Talar and Calcaneal Coordinate Axes Definitions across Foot Pathologies.

The understanding of foot and ankle biomechanics is improving as new technology provides more detailed information about the motion of foot and ankle bones with biplane fluoroscopy, as well as the ability to analyze the hindfoot under weightbearing conditions with weightbearing computed tomography. Three-dimensional anatomical coordinate systems are necessary to describe the 3D alignment and kinematics of the foot and ankle. The lack of standard coordinate systems across research study sites can significantly alter experimental data analyses used for pre-surgical evaluation and post-operative outcome assessments. Clinical treatment paradigms are changing based on the expanding knowledge of complex pes planovalgus morphologies or progressive collapsing foot deformity, which is present in both neurologic and non-neurologic populations. Four patient cohorts were created from 10 flexible PCFD, 10 rigid PCFD, 10 adult cerebral palsy, and 10 asymptomatic control patients. Six coordinate systems were tested on both the talus and calcaneus for all groups. The aim of this study was to evaluate axes definitions for the subtalar joint across four different patient populations to determine the influence of morphology on the implementation of previously defined coordinate systems. Different morphologic presentations from various pathologies have a substantial impact on coordinate system definitions, given that numerous axes definitions are defined through geometric fits or manual landmark selection. Automated coordinate systems that align with clinically relevant anatomic planes are preferred. Principal component axes are automatic, but do not align with clinically relevant planes and should not be used for such analysis where anatomic planes are critical.

Utility of cerebrovascular imaging biomarkers to detect cerebral amyloidosis.

INTRODUCTION: The relationship between cerebrovascular disease (CVD) and amyloid beta (Aß) in Alzheimer's disease (AD) is understudied. We hypothesized that magnetic resonance imaging (MRI)-based CVD biomarkers-including cerebral microbleeds (CMBs), lacunar infarction, and white matter hyperintensities (WMHs)-would correlate with Aß positivity on positron emission tomography (Aß-PET). METHODS: We cross-sectionally analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 1352). Logistic regression was used to calculate odds ratios (ORs), with Aß-PET positivity as the standard-of-truth. RESULTS: Following adjustment, WMHs (OR = 1.25) and superficial CMBs (OR = 1.45) remained positively associated with Aß-PET positivity (p < 0.001). Deep CMBs and lacunes exhibited a varied relationship with Aß-PET in cognitive subgroups. The combined diagnostic model, which included CVD biomarkers and other accessible measures, significantly predicted Aß-PET (pseudo-R2 = 0.41). DISCUSSION: The study highlights the translational value of CVD biomarkers in diagnosing AD, and underscores the need for more research on their inclusion in diagnostic criteria. CLINICALTRIALS: gov: ADNI-2 (NCT01231971), ADNI-3 (NCT02854033). HIGHLIGHTS: Cerebrovascular biomarkers linked to amyloid beta (Aß) in Alzheimer's disease (AD). White matter hyperintensities and cerebral microbleeds reliably predict Aß-PET positivity. Relationships with Aß-PET vary by cognitive stage. Novel accessible model predicts Aß-PET status. Study supports multimodal diagnostic approaches.

Recurrent Left Periprosthetic Posterior Knee Dislocation in an Elderly Woman With Dementia and Altered Mental Status: A Case Report.

The case presented in this article is one of recurrent left posterior periprosthetic knee dislocation (PPKD) in a patient with altered mental status (AMS). The patient, a 69-year-old female with a complex medical history including dementia, Ménière's syndrome, and left total knee arthroplasty, presented to the emergency department with AMS whereupon a left PPKD was discovered. Less than three weeks before this presentation, she sustained a left PPKD during a previous admission. During her current admission, she sustained yet another left PPKD after trials of closed reduction and immobilization. The patient eventually underwent a left cemented revision total knee arthroplasty with a hinged prosthesis. The implant was noted to be stable, and the patient had minimal pain postoperatively with no vascular or neurological injury. Upon outpatient follow-up, the patient reported doing well. There have been few documented cases of recurrent or chronic PPKD in individuals with AMS or restricted intellect. These comorbidities create a complex approach to diagnosing and treating the aforementioned orthopedic injury, and as this injury can have devastating consequences, quickly and effectively delivering diagnosis and treatment is vital. This case highlights the importance of early identification, risk factors, preoperative management, and appropriate operative course for patients with AMS and recurrent PPKDs.

