University of Alabama at Birmingham

Type 2 diabetes (T2D) risk is higher among non-Hispanic black (NHB) and Hispanic individuals, for reasons that are unclear. With this cross-sectional study, we tested the hypothesis that racial disparities in T2D prevalence can be partially traced to heterogeneity in etiology, as indicated by genetic subtypes that reflect distinct T2D phenotypes. Using a diverse sample of 361 US adults with T2D (69.5% women; 34.1% NHB; 13.9% Hispanic), we derived genetic risk scores (GRS) representing five distinct T2D pathophysiological pathways from 94 loci: beta-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. Genetic predisposition for insulin resistance (IR) was also assessed using a 52-SNP IR risk score. The beta-cell and proinsulin scores (as median [IQR]) were higher among NHB participants relative to NHW and Hispanics [beta-cell GRS (NHB, 0.842[0.784-0.887] vs NHW, 0.762[0.702-0.835] and Hispanic, 0.772[0.717-0.848]); proinsulin GRS (NHB, 1.006[0.973-1.070] vs NHW, 0.969[0.853-1.044] and Hispanic, 0.976[0.901-1.048])], whereas the liver/lipid and 52-SNP IR scores were higher in both NHB and Hispanic participants versus NHW [liver/lipid GRS (NHB, 1.09[0.78-1.18] and Hispanic, 0.895[0.736-1.227] vs NHW, 0.794[0.666-1.157]); 52-SNP IR GRS (NHB, 0.0095[0.009-0.010] and Hispanic, 0.0096 [0.0092-0.0101] vs NHW, 0.0090[0.0084-0.0095])]. Impaired beta-cell function may underlie T2D etiology more profoundly in NHB, whereas hepatic dysfunction, lipid metabolism abnormalities, and genetic IR contribute to T2D etiology to a greater degree in both NHB and Hispanics. Further validation of these findings may form the basis for a personalized medicine approach to prevention and treatment of T2D.

Background Drug-resistant hypertension affects approximately 9–18% of the United States hypertensive population. Recognized as hypertension that is resistant to three or more medications, drug-resistant hypertension can lead to fatal sequelae, such as heart failure, aortic dissection, and other vast systemic disease. The disruption of the homeostatic mechanisms that stabilize blood pressure can be treated procedurally when medication fails. These procedures include carotid body stimulation, renal denervation, sympathectomies, dorsal root ganglia stimulation, and more recently spinal cord stimulation and have all been utilized in the treatment of drug-resistant hypertension. Methods To identify the clinical trials of neuromodulation in drug-resistant hypertension, a PubMed search was performed that included all original clinical trials of neuromodulation treating drug-resistant hypertension. The 838 articles found were sorted using Covidence to find 33 unique primary clinical trials. There were no methods used to assess risk of bias as a meta-analysis was not feasible due to heterogeneity. Results Renal denervation and carotid body stimulation have both shown promising results with multiple clinical trials, while sympathectomies have mostly been retired due to the irreversible adverse effects caused. Dorsal root ganglion stimulation showed varying success rates. Spinal cord stimulation is a novel treatment of drug-resistant hypertension that shows promising initial results but requires further investigation and prospective studies of the treatment to provide guidelines for future DRH treatment. The limitations of the review are reporting bias and absence of a meta-analysis that compares the treatment modality due to the heterogeneity of reported outcomes. Conclusion Innovation in neuromodulation is necessary to provide alternative avenues of treatment in the face of contraindications for standard treatment. Treatment of drug-resistant hypertension is essential to delay dangerous sequelae. This review’s objective is to summarize the clinical trials for treatment of drug-resistant hypertension following PRISMA guidelines and suggests future directions in the treatment of drug-resistant hypertension.

While much research in veterinary medicine is aimed at optimising diagnosis and treatment in domestic animals, it must be remembered that it is the owners of the animals that ultimately decide on which treatments they consent to be given, and it is the owners who must attempt to accurately administer medications at home. It is thus important to understand what barriers there are to client compliance with veterinary recommendations, such as education, price and competing (usually online) misinformation. The following four studies examine client attitudes to various veterinary advice and procedures. Note that not all medications mentioned in this article are licensed for the species and/or indication discussed.

The nontargeted systematic sampling of 12-core (10–14 cores per guidelines) transrectal ultrasound (TRUS) guided biopsy has resulted in considerable undergrading of clinically significant prostate cancers (csPCa). Magnetic resonance imaging (MRI)/TRUS fusion-guided biopsy has emerged as an option for improved detection of csPCa. This technology, which combines high-resolution anatomic and functional prostate imaging via multiparametric MRI with real-time TRUS biopsy probe guidance, allows for precise targeted biopsies of MRI-specified lesions within the prostate suspicious for harboring cancer. As multiple studies have illustrated now, this biopsy method has revolutionized the way prostate cancer screening, risk stratification, and treatment decision-making take place. Herein, we provide a review of the MRI/TRUS fusion biopsy technique, an overview of the currently available fusion biopsy platforms, and reports of their clinical operational outcomes.

