Urinary and fecal potassium excretion prediction in dairy cattle: A meta-analytic approach.

Quantification of potassium (K) excretion in dairy cattle is important to understand the environmental impact of dairy farming. To improve and monitor the environmental impact of dairy cows, there is a need for a simple, inexpensive, and less laborious method to quantify K excretion on dairy farms. The adoption of empirical mathematical models has been shown to be a promising tool to address this issue. Thus, the current study aimed to develop empirical predictive models for K excretion in dairy cattle from urine and feces that can help evaluate efficiency and monitor the environmental impact of milk production. To develop urine K (KUr, g/d) and fecal K (KFa, g/d) excretion prediction models, published literature that involved 45 and 54 treatment means from 10 and 14 studies, respectively, were used. Some studies reported either urinary or fecal K excretion or both, but in total, treatment means used to develop the models were from 17 studies. The linear mixed models were fitted with the fixed effect of K intake, DMI, dietary K content, urine volume, milk yield, and water intake, and the random effect of study weighted according to the number of observations. Leave-one-study out cross-validation was used to evaluate the performance of the proposed models and the best model was based on the lowest root mean square prediction error as a percentage of the observed mean values (RMSPE%) and highest concordance correlation coefficient (CCC). As expected, most daily K excretion was through urine (202.5 ± 92.1 g/d) than through feces (43.5 ± 21.0 g/d), and among the proposed models, the model including dietary K concentration showed poor predictive ability for both KUr and KFa with the lowest CCC values (-0.15 and -0.02, respectively) and systematic bias. The model developed using DMI to predict KFa excretion showed reasonable accuracy, as indicated by RMSPE, CCC, and R2 marginal of 46.6%, 0.42, and 48%, respectively. Among the proposed models for KUr and KFa, the model with K intake demonstrated better predictive performance, showing minimal systematic bias and random errors due to data variability of >92%. While these proposed models suggested that reducing K intake can lead to a decrease in K excretion, it is important to ensure that dairy cows receive adequate amounts of this nutrient to maintain optimal health and productivity, especially during periods of heat stress.

Metabolic dysfunction and incidence of heart failure subtypes among Black individuals: The Jackson Heart Study.

AIMS: The extent to which metabolic syndrome (MetS) severity influences subclinical myocardial remodelling, heart failure (HF) incidence and subtypes, remains unclear. We assessed the association of MetS with incident HF (including ejection fraction subtypes) among Black individuals. METHODS AND RESULTS: We included 4069 Jackson Heart Study participants (mean age 54.4 years, 63.8% women, 37.2% with MetS) without HF. We categorized participants based on MetS status and MetS severity scores (based on waist circumference [MetS-Z-WC] and body mass index [MetS-Z-BMI]). We assessed the associations of MetS indices with echocardiographic parameters, biomarkers of myocardial damage (high-sensitivity cardiac troponin I [hs-cTnI] and B-type natriuretic peptide [BNP]) and incident HF hospitalizations including HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). MetS severity was associated with subclinical cardiac remodelling (assessed by echocardiographic measures and biomarkers of myocardial damage). Over a median of 12 years, 319 participants developed HF (157 HFpEF, 149 HFrEF and 13 HF of unknown type). MetS was associated with a twofold greater risk of HF (hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.64-2.61). Compared to the lowest quartile (Q1) of MetS-Z-WC, the highest quartile (Q4) conferred a higher risk of HF (HR 2.35, 95% CI 1.67-3.30), with a stronger association for HFpEF (Q4 vs. Q1: HR 4.94, 95% CI 2.67-9.14) vs. HFrEF (HR 1.69, 95% CI 1.06-2.70). CONCLUSIONS: Metabolic syndrome severity was associated with both HF subtypes among Black individuals, highlighting the importance of optimal metabolic health for preventing HF.

Molecular detection of Coxiella burnetii in ticks infesting wild and domestic animals in the Eastern region of Punjab, Pakistan.