Stent vs Stent-Less Ileal Conduits After Radical Cystectomy: Is There a Difference in Early Postoperative Outcomes?

INTRODUCTION: Placing ureteral stents at the uretero-ileal anastomosis for radical cystectomy with ileal conduit (RCIC) has long been common practice. Recently, some providers have begun omitting stents. We sought to investigate differences in perioperative and 30-day outcomes between patients who underwent radical cystectomy with ileal conduit (RCIC) with and without stents placed at the uretero-ileal anastomosis. METHODS: We identified RCICs performed between 2019 to 2021 in the National Surgical Quality Improvement Program database and corresponding Cystectomy-Targeted Participant Use File. Baseline demographics, comorbidities, and operative parameters were compared via Pearson's chi-square and t-tests between stented and stent-less RCICs. Outcomes of interest, including rates of urinary tract infections (UTIs), acute kidney injury (AKI), renal failure requiring dialysis, ileoileal anastomotic leaks, ureteral obstruction, urinary leak or fistula formation, reoperations, and 30-day hospital readmissions were compared using Pearson's chi-square. All statistical tests were 2 tailed with P < .05 considered significant. RESULTS: Five Thousand Four Hundred Eighteen RCICs were identified. Four hundred ninety-eight (9.2%) were stent-less. There were no differences in baseline demographics or comorbidities. Significantly fewer stented patients had robotic-assisted operations (23% vs 29%, P < .01). Stented patients had lower rates of urinary leak or fistula formation (3.1% vs 4.8%, P = .04). There was no significant difference in 30-day rates of UTIs, AKIs, renal failure, ileoileal anastomotic leaks, ureteral obstruction, reoperations, and readmissions. Limitations include retrospective design and lack of longitudinal tracking past 30 days. CONCLUSIONS: Stent-less patients had non-inferior outcomes compared to stented patients in most important 30-day outcomes. Our analysis suggests that stents may not be necessary in ileal conduit urinary diversion procedures.

Coronavirus awareness, prevention, and household hardship survey data for the CHAMPS HDSS network: Data collected between August and September of 2022 from the Bamako HDSS, Mali.

Data were gathered through a collaborative initiative to investigate impacts of the COVID-19 pandemic and related lockdowns on child and maternal health, economic hardships, and access to care for children and pregnant women by the Child Health and Mortality Prevention Surveillance (CHAMPS) Network. The data were gathered in Bamako, the capital city of Mali (population ∼2.9 million) between August and September of 2022 through a Health and Demographic Surveillance System (HDSS). Data collectors used a survey instrument specifically designed to measure household awareness, knowledge, and prevalence of COVID-19, as well as hardships that households experienced since the onset of the pandemic in March of 2020. The data are from two neighborhoods of Bamako, Banconi and Djicoroni; the Health and Demographic Surveillance System (HDSS) operating in these neighborhoods tracks the health of approximately 235,000 inhabitants. The data were collected using a stratified random sample of 454 households.

Neurological Symptoms and Cause of Death Among Young Children in Low- and Middle-Income Countries.