Objective The aim of this study was to examine how depressive symptoms change in midlife and across the menopause transition. Methods We conducted a secondary analysis of data from a prospective population-based cohort, the Coronary Artery Risk Development in Young Adults study. We included women ( n = 2,160) with ≥3 responses to the Center for Epidemiologic Studies Depression Scale (CES-D) beginning at examination year 5, at approximately 30 years of age, and again at years 10, 15, 20, 25, 30, and 35 (ages 35 through 60 years). We modeled trajectories of CES-D by chronologic age and compared these to trajectories of depressive symptoms by relation to age at menopause. Results We identified three trajectories of depressive symptoms: women with minimal ( n = 1,328, 61%, mean CES-D 8.1); intermediate ( n = 675, 31%, mean CES-D 15.6); or persistent depressive symptoms ( n = 157, 7%, mean CES-D 26.1). Trajectories were stable over time, among women who had undergone natural menopause ( n = 1,153), Black race (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.43 to 2.40), less than a high school education (OR, 1.83; 95% CI, 1.38 to 2.41), and low income (OR, 1.60; 95% CI, 1.18 to 2.18), along with tobacco use (OR, 1.35; 95% CI, 1.04 to 1.77), alcohol consumption (OR, 1.01; 95% CI, 1.004 to 1.02), estrogen use for vasomotor symptoms (OR, 1.71; 95% CI, 1.06 to 2.77), and higher body mass index (OR, 1.03; 95% CI, 1.01 to 1.05) that were also associated with persistent depressive symptoms. Hormonal contraceptive use at year 2 was associated with lower odds of persistent depressive symptoms (OR, 0.69; 95% CI, 0.51 to 0.93). Similar patterns were observed among women who underwent surgical menopause. Conclusions Depressive symptoms in the premenopause were similar to those in postmenopause, and risk factors could be identified early in reproductive life. Studies with more frequent assessments of depressive symptoms during the menopause transition are needed.

Periodontitis is initiated by dysbiosis of the oral microbiome. Pathogenic bacteria elicit ineffective immune responses, which damage surrounding tissues and lead to chronic inflammation. Although current treatments typically aim for microbial eradication, they fail to address the significance of immune cell reactions in disease progression. Here, we searched for small molecules as drug candidates and identified a bifunctional antibiotic, azithromycin (AZM), that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation. We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues. Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro. In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration. In addition, microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles, had similar or slightly enhanced therapeutic outcomes respectively. The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents, providing a practical and streamlined approach for clinical treatment. Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation.

Congenital CMV infection is the leading nongenetic cause of sensorineural hearing loss worldwide, yet most parents have never heard of it. The majority of infected newborns have no clinical signs of infection, although a substantial proportion may have hearing loss at birth or develop it later in life. As antiviral treatment with ganciclovir or valganciclovir initiated in the first month of age improves audiologic outcomes, there is an urgent need for timely identification of infected neonates. A targeted approach that tests neonates who refer on the newborn hearing screen has been implemented in many states and hospital programs, but it fails to identify about 40% of children who experience CMV-related hearing loss. A universal screening approach is optimal given the prevalence of congenital CMV infection, its associated sequelae, the availability of a simple saliva screening tool, the available antiviral treatment, and the directed therapies for hearing impairment.

Background Coronary artery bypass graft surgery is one of the most common cardiac procedures performed worldwide. The longer these patients remain in bed, the greater their risk of postoperative complications and prolonged length of stay. Local Problem At the authors’ institution, the average length of stay after coronary artery bypass graft surgery was 7.27 days, longer than the national average of 6.9 days. This quality improvement project was undertaken to increase these patients’ postoperative mobility and thereby reduce their length of stay. Methods Data on mobility and length of stay of patients with isolated coronary artery bypass graft surgery during an 8-week period were collected retrospectively to establish preintervention values. These values were compared with postintervention values for an equivalent period. An evidence-based nurse-driven early mobility protocol was used to mobilize appropriate patients from bed to chair on postoperative day 0. This level of mobility was documented as a score of 4 on the Johns Hopkins Highest Level of Mobility Scale. Results From before to after protocol implementation, the postoperative length of stay decreased by 1.04 days. None of the 103 patients in the preintervention group scored a 4 on the Johns Hopkins Highest Level of Mobility Scale, compared with 36 of 134 patients in the intervention group. The difference in postoperative length of stay was clinically but not statistically significant (2-sided P = 1.95). Conclusion Early mobility may help improve patient outcomes by reducing hospital length of stay and minimizing complications associated with prolonged immobility.

