Increased frequency of repeat expansion mutations across different populations.

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions and technological limitations leading to underascertainment. Here, leveraging whole-genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modeling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating underdiagnosis and/or incomplete penetrance. While some REDs are population specific, for example, Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (that is, Europeans, Africans, Americans, East Asians and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counseling of REDs.

Change in Talar Axial Rotation and Pain Intensity Following Correction of Progressive Collapsing Foot Deformity.

BACKGROUND: The talus is more internally rotated within the ankle mortise in progressive collapsing foot deformity (PCFD) patients. However, no studies have investigated the change in talar axial rotation (AR) in PCFD postoperatively. The primary aim was to investigate the change in talar AR following PCFD reconstruction. Secondary aims were to determine whether talar AR changes were associated with other radiographic measurements or specific procedures, and whether postoperative talar AR was associated with 2-year patient-reported outcome scores. METHODS: Twenty-seven patients older than 18 years who underwent flexible PCFD reconstruction with preoperative and at least 5-month postoperative weightbearing computed tomographic (WBCT) scans and radiographs and had preoperative and at least 2-year postoperative PROMIS scores were included. Patients with talonavicular fusions were excluded. Talar AR was the angle between the transmalleolar axis and talar axis on WBCT scans, with smaller angles representing more internal rotation as described by Kim et al. Hindfoot moment arm, Meary angle, fibulocalcaneal and talocalcaneal distance, subtalar middle facet uncoverage, and talonavicular angle were measured on radiographs. RESULTS: Postoperative talar AR was 49.7 degrees (IQR, 45.9, 57.3), which was more externally rotated than preoperative AR by a median of 8.3 degrees (IQR, 2.2, 15.7) (P > .001). The change in talar AR was not associated with changes in any radiographic parameter. Increasing external talar AR was associated with an increase in postoperative PROMIS pain intensity (rs = 0.38, 95% CI 0.00, 0.67). Lateral column lengthening and subtalar fusion procedures were not associated with changes in talar AR (P > .10). CONCLUSION: PCFD reconstruction results in external rotation of the talus within the ankle mortise. Kim et al found that control patients had approximately 40 to 60 degrees of talar AR, which is similar to this study's corrected position of the talus. However, increasing talar external rotation resulted in worse postoperative PROMIS pain intensity, suggesting the possibility of overcorrecting the internal AR deformity.

AOP report: Development of an adverse outcome pathway for deposition of energy leading to learning and memory impairment.

Understanding radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the risk assessment of medical (e.g., radiotherapy) and occupational (e.g., nuclear workers and astronauts) exposures. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was acquired through a documented scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs: increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered stress response signaling, tissue resident cell activation, increased pro-inflammatory mediators, and abnormal neural remodeling that encompasses atypical structural and functional alterations of neural cells and surrounding environment. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, can lead to abnormal neural remodeling impacting learning and memory processes. Identified knowledge gaps include improving quantitative understanding of the AOP across several KERs and additional testing of proposed modulating factors through experimental work. Broadly, it is envisioned that the outcome of these efforts could be extended to other cognitive disorders and complement ongoing work by international radiation governing bodies in their review of the system of radiological protection.

Advancing Antenatal Care in Ethiopia: The Impact of Tele-Ultrasound on Antenatal Ultrasound Access in Rural Ethiopia.

Introduction: Access to antenatal ultrasound is limited in low-income countries such as Ethiopia. Virtual care platforms that facilitate supervision and mentoring for ultrasound scanning may improve patient access by facilitating task-sharing of antenatal ultrasound with midlevel providers. The purpose of this study was to assess the feasibility of a large volume tele-ultrasound program in Ethiopia, its impact on antenatal care (ANC) and patient access, and its sustainability as it transitioned from a pilot project to a continuing clinical program. Methods: Health care providers at two health centers in the North Shoa Zone, Ethiopia, performed antenatal tele-ultrasound exams with remote guidance from obstetricians located in urban areas. Data regarding ANC and ultrasound utilization, participant travel, ultrasound findings, specialist referrals, and participant experience were collected through a mobile app. Results: Between November 2020 and December 2023, 7,297 tele-ultrasound exams were performed. Of these, 489 tele-ultrasound exams were performed during the period of data collection from October to December 2022. The availability of tele-ultrasound at the two health centers significantly reduced participant travel distance (4.2 km vs. 10.2 km; p < 0.01; one-way distance). Most participants (99.2%) indicated the tele-ultrasound service was very important or important, with high levels of satisfaction. Clinically significant findings were identified in 26 cases (5.3%), leading to necessary referrals. Conclusion: This study demonstrated the feasibility of a large volume tele-ultrasound program in Ethiopia, its impact on improving the quality of ANC, and its sustainability. These findings lay a foundation upon which low-income countries can develop tele-ultrasound programs to improve antenatal ultrasound access.

Postoperative Pain and Perioperative Antibiotic Management in Functional Rhinoplasty.