Importance: The emergence of acute neurological symptoms in children necessitates immediate intervention. Although low- and middle-income countries (LMICs) bear the highest burden of neurological diseases, there is a scarcity of diagnostic and therapeutic resources. Therefore, current understanding of the etiology of neurological emergencies in LMICs relies mainly on clinical diagnoses and verbal autopsies. Objective: To characterize the association of premortem neurological symptoms and their management with postmortem-confirmed cause of death among children aged younger than 5 years in LMICs and to identify current gaps and improve strategies to enhance child survival. Design, Setting, and Participants: This cross-sectional study was conducted between December 3, 2016, and July 22, 2022, at the 7 participating sites in the Child Health and Mortality Prevention Surveillance (CHAMPS) network (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa). Minimally invasive tissue sampling was performed at the CHAMPS sites with specimens from deceased children aged younger than 5 years. This study included deceased children who underwent a premortem neurological evaluation and had a postmortem-confirmed cause of death. Data analysis was performed between July 22, 2022, and January 15, 2023. Main Outcomes and Measures: Descriptive analysis was performed using neurological evaluations from premortem clinical records and from postmortem determination of cause of death (based on histopathology, microbiological testing, clinical records, and verbal autopsies). Results: Of the 2127 deaths of children codified during the study period, 1330 (62.5%) had neurological evaluations recorded and were included in this analysis. The 1330 children had a median age of 11 (IQR, 2-324) days; 745 (56.0%) were male and 727 (54.7%) presented with neurological symptoms during illness before death. The most common postmortem-confirmed neurological diagnoses related to death were hypoxic events (308 [23.2%]), meningoencephalitis (135 [10.2%]), and cerebral malaria (68 [5.1%]). There were 12 neonates with overlapping hypoxic events and meningoencephalitis, but there were no patients with overlapping meningoencephalitis and cerebral malaria. Neurological symptoms were similar among diagnoses, and no combination of symptoms was accurate in differentiating them without complementary tools. However, only 25 children (18.5%) with meningitis had a lumbar puncture performed before death. Nearly 90% of deaths (442 of 511 [86.5%]) with neurological diagnoses in the chain of events leading to death were considered preventable. Conclusions and Relevance: In this cross-sectional study of children aged younger than 5 years, neurological symptoms were frequent before death. However, clinical phenotypes were insufficient to differentiate the most common underlying neurological diagnoses. The low rate of lumbar punctures performed was especially worrying, suggesting a challenge in quality of care of children presenting with neurological symptoms. Improved diagnostic management of neurological emergencies is necessary to ultimately reduce mortality in this vulnerable population.

Rehabilitation and Return to Sport following Operative and Nonoperative Treatment of Anterior Shoulder Instability.

There has been growing interest in the rehabilitation process and timing of returning an athlete to sport following the management options for anterior shoulder instability. The purpose of this article is to review the current rehabilitation and return to sport (RTS) protocols for various nonoperative and operative management strategies following anterior shoulder instability events. When appropriate in the rehabilitation protocol, RTS testing should be criteria based, rather than time based, with a special focus given to psychological readiness in order to promote successful return to athletics and prevention of recurrent instability episodes in the future.

Outcomes After Anterior Cruciate Ligament Reconstruction With Quadriceps Tendon in Adolescent Athletes at Mean Follow-up of 4 Years.

Background: Despite increasing use of quadriceps tendon (QT) autograft in anterior cruciate ligament (ACL) reconstruction (ACLR), limited data exist regarding its outcomes in high-risk adolescent athletes. Purpose: To (1) report the outcomes after QT ACLR in adolescent athletes and (2) identify patient-related and surgery-related factors that may influence failure rates after QT ACLR. Study Design: Case series; Level of evidence, 4. Methods: All patients aged 14 to 17 years who underwent primary anatomic, transphyseal, single-bundle QT ACLR between 2010 and 2021 with a minimum 2-year follow-up were included for analysis. Demographic and surgical data as well as preoperative International Knee Documentation Committee (IKDC) and Marx activity scores were collected retrospectively. All patients were also contacted to assess postoperative patient-reported outcomes (PROs), including IKDC and Marx activity scores, and return-to-sports (RTS) data. Outcomes of interest included rates of revision ACLR and ipsilateral complications, contralateral ACL tears, difference in pre- and postoperative PROs, and rates of RTS. Patient and surgical characteristics were compared between groups who required revision ACLR versus those who did not. Results: A total of 162 patients met inclusion criteria, of which 89 adolescent athletes (mean age 16.2 ± 1.1 years, 64% female) were included for analysis at mean follow-up of 4.0 years. Postoperative IKDC scores were significantly higher than preoperative scores (88.5 vs 37.5; P < .001), whereas Marx activity scores decreased postoperatively (14.3 vs 12.2; P = .011). Successful RTS occurred in 80% of patients at a mean time of 9.7 ± 6.9 months, and 85% of these patients returned to the same or higher level of sports. The most common reasons for failure to RTS included lack of time (n = 7, 70%) and fearing reinjury in the operative knee (n = 5, 50%). The overall revision ACLR rate was 10% (n = 9), and contralateral ACL tears occurred in 14% (n = 12) of patients. The overall ipsilateral knee reoperation rate was 22.5% (n = 20). No statistically significant differences in patient or surgical characteristics were observed between patients who underwent revision ACLR and those who did not. Conclusion: At a minimum 2-year follow-up after QT ACLR, adolescent athletes experienced significantly improved postoperative IKDC scores, high rates of RTS, and low rates of graft failure, despite a relatively high ipsilateral reoperation rate. Surgeons may utilize this information when identifying the optimal graft choice for adolescent athletes who have sustained an ACL injury and wish to return to high level of sporting activities.

