A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50.

The anti-cancer target hRpn13 is a proteasome substrate receptor. However, hRpn13-targeting molecules do not impair its interaction with proteasomes or ubiquitin, suggesting other critical cellular activities. We find that hRpn13 depletion causes correlated proteomic and transcriptomic changes, with pronounced effects in myeloma cells for cytoskeletal and immune response proteins and bone-marrow-specific arginine deiminase PADI4. Moreover, a PROTAC against hRpn13 co-depletes PADI4, histone deacetylase HDAC8, and DNA methyltransferase MGMT. PADI4 binds and citrullinates hRpn13 and proteasomes, and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. When off proteasomes, hRpn13 can bind HDAC8, and this interaction inhibits HDAC8 activity. Further linking hRpn13 to transcription, its loss reduces nuclear factor κB (NF-κB) transcription factor p50, which proteasomes generate by cleaving its precursor protein. NF-κB inhibition depletes hRpn13 interactors PADI4 and HDAC8. Altogether, we find that hRpn13 acts dually in protein degradation and expression and that proteasome constituency and, in turn, regulation varies by cell type.

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.

Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.

Body image and psychosocial outcomes in youth and young adults with differences of sex development: a multi-method study.

OBJECTIVE: Differences of sex development (DSD) can affect the physical health, appearance, and psychosocial functioning of affected individuals, but little is known about how subjective appearance perceptions (body image) impact psychosocial outcomes. This study evaluated body image and its associations with psychosocial outcomes including quality of life, resilience, and psychosocial adjustment. METHODS: This cross-sectional, multi-method study assessed body image and psychosocial outcomes including quality of life, adjustment, and resilience in 97 youth and young adults with DSD (mean age = 17 ± 3.7 years; 56% assigned female in infancy) using psychometrically sound instruments. A subsample (n = 40) completed qualitative interviews. RESULTS: Quantitative results indicated that overall, participants were satisfied with their physical appearance, although less so with their primary sex characteristics. Body image dissatisfaction was associated with poorer psychosocial adjustment, quality of life, and resilience. Qualitatively, youth and young adults reported a variety of perceptions, both positive and negative, related to their body image and the impact of living with a DSD condition. Themes identified included appearance management; effects of DSD on body image; diagnostic factors and features; attitudes about diagnosis; and treatment. CONCLUSIONS: Body image is significantly associated with psychosocial outcomes in youth and young adults with DSD, with qualitative findings highlighting both positive and negative body image experiences. Results have implications for clinical care including screening for appearance concerns, normalization of appearance variations, and intervention development to better support healthy body image and psychosocial functioning in youth and young adults with DSD.

Socio-demographic predictors of not having private dental insurance coverage: machine-learning algorithms may help identify the disadvantaged.

BACKGROUND: For accessing dental care in Canada, approximately 62% of the population has employment-based insurance, 6% have some publicly funded coverage, and 32% have to pay out-of pocket. Those with no insurance or public coverage find dental care more unaffordable compared to those with private insurance. To support the development of more comprehensive publicly funded dental care programs, it is important to understand the socio-demographic attributes of all those, who find dental care unaffordable. METHODS: This study is a secondary analysis of the data collected from Ontarians during the latest available cycle of the Canadian Community Health Survey (2017-18), a cross-sectional survey that collects information on health status, health care utilization, and health determinants for the Canadian population. First, bivariate analysis was conducted to determine the characteristics of Ontarians who lack dental insurance. Afterwards, we employed machine learning (ML) to analyze data and identify risk indicators for not having private dental insurance. Specifically, we trained several supervised ML models and utilized Shapley additive explanations (SHAP) to determine the relative feature importance for not having private dental insurance from the best ML model [the gradient boosting (GBM)]. RESULTS: Approximately one-third of Ontarians do not have private insurance coverage for dental care. Individuals with an income below $20,000, those unemployed or working part-time, seniors aged above 70, and those unable to afford to have their own housing are more at risk of not having private dental insurance, leading to financial barriers in accessing dental care. CONCLUSION: In the future, government-funded programs can incorporate these identified risk indicators when determining eligible populations for publicly funded dental programs. Understanding these attributes is critical for developing targeted and effective interventions, ensuring equitable access to dental care for Canadians.