Importance New data and new antiretroviral drugs and formulations continue to become available for the prevention and management of HIV infection. Objective To provide updated recommendations for HIV treatment and clinical management and HIV prevention. Methods A panel of volunteer expert physician scientists were appointed to provide updated consensus recommendations for 2024. Relevant evidence in the literature since the last report was identified from PubMed and Embase searches (which initially yielded 3998 unique citations, of which 249 were considered relevant); from ongoing monitoring of the literature by the panel members; from data submitted by product manufacturers; and from studies presented at peer-reviewed scientific conferences between June 2022 and October 2024. Findings Antiretroviral therapy continues to be recommended for all individuals with HIV. For most people with HIV, initial regimens composed of an integrase strand transfer inhibitor (InSTI), specifically bictegravir or dolutegravir, with 2 (and in some cases 1) nucleoside or nucleotide reverse transcriptase inhibitors are recommended. Recommendations are made for those with particular clinical circumstances, such as pregnancy and active opportunistic diseases, as well as for those unable to take InSTIs. Regimens may need to be changed for virologic failure, adverse effects, convenience, or cost, among other reasons. Long-acting injectable therapy is available for those who prefer not to take daily oral medications and for people struggling with adherence to daily therapy. Recommendations are provided for laboratory monitoring, management of substance use disorders and weight changes, as well as use of statins for cardiovascular disease prevention. For HIV prevention, oral (daily or intermittent) and injectable long-acting medications are effective options for people at increased likelihood of HIV exposure. Further, new tools for maintaining health and well-being among people with HIV, such as doxycycline postexposure prophylaxis to avert sexually transmitted infection, and strategies to treat substance use disorders, are recommended. Disparities in HIV acquisition and care access are discussed and solutions proposed. Conclusions New approaches for treating and preventing HIV offer additional tools to help end the HIV epidemic, but achieving this goal depends on addressing disparities and inequities in access to care.

Introduction Cesarean delivery is the most common mode of delivery among extremely preterm infants but there are insufficient data regarding the best mode of delivery among extremely preterm singletons. The objective of this study was to compare the rate of death or severe neurodevelopmental impairment among extremely preterm singletons by actual mode of delivery. Material and Methods Observational study using prospectively collected data from 25 US medical centers. We included postnatally‐treated singletons with birth weight 401–1000 g, gestational age 22 + 0/7–26 + 6/7 weeks, without a major birth defect, born 2006–2016. Death or severe neurodevelopmental impairment (Bayley Scales of Infant Development‐3rd edition cognitive composite score<70, cerebral palsy (Gross Motor Function Classification Scale >3), bilateral blindness, or bilateral hearing loss) at 18–26 month follow‐up were compared by mode of delivery (cesarean, vaginal including vertex or breech) using propensity score analysis to adjust for baseline characteristics. Results There was no difference in death or severe neurodevelopmental impairment between cesarean and vaginal (vertex or breech) births (42.4% cesarean vs. 47.2% vaginal; adjusted odds ratio (aOR), 95% confidence intervals (CI); 1.03, 0.91–1.17). Both cesarean delivery (26.8% cesarean vs. 51.5% breech vaginal; aOR: 0.71; 95% CI: 0.55–0.92) and vertex vaginal delivery (28.5% vertex vaginal vs. 51.5% breech vaginal; aOR: 0.59; 95% CI: 0.45–0.76) were associated with lower mortality compared with breech vaginal delivery. Conclusions Among postnatally‐treated extremely preterm singletons, there was no difference in death or severe neurodevelopmental impairment between cesarean or vaginal delivery. Both vertex vaginal and cesarean delivery were associated with lower mortality compared with breech vaginal delivery.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects approximately 1:2500 individuals worldwide. The hallmark manifestation is the neurofibroma, a benign tumor of the nerve sheath, but many other tumor and nontumor manifestations occur, including malignant peripheral nerve sheath tumors, gliomas, skeletal dysplasia, learning disabilities, etc. The disorder is due to pathogenic variants in the NF1 gene, a large gene that encodes the protein neurofibromin. The gene functions as a tumor suppressor, at least in the pathogenesis of tumor-related manifestations. Genetic testing is available and has revealed over 3000 distinct pathogenic variants. Most lead to loss of function of the gene product, with only a small number of genotype–phenotype correlations identified. Neurofibromin is a complex protein that interacts with multiple other proteins in the cell. Its principal function, at least regarding the disorder NF1, appears to be the regulation of the conversion of RAS-GTP to RAS-GDP through a GTPase activating protein domain. Hyperactive RAS signaling can be demonstrated in tumors associated with NF1. Recognition of this mechanism has led to the development of treatments based on MAP-kinase kinase (MEK) inhibition, with one drug approved by the US Food and Drug Administration for the treatment of plexiform neurofibromas.