Timing of Surgery & Rehabilitation After Multiligamentous Knee Reconstruction.

PURPOSE OF REVIEW: To provide an overview of the current evidence of the timing of surgery and rehabilitation after multiligamentous knee injuries (MLKIs) and offer insights into the ongoing multi-center randomized controlled study, the 'STaR trial'. RECENT FINDINGS: Due to the complexity of the MKLIs, they are usually treated surgically with the goal of either repairing or reconstructing the injured ligaments. Although the current literature on MLKIs is relatively extensive, the consensus on the timing of surgery or rehabilitation following surgery for MLKIs is still lacking. While current literature mostly suggests early treatment, there is also evidence preferring delayed treatment. Furthermore, evidence on the timing of postoperative rehabilitation is limited. Thus, the current multi-center randomized controlled study, the 'STaR trial', is expected to respond to these questions by adding new high-level evidence. The MLKIs are often associated with knee dislocation and constitute a highly complex entity, including concomitant injuries, such as neurovascular, meniscal, and cartilaginous injuries. The treatment of MLKIs usually aims to either repair or reconstruct the injured ligaments, however, there is no general consensus on the timing of surgery or rehabilitation following an MLKI surgery. This current review stresses the need for more high-level research to address the paucity of evidence-based treatment guidelines for the treatment of complex MLKIs.

Impact of TP53 mutations on brain metastasis control in non-small cell lung cancer patients undergoing stereotactic radiosurgery.

Purpose: To investigate whether TP53 variants may be correlated with overall survival and local control following stereotactic radiosurgery (SRS) for brain metastases (BMs) from non-small cell lung cancer (NSCLC). Methods: Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified. Overall survival and freedom from local intracranial progression (FFLIP) were estimated via Kaplan-Meier method. Cox models assessed TP53 variant status (pathogenic variant, PV; variant not detected, ND). Results: 255 patients underwent molecular profiling for TP53, among whom 144 (56%) had a TP53 PV. Median follow-up was 11.6 months. OS was not significantly different across TP53 status. A trend toward superior FFLIP was observed for PV (95% CI 62.9 months-NR) versus ND patients (95% CI 29.4 months-NR; p=0.06). Superior FFLIP was observed for patients with one TP53 variant versus those with TP53 ND. Conclusion: Among NSCLC patients with BMs, the potential association between TP53 status and post-SRS FFLIP warrants further investigation in a larger prospective cohort.

Advancements in electrochemical immunosensors towards point-of-care detection of cardiac biomarkers.

Cardiovascular disease remains the leading cause of death worldwide, with mortality rates increasing annually. This underscores the urgent need for accurate diagnostic and monitoring tools. Electrochemical detection has emerged as a promising method for swiftly and precisely measuring specific biomarkers in bodily fluids. This approach is not only cost-effective and efficient compared to traditional clinical methods, but it can also be tailored to detect individual biomarkers, which makes it particularly well-suited for point-of-care (POC) applications. The ability to conduct testing at the point of care is crucial for timely interventions and personalized disease management, empowering healthcare providers to tailor treatment plans based on real-time biomarker data. Thanks to recent advancements in nanomaterials, we've seen significant progress in electrochemical detection, leading to the development of specialized rapid immunoassay systems. These systems utilize specific antibodies to target molecules, expanding the range of detectable biomarkers. This innovation has the potential to revolutionize the diagnosis and treatment of cardiovascular diseases by enhancing detection sensitivity and specificity. Ultimately, these advancements aim to improve patient outcomes by enabling earlier diagnosis, more precise monitoring, and personalized therapeutic interventions, which will contribute to more effective management of cardiovascular health globally.

