Haemodynamic contributors to pulmonary hypertension across the spectrum of adult congenital heart disease.

AIMS: Adult congenital heart disease (ACHD) includes multiple disease states that predispose to pulmonary hypertension (PH). Haemodynamically, PH depends on abnormalities in three components: pulmonary blood flow (Qp), pulmonary vascular resistance (PVR) and pulmonary venous pressure (PVP). We sought to evaluate the prevalence and prognostic impact of individual haemodynamic abnormalities in ACHD. METHODS AND RESULTS: Retrospective study of ACHD patients undergoing cardiac catheterization at Mayo Clinic between 1999 and 2022 who were followed for the combined endpoint of death/heart transplantation. Among 1005 patients, 37% had mean pulmonary artery pressure (mPAP) ≥25 mmHg with more systemic ventricular disease, cyanotic disease and shunt lesions, highest N-terminal pro-B-type natriuretic peptide and worse right heart remodelling/dysfunction. Among those with biventricular circulation, elevated PVP, PVR and mPAP were associated with prognosis, but not increased Qp >8 L/min. However, risk of death/transplant increased for PVR only at ≥3 Wood units (hazard ratio [HR] 3.00, 95% confidence interval [CI] 2.17-4.15; p < 0.0001) and for mPAP only at ≥25 mmHg (HR 3.15, 95% CI 2.17-4.58; p < 0.0001), not at current recommended lower cutpoints. Combined abnormalities in PVP and PVR were associated with worst outcome (HR 5.20, 95% CI 3.55-7.63; p < 0.0001) with intermediate risk with either abnormality (HR 2.11, 95% CI 1.46-3.04; p < 0.0001). Findings were consistent across type of biventricular ACHD. Only with the Fontan (univentricular) circulation was a lower mPAP threshold (20 mmHg) associated with adverse outcomes. CONCLUSIONS: Elevation of mPAP ≥25 mmHg in ACHD with a biventricular circulation is prognostically important regardless of disease phenotype, but milder PH of 21-25 mmHg is not associated with adverse outcome unless associated with Fontan circulation. Elevation in PVP >15 mmHg and PVR ≥3 Wood units were each individually associated with mortality with combined abnormalities associated with greatest risk. Categorizing PH in ACHD by haemodynamic mechanism (PVR, PVP or Qp) allows meaningful prognostication, and may allow more unified study of targeted therapies across heterogeneous disease states in ACHD.

Global incidence and prevalence of malignant orbital tumors.

Purpose: Aims to provide an overview of the contemporary epidemiology of malignant orbital tumors by analyzing population-based incidence patterns across various regions worldwide. Methods: In this article, we retrieved orbital malignancy data from the MEDLINE database and analyzed the incidence and prevalence of orbital malignancies worldwide. We performed the literature search by searching on the Mesh terms for malignant orbital tumors ("orbital", "tumor", "lymphoma", "malignant", "cancer", "incidence", and "epidemiology"). All included studies were published between 1993 and 2023 and were written in English. Results: Ocular or ophthalmic lymphoma most frequently occurred in the orbit, with a prevalence ranging from 47% to 54%. The incidence of malignant orbital tumors was increasing in the USA (2.0 per million (1981-1993), Netherlands (0.86 (1981-1985) to 2.49 (2001-2005) per million) and South Korea (0.3-0.8 per million (1999-2016)), respectively. Ophthalmic lymphoma which includes orbit lymphoma was increasing in Canada (0.17-1.47 per million (1992-2010)), Denmark (0.86 per million (1981-1985) to 2.49 per million (2001-2005)), respectively. Conclusions: The predominant primary malignant orbital tumor in adults was lymphoma. Ocular or ophthalmic lymphoma most frequently occured in the orbit. The limited data available suggested an increasing trend in the incidence of malignant orbital tumors in each country included, which were mainly attributed to the increase in lymphoma. Generally, incidence rates were found to increase with advancing age, with no difference between males and females.