The effect of surgical reconstruction on bladder function in cloacal malformation: A study of urodynamics.

BACKGROUND: Girls with cloacal malformation are at risk of bladder dysfunction, with nearly 90% exhibiting some degree of dysfunction. Surgical dissection, particularly with total urogenital mobilization (TUM), has been hypothesized as a cause of worsening bladder function despite this population commonly having associated vertebral and spinal cord abnormalities that may also explain bladder dysfunction. More recently there has been great effort to select the appropriate surgical technique for cloacal repair in each patient in order to minimize dissection and potential damage to the bladder. We aimed to evaluate the effect of surgical cloacal repair on bladder function based on pre and post-surgery urodynamics (UDS) testing. METHODS: A prospectively collected database of patients with anorectal malformation at a single center was queried for girls with cloacal malformations who had undergone surgical repair from 2015 to 2022. It is our current protocol to perform UDS before and after cloacal repair. Only patients who completed both pre and post-surgery UDS were included. UDS were evaluated and classified using the UMPIRE protocol. RESULTS: A total of 48 patients were included in the cohort. The majority of patients (79.2%) had stable or improved UDS post-op leaving 10 patients (20.8%) who had worsening UDS. Long common channel (≥3 cm) was the only factor significantly associated with worsening UDS. (p = 0.03) Nearly 30% (n = 8) of those undergoing UGS had worse post-op UDS compared to 9.5% (n = 2) with TUM. All patients who worsened UDS initially had safe UDS that changed to intermediate, except for one who worsened to hostile in the setting of significant social challenges and non-compliance. Only common channel length was predictive of worsening UDS, while the type of surgical approach and spine status were not. While the overall risk of worsening UDS after TUM is only 9.5%, patients with normal spines undergoing TUM had the lowest risk, seen in only one in 15 patients (6.6%). CONCLUSIONS: Common channel length was the most significant predictor of worsening UDS, while spine status and surgical technique (TUM vs UGS) did not significantly impact this finding. By following this established surgical protocol based on common channel and urethral lengths, is rare for the surgical cloacal repair to result in worsening post-op UDS, particularly in those undergoing TUM for short common channel and normal spine.

A Single Center's Experience With Spinal Anesthesia for Pediatric Patients Undergoing Surgical Procedures.

PURPOSE: To perform a single institution review of spinal instead of general anesthesia for pediatric patients undergoing surgical procedures. Spinal success rate, intraoperative complications, and postoperative outcomes including unplanned hospital admission and emergency department visits within seven days are reported. METHODS: Retrospective chart review of pediatric patients who underwent spinal anesthesia for surgical procedures from 2016 until 2022. Data collected included patient demographics, procedure and anesthetic characteristics, intraoperative complications, unplanned admissions, and emergency department returns. RESULTS: The study cohort included 1221 patients. Ninety-two percent of the patients tolerated their surgical procedure without requiring conversion to general anesthesia, and 78% of patients that had spinals placed successfully did not receive any sedation following lumbar puncture. The most common intraoperative event was systolic blood pressure below 60 mm Hg (14%), but no cases required administration of vasoactive agents, and no serious intraoperative adverse events were observed. Post-Anesthesia Care Unit Phase I was bypassed in 72% of cases with a median postoperative length of stay of 84 min. Forty-six patients returned to the emergency department following hospital discharge, but no returns were due to anesthetic concerns. CONCLUSIONS: Spinal anesthesia is a viable and versatile option for a diversity of pediatric surgical procedures. We noted a low incidence of intraoperative and postoperative complications. There remain numerous potential advantages of spinal anesthesia over general anesthesia in young pediatric patients particularly in the ambulatory setting. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective cohort treatment study.

Molecular and Functional Profiling of Gαi as an Intracellular pH Sensor.