Deciphering the relative importance of genetic elements in hypervirulent Klebsiella pneumoniae to guide countermeasure development.

BACKGROUND: Quantitating the contribution of phenotype-responsible elements in hypervirulent Klebsiella pneumoniae is needed. METHODS: Isogenic mutants of four hypervirulent clinical isolates that produced K1 (ST23), K2 (ST86), K20 (ST1544), or K54 (ST29) capsules (mean 2.2 log10 LD50 (range 1.5-2.9)) were created to measure the effects on LD50 in a murine model of the hypervirulence-associated plasmid (pVir), iucA, prmpA, prmpA2 (truncated), irp2, and clbBC. FINDINGS: Curing pVir had the greatest increase in survival (mean LD50 to 7.6 (range 7.0-9.0, p ≤ 0.0001), a dosage comparable to classical K. pneumoniae. Results also showed increased mean LD50s for ΔprmpA (5.9, p ≤ 0.0001), ΔiucA (3.6, p ≤ 0.0001), Δirp2 (3.4), ΔrmpAΔiucA (6.3, p ≤ 0.0001), and ΔpVirΔirp2 (8.7, p ≤ 0.0001). Notably ΔpVir had an additional mean LD50 increase of 1.3 compared to the pVir-encoded ΔprmpAΔiucA (p ≤ 0.01), suggesting presence of additional pVir-virulence genes. Truncated pRmpA2 did not contribute to virulence. Odd ratios in the absence of pVir/yersiniabactin, pVir, pRmpA/aerobactin, pRmpA, aerobactin, yersiniabactin, and colibactin demonstrated a 250-fold, 67-fold, 20-fold, 16.7-fold, 9.6-fold, and 1.7-fold decrease in lethality respectively. INTERPRETATION: These data can guide countermeasure development. FUNDING: This work was supported by NIH R21 AI123558-01 and 1R21AI141826-01A1 (Dr. Russo) and the Department of Veterans Affairs VA Merit Review (I01 BX004677-01) (Dr. Russo). This study was also partially funded by the U.S. Defense Health Program (DHP) Operations and Maintenance.

Low-dose sufentanil does not affect tolerance to LBNP-induced central hypovolemia or blood pressure responses during the cold pressor test.

Hemorrhage is a leading cause of death in the pre-hospital setting. Since pain often accompanies a hemorrhagic insult, the administered pain medication must not interfere with critical autonomic regulation of arterial blood pressure and vital organ perfusion. The purpose of this study was to test two unique hypotheses: a) sublingual sufentanil (Dsuvia) impairs tolerance to progressive central hypovolemia, and b) sublingual sufentanil attenuates pain sensation and the accompanying cardiovascular responses to a noxious stimulus. Twenty-nine adults participated in this double-blinded, randomized, crossover, placebo-controlled trial. Following sublingual administration of sufentanil (30 µg) or placebo, participants completed a progressive lower-body negative pressure (LBNP) challenge to tolerance, followed by a cold pressor test (CPT) after LBNP recovery. Addressing the first aim, tolerance to LBNP was not different between trials (p = 0.495). Decreases in systolic blood pressure from baseline to the end of LBNP also did not differ between trials (time: p<0.001, trial p=0.477, interaction p=0.587). Finally, increases in heart rate from baseline to the end of LBNP did not differ between trials (time: p < 0.001, trial p= p=0.626, interaction p = 0.424). Addressing the second aim, sufentanil attenuated perceived pain (p < 0.001) in response to the CPT, though the magnitude of the change in mean blood pressure during the CPT (p = 0.078) was not different between trials. These data demonstrate that sublingual sufentanil does not impair tolerance to progressive central hypovolemia. Additionally, sublingual sufentanil attenuates perceived pain, but not the accompanying mean blood pressure responses to the CPT.