Dermoscopic characteristics of Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous tumour with high mortality and frequently delayed diagnosis. Clinically, it often manifests as a rapidly growing erythematous to purple nodule usually located on the lower extremities or face and scalp of elderly patients. There is limited available data on the dermoscopic findings of MCC, and there are no specific features that can be used to definitively diagnose MCC. AIM OF THE STUDY: Here, we aimed to summarize existing published literature on dermatoscopic and reflectance confocal microscopy (RCM) features of MCC. MATERIALS AND METHODS: To find relevant studies, we searched the PubMed and Scopus databases from inception to April 12, 2023. Our goal was to identify all pertinent research that had been written in English. The following search strategy was employed: (" dermoscopy" OR " dermatoscopy" OR " videodermoscopy" OR " videodermatoscopy" OR " reflectance confocal microscopy") AND " Merkel cell carcinoma". Two dermatologists, DK and GE, evaluated the titles and abstracts separately for eligibility. For inclusion, only works written in English were taken into account. RESULTS: In total 16 articles were retrieved (68 cases). The main dermoscopic findings of MCC are a polymorphous vascular pattern including linear irregular, arborizing, glomerular, and dotted vessels on a milky red background, with shiny or non-shiny white areas. Pigmentation was lacking in all cases. The RCM images showed a thin and disarranged epidermis, and small hypo-reflective cells that resembled lymphocytes arranged in solid aggregates outlined by fibrous tissue in the dermis. Additionally, there were larger polymorphic hyper-reflective cells that likely represented highly proliferative cells. CONCLUSION: Dermoscopic findings of MCC may play a valuable role in evaluating MCC, aiding in the early detection and differentiation from other skin lesions. Further prospective case-control studies are needed to validate these results.

Perioperative and safety outcomes following tissue-sparing posterior cervical fusion to revise a pseudarthrosis: A multicenter retrospective review of 150 cases.

Background: Posterior cervical fusion (PCF) with lateral mass screws is a favorable treatment option to revise a symptomatic pseudarthrosis due to reliable rates of arthrodesis; however, this technique introduces elevated risk for wound infection and hospital readmission. A tissue-sparing PCF approach involving facet fixation instrumentation reduces the rates of postoperative complications while stabilizing the symptomatic level to achieve arthrodesis; however, these outcomes have been limited to small study cohorts from individual surgeons commonly with mixed indications for treatment. Materials and Methods: One hundred and fifty cases were identified from a retrospective chart review performed by seven surgeons across six sites in the United States. All cases involved PCF revision for a pseudarthrosis at one or more levels from C3 to C7 following anterior cervical discectomy and fusion (ACDF). PCF was performed using a tissue-sparing technique with facet instrumentation. Cases involving additional supplemental fixation such as lateral mass screws, rods, wires, or other hardware were excluded. Demographics, operative notes, postoperative complications, hospital readmission, and subsequent surgical interventions were summarized as an entire cohort and according to the following risk factors: age, sex, number of levels revised, body mass index (BMI), and history of nicotine use. Results: The average age of patients at the time of PCF revision was 55 ± 11 years and 63% were female. The average BMI was 29 ± 6 kg/m2 and 19% reported a history of nicotine use. Postoperative follow-up visits were available with a median of 68 days (interquartile range = 41-209 days) from revision PCF. There were 91 1-level, 49 2-level, 8 3-level, and 2 4±-level PCF revision cases. The mean operative duration was 52 ± 3 min with an estimated blood loss of 14 ± 1.5cc. Participants were discharged an average of 1 ± 0.05 days following surgery. Multilevel treatment resulted in longer procedure times (single = 45 min, multi = 59 min, P = 0.01) but did not impact estimated blood loss (P = 0.94). Total nights in the hospital increased by 0.2 nights with multilevel treatment (P = 0.01). Sex, age, nicotine history, and BMI had no effect on recorded perioperative outcomes. There was one instance of rehospitalization due to deep-vein thrombosis, one instance of persistent pseudarthrosis at the revised level treated with ACDF, and four instances of adjacent segment disease. In patients initially treated with multilevel ACDF, revisions occurred most commonly on the caudal level (48% of revised levels), followed by the cranial (43%), and least often in the middle level (9%). Conclusions: This chart review of perioperative and safety outcomes provides evidence in support of tissue-sparing PCF with facet instrumentation as a treatment for symptomatic pseudarthrosis after ACDF. The most common locations requiring revision were the caudal and cranial levels. Operative duration and estimated blood loss were favorable when compared to open alternatives. There were no instances of postoperative wound infection, and the majority of patients were discharged the day following surgery.