Tick-borne pathogens are significant for human, veterinary, and wildlife health. Coxiella burnetii is an example that is widely distributed across various hosts and can cross species boundaries. In Pakistan, there is a scarcity of data regarding C. burnetii at the intersection of wildlife and livestock. Ticks were collected from ruminants and wildlife from the districts of Kasur, Pakpattan, and Okara in Pakistan. Five tick species totaling 571 ticks were collected, with the following distribution: 56.4% Hyalomma anatolicum, 22.4% Rhipicephalus microplus, 10.5% Hyalomma marginatum, 7.9% Rhipicephalus sanguineus, and 2.8% Rhipicephalus turanicus. Fifty tick pools were screened for C. burnetii to amplify a segment of the IS1111 using real-time PCR assays. Ticks collected from sheep and goats had a greater rate of positivity for C. burnetii (40% and 38%, respectively) compared to Indian long-eared hedgehogs with a prevalence of 2%. Coxiella burnetii was prominent in Rhipicephalus microplus (92.3%) and Hyalomma anatolicum (88.9%), followed by Rhipicephalus turanicus (66.6%), Rhipicephalus sanguineus (33.3%), and Hyalomma marginatum (25.0%). Ticks from Pakpattan district displayed the highest prevalence of C. burnetii (88.9%), whereas the lowest was observed in ticks from Kasur district (77.3%). There was no significant association between tick gender and C. burnetii infection. Female host animals were more likely to harbor ticks containing C. burnetii, with a prevalence rate of 81.8%. The research underscores the urgent need for comprehensive studies on C. burnetii in Pakistan, especially at the interface of wildlife and livestock. The high prevalence rates observed in certain tick species and geographic regions emphasize the importance of targeted public health interventions. Future research should focus on elucidating the transmission dynamics and implementing effective control measures to mitigate the impact of these pathogens on human, veterinary, and wildlife health in the region.

Mixed-methods protocol for the WiSSPr study: Women in Sex work, Stigma and psychosocial barriers to Pre-exposure prophylaxis in Zambia.

INTRODUCTION: Women engaging in sex work (WESW) have 21 times the risk of HIV acquisition compared with the general population. However, accessing HIV pre-exposure prophylaxis (PrEP) remains challenging, and PrEP initiation and persistence are low due to stigma and related psychosocial factors. The WiSSPr (Women in Sex work, Stigma and PrEP) study aims to (1) estimate the effect of multiple stigmas on PrEP initiation and persistence and (2) qualitatively explore the enablers and barriers to PrEP use for WESW in Lusaka, Zambia. METHODS AND ANALYSIS: WiSSPr is a prospective observational cohort study grounded in community-based participatory research principles with a community advisory board (CAB) of key population (KP) civil society organi sations (KP-CSOs) and the Ministry of Health (MoH). We will administer a one-time psychosocial survey vetted by the CAB and follow 300 WESW in the electronic medical record for three months to measure PrEP initiation (#/% ever taking PrEP) and persistence (immediate discontinuation and a medication possession ratio). We will conduct in-depth interviews with a purposive sample of 18 women, including 12 WESW and 6 peer navigators who support routine HIV screening and PrEP delivery, in two community hubs serving KPs since October 2021. We seek to value KP communities as equal contributors to the knowledge production process by actively engaging KP-CSOs throughout the research process. Expected outcomes include quantitative measures of PrEP initiation and persistence among WESW, and qualitative insights into the enablers and barriers to PrEP use informed by participants' lived experiences. ETHICS AND DISSEMINATION: WiSSPr was approved by the Institutional Review Boards of the University of Zambia (#3650-2023) and University of North Carolina (#22-3147). Participants must give written informed consent. Findings will be disseminated to the CAB, who will determine how to relay them to the community and stakeholders.

Structures of the human leading strand Polε-PCNA holoenzyme.

In eukaryotes, the leading strand DNA is synthesized by Polε and the lagging strand by Polδ. These replicative polymerases have higher processivity when paired with the DNA clamp PCNA. While the structure of the yeast Polε catalytic domain has been determined, how Polε interacts with PCNA is unknown in any eukaryote, human or yeast. Here we report two cryo-EM structures of human Polε-PCNA-DNA complex, one in an incoming nucleotide bound state and the other in a nucleotide exchange state. The structures reveal an unexpected three-point interface between the Polε catalytic domain and PCNA, with the conserved PIP (PCNA interacting peptide)-motif, the unique P-domain, and the thumb domain each interacting with a different protomer of the PCNA trimer. We propose that the multi-point interface prevents other PIP-containing factors from recruiting to PCNA while PCNA functions with Polε. Comparison of the two states reveals that the finger domain pivots around the [4Fe-4S] cluster-containing tip of the P-domain to regulate nucleotide exchange and incoming nucleotide binding.

