats naturally exposed to the pathogen (P = .004). Conversely, variants in the TNF gene (rs668920841) and near the IFN gamma receptor 1 (IFNGR1) gene (microsatellite BMS2753) were significantly associated with presence of Brucella-specific antibodies at allelic (P = .042 and P = .046) and genotypic level (P = .012 and P = .041, respectively). Moreover, an in silico analysis predicted a functional role of the insertion-deletion polymorphism rs668920841 on the transcriptional regulation of the caprine TNF gene. Altogether, these results contribute to the identification of genetic factors that have a putative effect on the resistance / susceptibility phenotype of goats to Brucella infection.

The Link between Estradiol and Neuroplasticity in Transgender Women after Gender-Affirming Surgery: A Bimodal Hypothesis.

For transgender individuals, gender-affirming surgery (GAS) and cross-sex hormone therapy (CSHT) are part of the gender transition process. Scientific evidence supporting the maintenance of CSHT after GAS-related gonadectomy is accumulating. However, few data are available on the impact of CSHT on the brain structure following hypogonadism. Thus, we aimed to investigate links between estradiol and brain cortical thickness (CTh) and cognition in 18 post-gonadectomy transgender women using a longitudinal design. For this purpose, the participants underwent a voluntary period of CSHT washout of at least 30 days, followed by estradiol re-institution for 60 days. High-resolution T1-weighted brain images, hormonal measures, working and verbal memory were collected at 2 time points: on the last day of the washout (t1) and on the last day of the 2-month CSHT period (t2). Between these 2 time points, CTh increased within the left precentral gyrus and right precuneus but decreased within the right lateral occipital cortex. However, these findings did not survive corrections of multiple comparisons. Nevertheless, there was a significant negative correlation between changes in estradiol levels and changes in CTh. This effect was evident in the left superior frontal gyrus, the left middle temporal gyrus, the right precuneus, the right superior temporal gyrus, and the right pars opercularis. Although there was an improvement in verbal memory following hypogonadism correction, we did not observe a significant relationship between changes in memory scores and CTh. Altogether, these findings suggest that there is a link between estradiol and CTh.

Effects of Estradiol Therapy on Resting-State Functional Connectivity of Transgender Women After Gender-Affirming Related Gonadectomy.

An extreme incongruence between sex and gender identity leads individuals with gender dysphoria (GD) to seek cross-sex hormone therapy (CSHT), and gender-affirming surgery (GAS). Although few studies have investigated the effects of CSHT on the brain prior to GAS, no studies in the extant literature have evaluated its impact during hypogonadism in post-GAS individuals. Here, we aimed to evaluate the effects of estradiol on resting-state functional connectivity (rs-FC) of the sensorimotor cortex (SMC) and basal ganglia following surgical hypogonadism. Eighteen post-GAS (male-to-female) participants underwent functional magnetic resonance imaging (fMRI) and neuropsychiatric and hormonal assessment at two time points (t1, hormonal washout; t2, CSHT reintroduction). Based on the literature, the thalamus was selected as a seed, while the SMC and the dorsolateral striatum were targets for seed-based functional connectivity (sbFC). A second sbFC investigation consisted of a whole-brain voxel exploratory analysis again using the thalamus as a seed. A final complementary data-driven approach using multivoxel pattern analysis (MVPA) was conducted to identify a potential seed for further sbFC analyses. An increase in the rs-FC between the left thalamus and the left SCM/putamen followed CSHT. MVPA identified a cluster within the subcallosal cortex (SubCalC) representing the highest variation in peak activation between time points. Setting the SubCalC as a seed, whole-brain analysis showed a decoupling between the SubCalC and the medial frontal cortex during CSHT. These results indicate that CSHT with estradiol post-GAS, modulates rs-FC in regions engaged in cognitive, emotional, and sensorimotor processes.

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.