Post-rhinoplasty pain control should use a multimodal regimen. Evidence suggests decreasing routine prescriptions of narcotics is reasonable for most individuals, and acetaminophen and nonsteroidal antiinflammatory drug combinations may be equivalent to as-needed opioids for postsurgical pain management. Preoperative pain counseling is important to set post-rhinoplasty pain expectations and reduce opioid use. A single intravenous dose of prophylactic antibiotics before incision is sufficient for most cases of functional rhinoplasty. Additional considerations are given to complex revision cases, use of allogenic grafts or implants, external osteotomies, or patients with immunosuppression or at risk of endocarditis.

Balance Assessment Using a Handheld Smartphone with Principal Component Analysis for Anatomical Calibration.

Most balance assessment studies using inertial measurement units (IMUs) in smartphones use a body strap and assume the alignment of the smartphone with the anatomical axes. To replace the need for a body strap, we have used an anatomical alignment method that employs a calibration maneuver and Principal Component Analysis (PCA) so that the smartphone can be held by the user in a comfortable position. The objectives of this study were to determine if correlations existed between angular velocity scores derived from a handheld smartphone with PCA functional alignment vs. a smartphone placed in a strap with assumed alignment, and to analyze acceleration score differences across balance poses of increasing difficulty. The handheld and body strap smartphones exhibited moderately to strongly correlated angular velocity scores in the calibration maneuver (r = 0.487-0.983, p < 0.001). Additionally, the handheld smartphone with PCA functional calibration successfully detected significant variance between pose type scores for anteroposterior, mediolateral, and superoinferior acceleration data (p < 0.001).

Open Access Data Repository and Common Data Model for Pulse Oximeter Performance Data.

The OpenOximetry Repository is a structured database storing clinical and lab pulse oximetry data, serving as a centralized repository and data model for pulse oximetry initiatives. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration). Data contributions are encouraged. All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate research on pulse oximeter performance across diverse human characteristics, addressing performance issues and promoting accurate pulse oximeters. The initial release includes controlled lab desaturation studies (CLDS), with ongoing updates planned as further data from clinical trials and CLDS become available.

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans.

Immunotherapy leads to cancer eradication despite the tumor's immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8 + T cells in the tumor. In zebrafish, CD8 + T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8 + T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer.

Ovarian cancers and microsatellite stable (MSS) colorectal cancers (CRC) are insensitive to anti-PD1 immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggests a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase 1 dose-escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS CRC. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval: 2.5-15.9%). Three patients with MSS CRC had durable responses for ≥3 years. One responding patient's CRC harbored a POLE mutation. The other two responding patients had left-sided CRCs with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2 amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability.

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE-trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay.

Genicular Artery Embolization for Treatment of Symptomatic Knee Osteoarthritis - Two Year Outcome Data.

PURPOSE: To report the 24-month outcomes and subgroup analysis evaluating the safety and effectiveness of the genicular artery embolization (GAE) for the treatment of symptomatic knee osteoarthritis (OA). MATERIALS AND METHODS: Forty participants with symptomatic moderate to severe knee OA from a single-center, single-arm prospective trial of GAE were included in this study. Abnormal genicular artery neovascularity was identified at the subject's focal knee pain with digital subtraction angiography and cone-beam computed tomography. Embolization was performed with 100-µm microspheres. The primary end point was treatment effectiveness as measured by sustained improvement in OA symptoms at 24 months, quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Treatment success was defined as ≥50% decrease in WOMAC relative to baseline. Clinical outcomes were assessed with mean age of 66.0 ± 8.1 years and BMI of 30.1 ± 6.2 kg/m2. RESULTS: Two of the forty (5.0%) patients were lost to follow up. Overall, 18 of 38 (47.4%) patients demonstrated ≥50% reduction in WOMAC at 24 months. In the subset of patients with initial clinical success at 12 months, 18 of 25 (72.0%) reported sustained clinical success at 24 months. Seven of 25 (28.0%) had symptom recurrence between 12 and 24 months and were determined to be clinical failures. All treatment-related adverse events occurred within 12 months following GAE, without additional events after 12 months. CONCLUSION: GAE is effective in achieving sustained symptom relief related to moderate to severe knee OA for up to 24 months with an acceptable safety profile.

Fractional Doses of Pneumococcal Conjugate Vaccine - A Noninferiority Trial.