Implications of subclinical tuberculosis for vaccine trial design and global effect.

Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies.

Caregiver preferences for physically harsh discipline of children in rural Uganda.

Purpose: Physically harsh discipline is associated with poor developmental outcomes among children. These practices are more prevalent in areas experiencing poverty and resource scarcity, including in low- and middle-income countries. Designed to limit social desirability bias, this cross-sectional study in rural Uganda estimated caregiver preferences for physically harsh discipline; differences by caregiver sex, child sex, and setting; and associations with indicators of household economic stress and insecurity. Method: Three-hundred-fifty adult caregivers were shown six hypothetical pictographic scenarios depicting children whining, spilling a drink, and kicking a caregiver. Girls and boys were depicted engaging in each of the three behaviors. Approximately half of the participants were shown scenes from a market setting and half were shown scenes from a household setting. For each scenario, caregivers reported the discipline strategy they would use (time out, beating, discussing, yelling, ignoring, slapping). Results: Two thirds of the participants selected a physically harsh discipline strategy (beating, slapping) at least once. Women selected more physically harsh discipline strategies than men (b = 0.40; 95% confidence interval [CI], 0.26 to 0.54). Participants shown scenes from the market selected fewer physically harsh discipline strategies than participants shown scenes from the household (b = -0.51; 95% CI, -0.69 to -0.33). Finally, caregivers selected more physically harsh discipline strategies in response to boys than girls. Indicators of economic insecurity were inconsistently associated with preferences for physically harsh discipline. Conclusions: The high prevalence of physically harsh discipline preferences warrant interventions aimed at reframing caregivers' approaches to discipline.

Water Treatment Practices and Misperceived Social Norms among Women Living with Young Children in Rural Uganda.

Access to water safe for consumption is critical for health and well-being, yet substantial structural barriers often necessitate household action to make water safer. Social norms about water treatment practices are understudied as a driver of personal water treatment practice. This study assesses reported and perceived water treatment practices among women in a rural, water insecure setting. We used cross-sectional data from a population-based study of women living with children under 5 years old across eight villages in southwest Uganda. Participants reported their typical household water treatment practices and what they perceived to be the common practices among most other women with young children in their own village. Modified multivariable Poisson regression models estimated the association between individual behavior and perceptions. Of 274 participants (78% response rate), 221 (81%) reported boiling water and 228 (83%) reported taking at least one action to make water safer. However, 135 (49%) misperceived most women with young children in their village not to boil their water, and 119 (43%) misperceived most to take no action. Participants who misperceived these norms were less likely to practice safe water treatment (e.g., for boiling water, adjusted relative risk = 0.80; 95% CI 0.69-0.92, P = 0.002), adjusting for other factors. Future research should assess whether making actual descriptive norms about local water treatment practices visible and salient (e.g., with messages such as "most women in this village boil their drinking water") corrects misperceived norms and increases safe water treatment practices by some and supports consistent safe practices by others.

A simple optical flow model explains why certain object viewpoints are special.

A core challenge in perception is recognizing objects across the highly variable retinal input that occurs when objects are viewed from different directions (e.g. front versus side views). It has long been known that certain views are of particular importance, but it remains unclear why. We reasoned that characterizing the computations underlying visual comparisons between objects could explain the privileged status of certain qualitatively special views. We measured pose discrimination for a wide range of objects, finding large variations in performance depending on the object and the viewing angle, with front and back views yielding particularly good discrimination. Strikingly, a simple and biologically plausible computational model based on measuring the projected three-dimensional optical flow between views of objects accurately predicted both successes and failures of discrimination performance. This provides a computational account of why certain views have a privileged status.