A service evaluation of weight management for glycaemic control and remission of type 2 diabetes using traditional food in Nepal (Ho-DIRECT NEPAL): a single-arm trial.

Background: Remission of early type 2 diabetes (T2D) is possible; however, diet programmes proven effective are unaffordable in many southeast Asian populations where T2D is more frequent and more aggressive at lower body weight and younger age. We evaluate an entirely food-based service. Methods: This study employed a single-arm intervention and follow-up design for intervention evaluation in existing hospital people with T2D of under 5 years known duration. Individuals attending a diabetes clinic in Kathmandu with early T2D (<5 years) aged 30-70 years, BMI ≥23 kg/m2, were offered a low-cost nutritionally complete diet-programme, using traditional Nepali foods to provide 8-weeks ∼850 kcal/day weight loss induction, and then weight maintenance. The participants received 4-weekly dietetic appointments (30-45 min) and verbo-pictorial leaflets using household measures. Glucose-lowering medications (49/70 at baseline) were stopped at baseline or soon after. The study was registered as ISRCTN10671396, testing a traditional food-based intervention for weight loss and T2D remission. Findings: For 70 individuals (45 female) invited between March 19, 2022 and September 19, 2023, baseline mean (SD) age was 48.6 (9.9) years, bodyweight 74.6 (9.5) kg, BMI 29.7 (3.6) kg/m2, known diabetes duration 2.5 (1.9) years, HbA1c on treatment 8.1 (1.6) %. At 12, 24 and 52 weeks respectively, evaluating n = 44, 46, 45, bodyweight was 70.1 (8.5), 69.8 (8.9), 70.0 (8.8) kg, HbA1c 6.8 (0.9), 6.9 (1.5), 7.1 (1.3) %; HbA1c <6.5% was recorded for 46%, 48% and 36% and remission of T2D (HbA1c <6.5% off medication >3 months) in 43%, 39% and 29%. The main reported adherence barriers were fears of weakness, hunger, and inconvenience during travel. Incentives were ease of the diet, reduced doses and costs of medications, and improved appearance. Interpretation: Traditional food-based weight management can valuably improve control, reduce medication needs, and generate remissions of established T2D, but adherence barriers must be overcome to optimise outcomes. Funding: All Saints Educational Trust, England.

Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.

BACKGROUND: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. RESULTS: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. CONCLUSION: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Robotic mitral surgery: recent advances and outcomes.

PURPOSE OF REVIEW: This review explores recent advancements in robotic cardiac surgery, specifically focusing on its application in diverse mitral valve surgeries. The aim is to provide an overview of current clinical practices and supporting evidence in this evolving field. RECENT FINDINGS: A literature review indicates a 30% surge in robotic mitral valve repair from 2015 to 2021, paralleled by a decline in sternotomy-based repair per the STS database. Robotic mitral valve repair consistently shows effective and safe outcomes, with comparable mortality but lower morbidity risks than sternotomy and thoracotomy. The robotic approach exhibits lower conversion to valve replacement, shorter ICU stays, and reduced 30-day readmissions. For experienced programs, robotic techniques prove versatile in various pathologies, including rheumatic heart valve disease, infective endocarditis, ischemic cardiomyopathy, and mitral annular calcification necessitating valve replacement. Literature supports their selective use in high-risk scenarios, including redo surgeries and elderly patients. SUMMARY: Recent evidence supports the growing use of robotic approaches in mitral valve surgery, highlighting their efficacy with comparable mortality rates but lower morbidity risks. Robotic techniques consistently yield positive outcomes across various pathologies and patient profiles, signaling a potential paradigm shift in mitral valve interventions.

CC-Connect: Identifying solutions to elevating the cancer experience for adolescents and young adults (AYA) with cancer.

Adolescents and young adults with cancer (AYAs, aged 15 to 39 years) experience unique challenges due to their developmental life stage, and many have limited access to support and resources. CC-Connect, the patient assistance component of the White House Cancer Moonshot CC-DIRECT initiative that aims to help childhood cancer families find the best care for their child, undertook a multipronged effort to identify key strategies for addressing the unique needs of AYAs with cancer. This paper describes the four strategies that emerged to form a comprehensive framework for addressing the unmet needs of AYAs with cancer, which can improve outcomes and enhance the cancer care experience for this vulnerable population.

Identification of functional white matter networks in BOLD fMRI.

White matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimer's Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLD-FMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well-defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.

Antipsychotic exposure and infection risk in people with schizophrenia spectrum disorders during the COVID-19 pandemic: a Danish nationwide registry study.

BACKGROUND: Infection risk and mortality are increased in schizophrenia spectrum disorders, which was corroborated during the COVID-19 pandemic. However, evidence is lacking regarding the additional impact of antipsychotic drugs, and the highly debated safety of clozapine treatment during large-scale infection outbreaks. Therefore, we aimed to investigate risk of COVID-19 and non-COVID respiratory infections during exposure to antipsychotics. METHODS: We used several nationwide Danish registers (National Prescription Registry, National Hospital Registry, Psychiatric Research Register, Microbiology Database, Vaccination Registry, Cause of Death Registry, and Database for Labour market Research) to investigate all individuals aged 18 years or older with a schizophrenia spectrum disorder (ICD-10: F20-F29) living in Denmark between Jan 1 and March 1, 2020. Antipsychotic exposure groups were defined as prevalent-users and incident-users. The full observation period was March 1, 2020 to Dec 31, 2021. Antipsychotic exposure was defined in a time-varying manner and compared with non-exposure. Risk was calculated for mild infection outcomes (positive SARS-CoV-2 PCR and anti-infective drug prescriptions) and severe infection outcomes (hospitalisation and death) related to COVID-19 and non-COVID-19 respiratory infections. Outcomes were adjusted for demographics, socio-economic factors, and comorbidity. FINDINGS: Of 85 083 individuals (44 293 men [52·1%] and 40 790 women [47·9%], median age 45·8 years [IQR 31·1-60·2]) with pre-existing schizophrenia spectrum disorders, 30 984 had antipsychotic exposure periods. Ethnicity data were not available. During antipsychotic exposure compared with non-exposed periods, assessing mild infection outcomes, risk of a positive SARS-CoV-2 test was decreased (hazard ratio 0·91 [95% CI 0·85-0·97]) and risk of redeeming an anti-infective drug was not statistically significantly different (1·01 [0·97-1·06]). For severe infection outcomes, COVID-19-related hospitalisation risk was increased (1·28 [1·07-1·52]) although COVID-19-related death was not statistically significantly increased (1·24 [0·82-1·86]). For non-COVID-19 respiratory infections, risk was increased both for hospitalisation (1·61 [1·44-1·79]) and death (1·61 [1·18-2·21]). Specifically, COVID-19 hospitalisation risk was increased in individuals older than 70 years, and non-COVID-19 hospitalisation risk increased in individuals older than 40 years and death risk in age groups of 50-59 years and 70-79 years. Based on homogeneity testing, no apparent excess risk of any outcome was observed with clozapine exposure compared with other antipsychotics. INTERPRETATION: During antipsychotic exposure compared with unexposed periods, risk of severe infection outcomes increases. It seems reasonable to initiate infection countermeasures, such as pneumococcal vaccination, in people older than 40 years with schizophrenia spectrum disorders, who commence or are treated with antipsychotics. We do not suggest the avoidance of specific antipsychotics but rather adherence to treatment guidelines and a call for increased vigilance regarding this at-risk group. FUNDING: Mental Health Services of the Capital Region of Denmark.

Annealing 1,2,4-triazine to iridium(III) complexes induces luminogenic behaviour in bioorthogonal reactions with strained alkynes.

A phenanthroline-type ligand containing an annealed 1,2,4-triazine ring was used to prepare novel Ir(III) complexes 3 and 4. The complexes are non-luminescent but show luminogenic behaviour following the inverse electron demand Diels-Alder (IEDDA) reaction with bicyclononyne (BCN) derivatives. It was observed that the complexes react with BCN-C10 faster than the corresponding free ligands. The magnitude of this accelerating metal-coordination effect, however, is less profound than in previously reported Ir(III) complexes of 1,2,4-triazines, in which the triazine was directly coordinated to the Ir(III) metal centre. Nevertheless, luminogenic behaviour opens prospects for the use of such complexes in bioimaging applications, which was demonstrated by developing a convenient methodology using the "chemistry on the complex" concept for labelling antibodies with luminescent Ir(III) complexes. The bioorthogonal reactivity of complex 4 was demonstrated by metabolically labelling live cells with BCN groups, followed by a luminogenic IEDDA reaction with the triazine iridium complex.