Heterotrimeric G proteins (Gα, Gß and Gγ) act downstream of G-protein-coupled receptors (GPCRs) to mediate signaling pathways that regulate various physiological processes and human disease conditions. Previously, human Gαi and its yeast homolog Gpa1 have been reported to function as intracellular pH sensors, yet the pH sensing capabilities of Gαi and the underlying mechanism remain to be established. Herein, we identify a pH sensing network within Gαi, and evaluate the consequences of pH modulation on the structure and stability of the G-protein. We find that changes over the physiological pH range significantly alter the structure and stability of Gαi-GDP, with the protein undergoing a disorder-to-order transition as the pH is raised from 6.8 to 7.5. Further, we find that modulation of intracellular pH in HEK293 cells regulates Gαi-Gßγ release. Identification of key residues in the pH-sensing network allowed the generation of low pH mimetics that attenuate Gαi-Gßγ release. Our findings, taken together, indicate that pH-dependent structural changes in Gαi alter the agonist-mediated Gßγ dissociation necessary for proper signaling.

Structural Relationships to Efficacy for Prazole-Derived Antivirals.

Here, an in vitro characterization of a family of prazole derivatives that covalently bind to the C73 site on Tsg101 and assay their ability to inhibit viral particle production is presented. Structurally, increased steric bulk on the 4-pyridyl of the prazole expands the prazole site on the UEV domain toward the ß-hairpin in the Ub-binding site and is coupled to increased inhibition of virus-like particle production in HIV-1. Increased bulk also increased toxicity, which is alleviated by increasing flexibility. Further, the formation of a novel secondary Tsg101 adduct for several of the tested compounds and the commercial drug lansoprazole. The secondary adduct involved the loss of the 4-pyridyl substituent to form an irreversible species, with implications for increasing the half-life of the active species or its specificity toward Tsg101 UEV. It is also determined that sulfide derivatives display effective viral inhibition, presumably through cellular sulfoxidation, allowing for delayed conversion within the cellular environment, and identify SARS-COV-2 as a target of prazole inhibition. These results open multiple avenues for the design of prazole derivatives for antiviral applications.

Longitudinal Biochemical and Behavioral Alterations in a Gyrencephalic Model of Blast-Related Mild Traumatic Brain Injury.

Blast-related traumatic brain injury (bTBI) is a major cause of neurological disorders in the U.S. military that can adversely impact some civilian populations as well and can lead to lifelong deficits and diminished quality of life. Among these types of injuries, the long-term sequelae are poorly understood because of variability in intensity and number of the blast exposure, as well as the range of subsequent symptoms that can overlap with those resulting from other traumatic events (e.g., post-traumatic stress disorder). Despite the valuable insights that rodent models have provided, there is a growing interest in using injury models using species with neuroanatomical features that more closely resemble the human brain. With this purpose, we established a gyrencephalic model of blast injury in ferrets, which underwent blast exposure applying conditions that closely mimic those associated with primary blast injuries to warfighters. In this study, we evaluated brain biochemical, microstructural, and behavioral profiles after blast exposure using in vivo longitudinal magnetic resonance imaging, histology, and behavioral assessments. In ferrets subjected to blast, the following alterations were found: 1) heightened impulsivity in decision making associated with pre-frontal cortex/amygdalar axis dysfunction; 2) transiently increased glutamate levels that are consistent with earlier findings during subacute stages post-TBI and may be involved in concomitant behavioral deficits; 3) abnormally high brain N-acetylaspartate levels that potentially reveal disrupted lipid synthesis and/or energy metabolism; and 4) dysfunction of pre-frontal cortex/auditory cortex signaling cascades that may reflect similar perturbations underlying secondary psychiatric disorders observed in warfighters after blast exposure.

A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins.

Proteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13Pru by degradation of its UCHL5/Uch37-binding DEUBAD domain and retention of an intact proteasome- and ubiquitin-binding Pru domain. By using structure-guided virtual screening, we identify an hRpn13 binder (XL44) and solve its structure ligated to hRpn13 Pru by integrated X-ray crystallography and NMR to reveal its targeting mechanism. Surprisingly, hRpn13Pru is depleted in myeloma cells following treatment with XL44. TMT-MS experiments reveal a select group of off-targets, including PCNA clamp-associated factor PCLAF and ribonucleoside-diphosphate reductase subunit M2 (RRM2), that are similarly depleted by XL44 treatment. XL44 induces hRpn13-dependent apoptosis and also restricts cell viability by a PCLAF-dependent mechanism. A KEN box, but not ubiquitination, is required for XL44-induced depletion of PCLAF. Here, we show that XL44 induces ubiquitin-dependent loss of hRpn13Pru and ubiquitin-independent loss of select KEN box containing proteins.