Rapid Autopsy to Define Dendritic Cell Spatial Distribution and T Cell Association in Lung Adenocarcinoma.

Immunotherapy response is associated with the presence of conventional dendritic cells (cDCs). cDC type 1 (cDC1) is critically important for CD8+ T cell activation, cDC type 2 (cDC2) regulates CD4+ T cell responses, and mature regulatory cDCs may dampen T cell responses in the tumor microenvironment (TME). However, we lack a clear understanding of cDC distribution in the human TME, cDC prevalence in metastatic sites, and cDC differences in early- versus late-stage disease. Rapid autopsy specimens of 10 patients with lung adenocarcinoma were evaluated to detect cDCs and immune cells via multiplex immunofluorescence using 18 markers and 42 tumors. First, we found that T cells, cDC1, and cDC2 were confined to stroma, whereas mature regulatory DCs were enriched in tumor, suggesting unique localization-specific functions. Second, lung and lymph node tumors were more enriched in T cells and cDCs than liver tumors, underscoring differences in the TME of metastatic sites. Third, although the proportion of T cells and cDC1 did not differ in different stages, an increase in the proportion of cDC2 and macrophages in late stage suggests potential differences in regulation of T cell responses in different stages. Collectively, these findings provide new, to our knowledge, insights into cDC biology in human cancer that may have important therapeutic implications.

Evaluating urine volume and host depletion methods to enable genome-resolved metagenomics of the urobiome.

Background: The gut microbiome has emerged as a clear player in health and disease, in part by mediating host response to environment and lifestyle. The urobiome (microbiota of the urinary tract) likely functions similarly. However, efforts to characterize the urobiome and assess its functional potential have been limited due to technical challenges including low microbial biomass and high host cell shedding in urine. Here, to begin addressing these challenges, we evaluate urine sample volume (100 ml - 5 mL), and host DNA depletion methods and their effects on urobiome profiles in healthy dogs, which are a robust large animal model for the human urobiome. We collected urine from seven dogs and fractionated samples into aliquots. One set of samples was spiked with host (canine) cells to model a biologically relevant host cell burden in urine. Samples then underwent DNA extraction followed by 16S rRNA gene and shotgun metagenomic sequencing. We then assembled metagenome assembled genomes (MAGs) and compared microbial composition and diversity across groups. We tested six methods of DNA extraction: QIAamp BiOstic Bacteremia (no host depletion), QIAamp DNA Microbiome, Molzym MolYsis, NEBNext Microbiome DNA Enrichment, Zymo HostZERO, and Propidium Monoazide. Results: In relation to urine sample volume, 3 3.0 mL resulted in the most consistent urobiome profiling. In relation to host depletion, individual (dog) but not extraction method drove overall differences in microbial composition. DNA Microbiome yielded the greatest microbial diversity in 16S rRNA sequencing data and shotgun metagenomic sequencing data, and maximized MAG recovery while effectively depleting host DNA in host-spiked urine samples. As proof-of-principle, we then mined MAGs for core metabolic functions and environmental chemical metabolism. We identified long chain alkane utilization in two of the urine MAGs. Long chain alkanes are common pollutants that result from industrial combustion processes and end up in urine. Conclusions: This is the first study, to our knowledge, to demonstrate environmental chemical degradation potential in urine microbes through genome-resolved metagenomics. These findings provide guidelines for studying the urobiome in relation to sample volume and host depletion, and lay the foundation for future evaluation of urobiome function in relation to health and disease.

Cancer incidence and survival for 11 cancers in the Commonwealth: a simulation-based modelling study.