Background Esketamine nasal spray (ESK) is approved, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression in adults and for the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. No adverse events (AEs) of respiratory depression were reported in ESK phase 3 clinical trials; however, postmarketing incidents of respiratory depression associated with ESK use have been observed. Methods The Janssen Global Medical Safety (GMS) database was reviewed for cases meeting criteria for respiratory depression with ESK using 47 months of postapproval data, based on the Standardized Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) acute central respiratory depression (broad). FAERS, EudraVigilance, and literature searches were performed to identify reports of respiratory depression related to ESK use. Results Fifty cases, representing 50 patients, in the GMS database met the case definition for respiratory depression; 8 of these had a stronger association with ESK use. The MedDRA PT hypopnea met the threshold for disproportionality with ESK in FAERS. The MedDRA PTs asphyxia, oxygen saturation decreased, respiratory depression, and apnea, met the threshold for disproportionality with ESK in EudraVigilance. Conclusion Despite extensive soliciting of AEs for ESK with the US Risk Evaluation and Mitigation Strategy program, respiratory depression is infrequently observed with ESK treatment in the postmarketing setting (estimated incidence: 1 case per 20,000 treatment sessions). Symptoms are manageable and resolve with minor supportive measures. Monitoring for symptoms of respiratory depression, including pulse oximetry, is recommended within the postdose observation period.

The polysaccharide (PS) capsule of Streptococcus pneumoniae (pneumococcus) is the immunodominant surface structure that shields the bacteria from the host immune system. Since the capsule is the primary target of currently available pneumococcal vaccines, anti-capsular antibodies are highly protective but serotype-specific. Pneumococci may evade host or vaccine-induced immunity as a result of variation in capsule structure mediated via multiple mechanisms, such as the loss or gain of O-acetylation. Previous biochemical studies of serogroup 20 isolates have identified two subtypes—20A and 20B, whose capsule PS differs in the WhaF-mediated glucose side chain. Herein, we characterize a newly discovered capsule type, 20C, that differs from serotype 20B via the inactivation of capsule O-acetyltransferase gene, wciG . Structural analysis demonstrated that 20C and 20B share an identical repeat unit [→3)-α-D-Glc p NAc-[β-D-Gal f -(1→4)][α-D-Glc p -(1→6)]-(1→P→6)-α-D-Glc p -(1→6)- β-D-Glc p -(1→3)-β-D-Gal f 5,6Ac 2 -(1→3)-β-D-Glc p -(1→], except for the absence of WciG-mediated O - acetyl group at terminal galactofuranose (β-D-Gal f ). We confirmed that deletion of the wciG gene in a 20B strain resulted in the expression of the 20C capsule. Serotype 20C is serologically indistinguishable from the canonical 20A and 20B using conventional serotyping antibodies, but serogroup 20 subtypes can be distinguished by sequencing of cps genes— whaF , wciG , and wcjE . While genetic screening suggests 20C to be globally less prevalent, a new variant was identified which appears to have both wciG and whaF genes inactive, potentially indicating it to be a new serotype. Consequently, genome-based serotyping/bioinformatic tools must scrutinize all cps genes for mutations that might inactivate/modify cps -encoded enzymes, ensuring effective tracking of emerging capsule variants in response to ongoing vaccination efforts. IMPORTANCE Streptococcus pneumoniae (pneumococcus) is a significant human pathogen known for producing a wide array of antigenically and structurally diverse capsule types, a fact that poses a serious challenge to the effectiveness of vaccines targeting pneumococcal capsule polysaccharide (PS). Herein, we provide a comprehensive analysis-genetic, antigenic, and biochemical of a newly identified capsule type, 20C, which differs from the canonical serotype 20B due to the inactivation of the capsule O-acetyltransferase gene, wciG . Our findings highlight how pneumococci can alter their capsule PS structure and immunological characteristics through minor genetic modifications. Since the appearance of new capsule types can directly affect pneumococcal conjugate vaccine (PCV) implementation, a deeper understanding of capsule PS at the genetic, immunological, and biochemical levels is critical for the development of future diagnostic tools and vaccines.