A cross sectional study of the prevalence of hypertension and associated risk factors in coastal Andhra Pradesh

Background: Hypertension (HTN) accounts for 9.4 million deaths worldwide every year. A rise in HTN is projected by the global burden of HTN 2005 study, it portrays a grim picture. Community level data for hypertension is scarce in Andhra Pradesh. A cross sectional study was conducted to know the prevalence of hypertension in Vijayawada.Methods: 1009 apparently healthy adults visiting the hospital accompanying patients in outpatient department were screened for hypertension by blood pressure recording. All measurements were obtained by automated blood pressure measuring (AOBPM) systems.Results: Of the total population screened, hypertension accounted for 42.5% (n=429). A multivariate analysis showed that hypertension is more common in age group >50 years [odds ratio (OR)=3.004, 95% confidence interval CI being=2.2707-3.9645], in diabetics (OR=2.9091, 95% CI=2.0595-4.1092), in males (odds ratio=1.3223, 95% CI=1.0214-1.7118) and in smokers (OR=1.7442, 95% CI=1.0469-2.9059). A linear positive association was found between obesity and hypertension. No significant association was found between hypertension and alcohol intake. This study also showed that awareness was present in only 44% and 37% had hypertension under control of known hypertensive subjects.Conclusions: This is the first cross sectional study done with AOBPM. Our study finds that hypertension is an important public health burden in coastal Andhra Pradesh with low awareness, treatment, and control. It implies that strategies need to be developed to improve effective primary care management of hypertension.

Breeding for Tolerance to Stress Triggered by Salinity in Rice.

Rice is one of the world’s most important staple crops. Although rice is considered as a sensitive crop to salinity, it is one of the most widely grown crops in coastal areas. In the present, salinity is the second most widespread soil problem in rice growing countries next to drought and considers as a serious constraint to increased rice production worldwide. Genetic Evaluation and Utilization (GEU) Program at IRRI in 1969 have been screened 138,000 rice genotypes. Of these, 17% had acceptable tolerance at electrical conductivity (EC) of 10 dS/m at the seedling stage. Traditional cultivars are the most tolerant to abiotic stresses. Cultivars Pokkali, Cheriveruppu, Nona Bokra, SR26B, Damodar and Getu are tolerant of salinity but possess poor agronomic characters. There exists tremendous variation for salt tolerance within species in rice, providing opportunities to improve crop salt-stress tolerance through genetic means. Some attempts to develop salt-tolerant genotypes were based on highly tolerant traditional rice cultivars i.e. Pokkali and Nona-Bokra (Akbar et al., 1985). Mahsuri which is saline tolerant and introduced from Malaysia. Damodar (CSR 1), Dasal (CSR 2), Getu (CSR 3), Pokkali, Vytilla 1, Vytilla 2, Vytilla 3, Vytilla 4, Vytilla 5 etc were developed through pureline selection. CSR 10, CSR13, CSR23, CSR27, CSR30, CSR36, CR Dhan 402, CR Dhan 403, TRY 1, TRY 2, TRY 3, White ponni, CO 43 etc. were developed through recombinant varieties. CORH 2 is developed through three line breeding method. Somaclonal variants of Pokkali with improved agronomic traits were identified. The variant (TCCP 266-2-49-B-B-3) had desirable levels of all tested characteristics and retained salinity tolerance equal to Pokkali. The variant is semidwarf and has vigorous growth and high yield potential without lodging. TCCP 266-2-49-B-B-3 had a white pericarp and also improved cooking quality, with medium gel consistency. High-yielding salt-tolerant AC-derived lines (IR51500-AC11-1, IR51500-AC17, IR51485- AC6534-4, IR72132-AC6-1, IR69997-AC1, IR69997- AC2, IR69997- AC3 and IR69997-AC4) had been generated in just 3 years (Senadhira et al., 1994). A major quantitative trait locus (QTL) for salt tolerance named Saltol was mapped on chromosome 1 using F8 recombinant inbred lines (RILs) of Pokkali/IR29 cross, which is responsible for low Na+, high K+ uptake and maintaining Na+/K+ homeostasis in the rice shoots (Nejad et al., 2008).