[Management of post-traumatic aphakia and aniridia: Retrospective study of 17 patients undergoing scleral-sutured artificial iris intraocular lens implantation. Management of aphakia-aniridia with scleral-sutured artificial iris intraocular lenses]. / Prise en charge de l'aphakie et de l'aniridie post-traumatiques. Étude rétrospective de 17 patients opérés d'implants intraoculaires suturés à la sclère à iris artificiel. Gestion de l'aphakie-aniridie par implants suturés à la sclère à iris artificiel.

PURPOSE: To evaluate the long-term outcomes of artificial iris intraocular lenses sutured to the sclera for managing traumatic aphakia and aniridia. METHODS: All consecutive cases receiving a Morcher® combination implant from June 2008 to February 2016 in Edouard-Herriot Hospital (Lyon, France) were included in this single-center retrospective study. Visual acuity, subjective degree of glare, quality of life and surgical complications were evaluated. RESULTS: Seventeen eyes of 17 patients were included, among which 82% were male. The mean age was 42 years. The injuries consisted of 23.5% contusion and 70.5% open globe injuries, of which 41% were globe ruptures. There was one postoperative case. A penetrating keratoplasty was performed at the same time for eight eyes. The mean follow-up was 32 months. Best-corrected visual acuity improved in 41.2%, remained the same in 17.6% and decreased in 41.2% of our cases. Distance vision averaged 1±0.25 line better and near vision 2.2±0.32 lines better when visual acuity was quantifiable before surgery. Glare improved in 80% of patients and remained stable in 20%, decreasing on average from 3.3/5 [min. 3-max. 4; SD: 0.48] before surgery to 1.9/5 [min. 0-max. 4; SD: 1.197] after surgery. Regarding the esthetic results, 78% of the patients declared themselves reasonably to very satisfied; 57% reported no limitation of activities of daily living, and 43% reported mild limitation. Ocular hypertension and glaucoma, found in 40% of eyes, were the main postoperative complications. CONCLUSION: Implantation of prosthetic iris device combined with an intraocular lens appears to be safe and effective in reducing glare disability and improving visual acuity. Close, long-term monitoring is essential for the success of this surgery.

BOLA-DRB3 gene polymorphisms influence bovine leukaemia virus infection levels in Holstein and Holstein × Jersey crossbreed dairy cattle.

Bovine leukemia virus (BLV) infections, causing persistent lymphocytosis and lethal lymphosarcoma in cattle, have reached high endemicity on dairy farms. We observed extensive inter-individual variation in the level of infection (LI) by assessing differences in proviral load in peripheral blood. This phenotypic variation appears to be determined by host genetics variants, especially those located in the BoLA-DRB3 MHCII molecule. We performed an association study using sequencing-based typed BOLA-DRB3 alleles from over 800 Holstein and Holstein × Jersey cows considering LI in vivo and accounting for filial relationships. The DBR3*0902 allele was associated with a low level of infection (LLI) (<1% of circulating infected B-cells), whereas the DRB3*1001 and DRB3*1201 alleles were related to a high level of infection (HLI). We found evidence that 13 polymorphic positions located in the pockets of the peptide-binding cleft of the BOLA-DRB3 alleles were associated with LI. DRB3*0902 had unique haplotypes for each of the pockets: Ser13 -Glu70 -Arg71 -Glu74 (pocket 4), Ser11 -Ser30 (pocket 6), Glu28 -Trp61 -Arg71 (pocket 7) and Asn37 -Asp57 (pocket 9), and all of them were significantly associated with LLI. Conversely, Lys13 -Arg70 -Ala71 -Ala74 and Ser13 -Arg70 -Ala71 -Ala74 , corresponding to the DRB3*1001 and *1201 alleles respectively, were associated with HLI. We showed that the specific amino acid pattern in the DRB3*0902 peptide-binding cleft may be related to the set point of a very low proviral load level in adult cows. Moreover, we identified two BOLA-DRB3 alleles associated with a HLI, which is compatible with a highly contagious profile.