BACKGROUND: The number of new cancer cases in Commonwealth countries rose by 35% between 2008 and 2018, but progress in cancer control has been slow in many low-income and lower-middle-income member states. We aimed to examine cancer outcomes and priority areas in the Commonwealth to provide insight and guidance on prioritisation of efforts to improve cancer survival and make the best use of scarce resources. METHODS: We adapted a previously developed microsimulation model of global cancer survival for 11 cancer sites (oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, breast, cervix uteri, and prostate). All 56 Commonwealth countries were included and classified based on the 2020 World Bank Income groups (low-income, lower-middle-income, upper-middle-income, and high-income countries) and Commonwealth geographical areas. We modelled the number of incident cancer cases in each Commonwealth country in 2020, based on age group-specific estimates of incidence rates from GLOBOCAN 2020. We simulated 5-year net survival for each patient, accounting for the stage at diagnosis (I-IV), availability of specific treatment and imaging modalities, and quality of care (based on residual differences in expected versus observed survival after accounting for the availability and effectiveness of treatment and imaging modalities). We also simulated counterfactual policy scenarios, in which we scaled up various aspects of cancer care to the mean level of high-income countries to estimate the comparative effectiveness of different policies. FINDINGS: Incident cancers in the Commonwealth accounted for an estimated 14·3% of global diagnosed cancer cases in 2020 among the 11 cancers modelled (1 610 000 Commonwealth cases [95% UI 1 556 000-1 674 000] of 11 227 000 global cases [11 069 000-11 406 000]) and are estimated to increase to 17·3% in 2050 due to population growth (3 330 000 [3 154 000-3 539 000] of 19 308 000 [18 706 000-19 911 000]). The 5-year net survival across 11 cancers combined in 2020 was 30·7% (95% UI 22·4-38·6) in Commonwealth countries, ranging from 4·1% (0·04-15·2) in low-income countries, 17·8% (3·7-30·9) in lower-middle-income countries, 33·1% (23·7-46·0) in upper-middle-income countries, to 59·0% (57·8-60·2) in high-income countries. Among single treatment policies, scaling up access to radiotherapy had the largest survival impact in low-income countries, surgery had the largest impact in lower-middle-income and upper-middle-income countries, and targeted therapy had the largest impact in high-income countries. By geographical area, improving radiotherapy availability was estimated to have the largest impact in Africa, surgery in Asia, targeted therapy in the Caribbean and the Americas and Europe, and quality of care in the Pacific Commonwealth countries. Comparing packages of scaling up the availability of all treatment modalities versus imaging modalities, expanding availability of imaging yielded the largest benefits in high-income countries, and in the Caribbean and the Americas, Europe, and the Pacific, whereas expanding treatment yielded larger benefits in all other income groups and geographical areas. INTERPRETATION: We found large variation in 5-year net survival, with a nearly 15-times difference in cancer survival by country income group within the Commonwealth. Efforts to improve the availability of treatment and imaging modalities and quality of care will be crucial to reduce these disparities, with specific priorities of scale-up policies varying by setting. The Commonwealth could leverage a broad range of knowledge and resources and have an important role in supporting member countries with setting-specific priorities to improve cancer outcomes. FUNDING: Harvard T H Chan School of Public Health.

Elucidation of the genetic architecture of water absorption capacity in hard winter wheat through genome wide association study.

Water absorption capacity (WAC) influences various aspects of bread making, such as loaf volume, bread yield, and shelf life. Despite its importance in the baking process and end-product quality, its genetic determinants are less explored. To address this limitation, a genome-wide association study was conducted on 337 hard wheat (Triticum aestivum L.) genotypes evaluated over 5 years in multi-environmental trials. Phenotyping was done using the solvent retention capacity (SRC) test with water (SRC-water), sucrose (SRC-sucrose), lactic acid (SRC-lactic acid), and sodium carbonate (SRC-carbonate) as solvents. Individuals were genotyped using genotyping-by-sequencing to detect single nucleotide polymorphisms across the wheat genome. To detect the genomic regions that underline the SRCs and gluten performance index (GPI), a genome-wide association study was performed using six multi-locus models using the mrMLM package in R. Adjusted means for SRC-water ranged from 54.1% to 66.5%, while SRC-carbonate exhibited a narrow range from 84.9% to 93.9%. Moderate to high genomic heritability values were observed for SRCs and GPI, ranging from h2 = 0.61 to 0.88. The genome-wide association study identified a total of 42 quantitative trait nucleotides (QTNs), of which five explained over 10% of the phenotypic variation (R2 ≥ 10%). Most of the QTNs were detected on chromosomes 1A, 1B, 3B, and 5B. Few QTNs, such as S1A_5190318, S1B_3282665, S4D_472908721, and S7A_37433960, were located near gliadin, glutenin starch synthesis, and galactosyltransferase genes. Overall, these results show WAC to be under polygenic genetic control, with genes involved in the synthesis of key flour components influencing overall water absorption.