BACKGROUND: Pneumococcal conjugate vaccines are an expensive component of the routine immunization schedule. Fractional-dose regimens may be one option to increase the sustainability of the vaccine program. METHODS: We assessed whether the immunogenicity of fractional doses of the 10-valent and 13-valent pneumococcal conjugate vaccines (PCV10 [GSK] and PCV13 [Pfizer], respectively) would be noninferior to that of the full doses and analyzed the prevalence of vaccine-serotype carriage. We randomly assigned healthy infants in Kenya to one of seven equal-sized trial groups. Participants in groups A through F were assigned to receive either a fractional or full dose of PCV10 or PCV13, administered as two primary doses plus one booster dose. In group A, participants received a full dose of PCV13; group B, a 40% dose of PCV13; group C, a 20% dose of PCV13; group D, a full dose of PCV10; group E, a 40% dose of PCV10; and group F, a 20% dose of PCV10. Participants in the seventh group (group G) received a full dose of PCV10 as three primary doses without a booster. Immunogenicity was assessed 4 weeks after the primary series of doses and 4 weeks after the booster dose. Noninferiority could be declared 4 weeks after the primary series if the difference in the percentage of participants with a threshold response was not more than 10% and 4 weeks after administration of the booster if the ratio of the geometric mean concentration (GMC) of IgG was more than 0.5. A vaccine dose was prespecified as noninferior if it met the noninferiority criterion for at least 8 of the 10 vaccine types in the PCV10 groups or at least 10 of the 13 vaccine types in the PCV13 groups. Carriage was assessed when participants were 9 months and 18 months of age. RESULTS: In the per-protocol analysis, 40% of a full dose of PCV13 met the noninferiority criterion for 12 of 13 serotypes after the primary series and for 13 of 13 serotypes after the booster. The immunogenicity of the 20% dose of PCV13 and of the 40% and 20% doses of PCV10 was not noninferior to that of the full doses. Vaccine serotype-type carriage prevalence was similar across the PCV13 groups at 9 months and 18 months of age. CONCLUSIONS: In a three-dose schedule (two primary doses and a booster), 40% doses of PCV13 were noninferior to full doses for all included serotypes. Lower doses of PCV13 and PCV10 did not meet the criteria for noninferiority. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03489018; Pan African Clinical Trial Registry number, PACTR202104717648755.).

Conformational ensembles in Klebsiella pneumoniae FimH impact uropathogenesis.

Klebsiella pneumoniae is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer from recurrent UTI, reducing quality of life and causing substantial morbidity and mortality, especially in the hospital setting. Uropathogenic E. coli (UPEC) is the most prevalent cause of UTI. Like UPEC, K. pneumoniae relies on type 1 pili, tipped with the mannose-binding adhesin FimH, to cause cystitis. However, K. pneumoniae FimH is a poor binder of mannose, despite a mannose-binding pocket identical to UPEC FimH. FimH is composed of two domains that are in an equilibrium between tense (low-affinity) and relaxed (high-affinity) conformations. Substantial interdomain interactions in the tense conformation yield a low-affinity, deformed mannose-binding pocket, while domain-domain interactions are broken in the relaxed state, resulting in a high-affinity binding pocket. Using crystallography, we identified the structural basis by which domain-domain interactions direct the conformational equilibrium of K. pneumoniae FimH, which is strongly shifted toward the low-affinity tense state. Removal of the pilin domain restores mannose binding to the lectin domain, thus showing that poor mannose binding by K. pneumoniae FimH is not an inherent feature of the mannose-binding pocket. Phylogenetic analyses of K. pneumoniae genomes found that FimH sequences are highly conserved. However, we surveyed a collection of K. pneumoniae isolates from patients with long-term indwelling catheters and identified isolates that possessed relaxed higher-binding FimH variants, which increased K. pneumoniae fitness in bladder infection models, suggesting that long-term residence within the urinary tract may select for higher-binding FimH variants.

Structural basis for adhesin secretion by the outer-membrane usher in type 1 pili.

Gram-negative bacteria produce chaperone-usher pathway pili, which are extracellular protein fibers tipped with an adhesive protein that binds to a receptor with stereochemical specificity to determine host and tissue tropism. The outer-membrane usher protein, together with a periplasmic chaperone, assembles thousands of pilin subunits into a highly ordered pilus fiber. The tip adhesin in complex with its cognate chaperone activates the usher to allow extrusion across the outer membrane. The structural requirements to translocate the adhesin through the usher pore from the periplasm to the extracellular space remains incompletely understood. Here, we present a cryoelectron microscopy structure of a quaternary tip complex in the type 1 pilus system from Escherichia coli, which consists of the usher FimD, chaperone FimC, adhesin FimH, and the tip adapter FimF. In this structure, the usher FimD is caught in the act of secreting its cognate adhesin FimH. Comparison with previous structures depicting the adhesin either first entering or having completely exited the usher pore reveals remarkable structural plasticity of the two-domain adhesin during translocation. Moreover, a piliation assay demonstrated that the structural plasticity, enabled by a flexible linker between the two domains, is a prerequisite for adhesin translocation through the usher pore and thus pilus biogenesis. Overall, this study provides molecular details of adhesin translocation across the outer membrane and elucidates a unique conformational state adopted by the adhesin during stepwise secretion through the usher pore. This study elucidates fundamental aspects of FimH and usher dynamics critical in urinary tract infections and is leading to antibiotic-sparing therapeutics.