Twice-Yearly Depemokimab in Severe Asthma with an Eosinophilic Phenotype.

BACKGROUND: Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals. METHODS: In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks. RESULTS: Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials. CONCLUSIONS: Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).

Case Report: Glossopharyngeal Allodynia-Related Odynophagia and Dysphagia Post Anterior Cervical Discectomy and Fusion Managed with Glossopharyngeal Nerve Block.

Dysphagia after anterior cervical spine surgery has a 5% to 15% incidence beyond 1-year postsurgery, often attributed to mechanical factors such as pharyngeal thickening and epiglottis inversion. Despite normal neurological examination and electromyography, nerve distortion related to stretching also remains a possibility in these patients and may cause allodynia resulting in odynophagia and dysphagia. Current treatment options for dysphagia after anterior cervical discectomy and fusion are limited to local intraoperative steroid injections and tracheal traction exercises. In our patient, a glossopharyngeal nerve block was effectively used to manage the glossopharyngeal allodynia, thereby reducing the odynophagia and dysphagia, ultimately enhancing oral tolerance.

Short-term survival of the cementless triathlon total knee arthroplasty in a young patient cohort.

BACKGROUND: The purpose of this study is to assess the short-term survivorship of a new cementless total knee arthroplasty (TKA) design in comparison to its cemented predecessor design in a young patient cohort less than 65 years of age. METHODS: We performed a retrospective cohort study of all primary TKAs (cemented and cementless) in patients under the age of 65 at the time of the index procedure, in a single institution between May 2018 and May 2019. Primary outcome variables included aseptic revision and all-cause revision. Operative time was a secondary variable. Independent variables considered included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) grade, implant type (cruciate-retaining (CR) or posterior-stabilised (PS)) and the use of cemented or cementless implants. RESULTS: There were 106 cemented TKAs and 152 cementless TKAs (Triathlon, Stryker Inc, Mahwah, NJ ) implanted. The minimum follow-up for all cases was 2 years (mean cementless 32.5 months, mean cemented 34.9 months). Of the entire 258 implants only 2 were revised. Both revisions occurred in the cemented cohort for prosthetic joint infection (PJI). The all-cause revision rate in the cementless cohort was 0% compared to 1.8% in the cemented cohort (p = 0.168). Operative times were significantly reduced from 62 min in the cemented cohort to 52.2 min in the cementless cohort (p < 0.001). CONCLUSION: In a young patient cohort, the cementless Triathlon TKA demonstrates excellent survivorship at short-term follow-up with significant reductions in operative times when compared to the cemented Triathlon TKA.

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial.

Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.

Pulmonary infection by Mycobacterium riyadhense: first case report in United Arab Emirates.

Mycobacterium riyadhense is an emerging slowly growing species that belongs to the group of nontuberculous mycobacteria (NTM) with approximately 20 cases reported worldwide. We highlight the first case of pulmonary infection by Mycobacterium riyadhense in United Arab Emirates (UAE). A 44-year-old female presented with chronic productive cough; a bronchial breathing pattern was appreciated on auscultation of her right upper lung. She was treated multiple times with allergic medications and antibiotics. Thorough investigations revealed Mycobacterium riyadhense and antitubercular drugs were started, eventually she was cured, however she had multiple relapses later. This case report holds a significant potential to make considerable contribution to the diagnosis of NTM, primarily because it presents the first documented case in UAE, as well as insights on how to address possible similar cases in the future.

Tractography with T1-weighted MRI and associated anatomical constraints on clinical quality diffusion MRI.

Diffusion MRI (dMRI) streamline tractography, the gold-standard for in vivo estimation of white matter (WM) pathways in the brain, has long been considered as a product of WM microstructure. However, recent advances in tractography demonstrated that convolutional recurrent neural networks (CoRNN) trained with a teacher-student framework have the ability to learn to propagate streamlines directly from T1 and anatomical context. Training for this network has previously relied on high resolution dMRI. In this paper, we generalize the training mechanism to traditional clinical resolution data, which allows generalizability across sensitive and susceptible study populations. We train CoRNN on a small subset of the Baltimore Longitudinal Study of Aging (BLSA), which better resembles clinical scans. We define a metric, termed the epsilon ball seeding method, to compare T1 tractography and traditional diffusion tractography at the streamline level. We show that under this metric T1 tractography generated by CoRNN reproduces diffusion tractography with approximately three millimeters of error.