Common celiacomesenteric trunk: a rare anatomic variation / Tronco único celíaco-mesentérico: uma variante anatômica rara

Common celiacomesenteric trunk, with the celiac and superior mesenteric arteries having a common origin from the aorta, is the least frequently reported anatomic variation of all abdominal vascular anomalies. Knowledge of variations concerning the celiac trunk and superior mesenteric artery are of great importance for both surgical approaches and angiographic examinations. Clinicians should keep in mind these variations to avoid complications.

O tronco único celíaco-mesentérico, com as artérias celíaca e mesentérica superior tendo uma origem comum a partir da aorta, é a variante anatômica menos reportada dentre todas as anomalias vasculares abdominais. Conhecer as variantes do tronco celíaco e da artéria mesentérica superior é de grande importância tanto para abordagens cirúrgicas quanto para exames angiográficos. É importante que os médicos tenham em mente essas variantes a fim de evitar complicações.

Combined hepatocellular and cystadenocarcinoma presenting as a giant cyst of the liver--a case report.

Primary cystic lesions of the liver are very rare. Most of the solid tumours are hepatocellular carcinomas (HCC) with a smaller number being cholangiocarcinomas. The association of HCC with other primary liver malignancies is also extremely rare. This case report is about a 27 year old male patient who presented with a giant cystic lesion of the left liver. A CT scan showed a cystic lesion with internal septations and a thrombus in the main portal vein. The patient underwent an extended left hepatectomy and a portal venotomy with removal of the thrombus. Coexistent hepatocellular and cystadenocarcinoma were reported on histopathological examination. The patient was put on 5-FU postoperatively. He is doing well 11 months after surgery.

Caudal epidural blockade in adolescents

Various options are available for the provision of analgesia following major surgical procedures including systemic opioids and regional anesthetic techniques. Regional anesthetic techniques offer the advantage of providing analgesia while avoiding the deleterious adverse effects associated with opioids including nausea, vomiting, sedation and respiratory depression. Although used commonly in infants and children, there is a paucity of experience with the use of caudal epidural blockade in adolescents. We retrospectively reviewed the perioperative care of adolescents undergoing major urologic or orthopedic surgical procedures for whom a caudal epidural block was placed for postoperative analgesia. The cohort for the study included 5 adolescents, ranging in age from 13 to 18 years and in weight from 42 to 71 kilograms. Caudal epidural analgesia was accomplished after the induction of anesthesia and prior to the start of the surgical procedure using 20-25 mL of either 0.25% bupivacaine or 0.2% ropivacaine with clonidine [1 micro g/kg]. The patients denied pain the recovery room. The time to first request for analgesia varied from 12 to 18 hours with the patients requiring 1-3 doses of analgesic agents during the initial 24 postoperative hours. Our preliminary experience demonstrates the efficacy of caudal epidural block in providing analgesia following major urologic and orthopedic surgical procedures. The applications of this technique as a means of providing postoperative analgesia are discussed

Bilateral transversus abdominis plane [TAP] catheters for postoperative analgesia in a child with spinal dysraphism

Regional analgesic techniques have become indispensable in the management of adult postoperative pain, and are gaining popularity in the pediatric population. Several case reports have been published describing the use of transversus abdominis plane [TAP] blocks for the provision of analgesia following lower and middle abdominal surgery in the adult population. Although there are several anecdotal reports and a few case series describing TAP blocks in the pediatric population, there are a limited number of reports regarding the use of continuous TAP catheters in the pediatric population. We present our experience with the use of bilateral TAP catheters to provide postoperative analgesia following major abdominal surgery [appendicovesicostomy] in a 5-year old, 17.8 kg pediatric patient with spina bifida. Applications of the technique are discussed and previous reports from the adult and pediatric population regarding the use of TAP catheters are reviewed