Evaluation of Open-Source Ciliary Analysis Software in Primary Ciliary Dyskinesia: A Comparative Assessment.

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by alterations in motile cilia function. The diagnosis of PCD is challenging due to the lack of standardized methods in clinical practice. High-speed video microscopy analysis (HSVA) directly evaluates ciliary beat frequency (CBF) in PCD. Recently, open-source ciliary analysis software applications have shown promise in measuring CBF accurately. However, there is limited knowledge about the performance of different software applications, creating a gap in understanding their comparative effectiveness in measuring CBF in PCD. We compared two open-source software applications, CiliarMove (v219) and Cilialyzer (v1.2.1-b3098cb), against the manual count method. We used high-speed videos of nasal ciliary brush samples from PCD RSPH4A-positive (PCD (RSPH4A)) patients and healthy controls. All three methods showed lower median CBF values for patients with PCD (RSPH4A) than in healthy controls. CiliarMove and Cilialyzer identified lower CBF in patients with PCD (RSPH4A), similarly to the manual count. Cilialyzer, CiliarMove, and manual count methods demonstrated statistical significance (p-value < 0.0001) in the difference of median CBF values between patients with PCD (RSPH4A) and healthy controls. Correlation coefficients between the manual count values against both software methods demonstrated positive linear relationships. These findings support the utility of open-source software-based analysis tools. Further studies are needed to validate these findings with other genetic variants and identify the optimal software for accurate CBF measurement in patients with PCD.

The Approved Live-Attenuated Chikungunya Virus Vaccine (IXCHIQ®) Elicits Cross-Neutralizing Antibody Breadth Extending to Multiple Arthritogenic Alphaviruses Similar to the Antibody Breadth Following Natural Infection.

The first vaccine against chikungunya virus (CHIKV) was recently licensed in the U.S., Europe, and Canada (brand IXCHIQ®, referred to as VLA1553). Other pathogenic alphaviruses co-circulate with CHIKV and major questions remain regarding the potential of IXCHIQ to confer cross-protection for populations that are exposed to them. Here, we characterized the cross-neutralizing antibody (nAb) responses against heterotypic CHIKV and additional arthritogenic alphaviruses in individuals at one month, six months, and one year post-IXCHIQ vaccination. We characterized nAbs against CHIKV strains LR2006, 181/25, and a 2021 isolate from Tocantins, Brazil, as well as O'nyong-nyong virus (ONNV), Mayaro virus (MAYV), and Ross River virus (RRV). IXCHIQ elicited 100% seroconversion to each virus, with the exception of RRV at 83.3% seroconversion of vaccinees, and cross-neutralizing antibody potency decreased with increasing genetic distance from CHIKV. We compared vaccinee responses to cross-nAbs elicited by natural CHIKV infection in individuals living in the endemic setting of Puerto Rico at 8-9 years post-infection. These data suggest that IXCHIQ efficiently and potently elicits cross-nAb breadth that extends to related alphaviruses in a manner similar to natural CHIKV infection, which may have important implications for individuals that are susceptible to alphavirus co-circulation in regions of potential vaccine rollout.

Investigating Protein-Nucleic Acid Binding Interactions with Diethylpyrocarbonate Covalent Labeling-Mass Spectrometry.

Nucleic acids are important biomolecules that facilitate numerous cellular functions and have in recent years become promising candidates for treating disease. Consequently, there is a need for methods to characterize protein interactions with these molecules. Here, we demonstrate that diethylpyrocarbonate (DEPC) covalent labeling-mass spectrometry (CL-MS) can provide structural information for protein-nucleic acid binding by characterizing the binding sites of two DNA aptamers specific to thrombin. Reductions in thrombin labeling are observed at the pair's binding interfaces. Furthermore, we find that binding of the aptamers causes changes in labeling at residues in the thrombin active site and known exosites for each aptamer, showcasing the sensitivity of DEPC CL-MS to significant allosteric changes.