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

A bias in transsaccadic perception of spatial frequency changes.

Visual processing differs between the foveal and peripheral visual field. These differences can lead to different appearances of objects in the periphery and the fovea, posing a challenge to perception across saccades. Differences in the appearance of visual features between the peripheral and foveal visual field may bias change discrimination across saccades. Previously it has been reported that spatial frequency (SF) appears higher in the periphery compared to the fovea (Davis et al., 1987). In this study, we investigated the visual appearance of SF before and after a saccade and the discrimination of SF changes during saccades. In addition, we tested the contributions of pre- and postsaccadic information to change discrimination performance. In the first experiment, we found no differences in the appearance of SF before and after a saccade. However, participants showed a clear bias to report SF increases. Interestingly, a 200-ms postsaccadic blank improved the precision of the responses but did not affect the bias. In the second experiment, participants showed lower thresholds for SF increases than for decreases, suggesting that the bias in the first experiment was not just a response bias. Finally, we asked participants to discriminate the SF of stimuli presented before a saccade. Thresholds in the presaccadic discrimination task were lower than in the change discrimination task, suggesting that transsaccadic change discrimination is not merely limited by presaccadic discrimination in the periphery. The change direction bias might stem from more effective masking or overwriting of the presaccadic stimulus by the postsaccadic low SF stimulus.

Sport-specific Differences in Cartilage Treatment.

Articular cartilage defects in the knee are common in athletes who have a variety of loading demands across the knee. Athletes of different sports may have different baseline risk of injury. The most studied sports in terms of prevalence and treatment of cartilage injuries include soccer (football), American football, and basketball. At this time, the authors do not specifically treat patients by their sport; however, return to sports timing may be earlier in sports with fewer demands on the knee based on the rehabilitation protocol. If conservative management is unsuccessful, the authors typically perform a staging arthroscopy with chondroplasty, followed by osteochondral allograft transplantation with possible additional concomitant procedures, such as osteotomies or meniscal transplants. Athletes in a variety of sports and at high levels of competition can successfully return to sports with the appropriate considerations and treatment.

IFN-γ production by functionally reprogrammed Treg cells promotes anti-tumor efficacy of OX40/CD137 bispecific agonist therapy.

Regulatory T (Treg) cells are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Treg cells to contribute to anti-tumor immunity. OX40 and CD137 are expressed highly on Treg cells, activated and memory T cells, and NK cells. Here, using a novel tetravalent bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonists induce potent anti-tumor immunity partially dependent upon IFN-γ-production by functionally reprogrammed Treg cells. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Treg cells into both fragile Foxp3+ IFN-γ+ cells with decreased suppressive function, and lineage instable Foxp3- IFN-γ+ cells. Treg cell fragility is partially dependent upon IFN-γ signaling, whereas Treg cell instability is associated with reduced IL-2 signaling upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Treg cells and their progeny partially reverses the anti-tumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Treg cells into IFN-γ-producing cells contributes to the efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting co-stimulatory receptors highly expressed by Treg cells potentiate anti-tumor immunity in mouse models.

Quantitative ultrasound of submental and masticatory muscles in children with cerebral palsy.

PURPOSE: Quantitative muscle ultrasound (QMUS) is potentially valuable as a diagnostic tool in central neurological disorders, as it provides information about changes in muscle architecture. This study aimed to investigate whether ultrasound images of the submental and masticatory muscles in children with spastic cerebral palsy (CP) differ from those obtained in a reference group, and whether observed ultrasound abnormalities differ between subgroups of children with different Eating and Drinking Ability Classification System (EDACS) levels to support its construct validity. METHODS: A prospective cohort study was conducted in 25 children with spastic CP aged 3-18 years. QMUS of selected muscles was performed. Muscle thickness and echogenicity in the CP group were compared to previously collected reference values, and between different EDACS levels within the CP group. RESULTS: Median echogenicity of all muscles was significantly higher in children with CP than in healthy controls. The temporalis muscle was significantly thinner in the CP group. There were no differences in muscle thickness or echogenicity between EDACS levels. CONCLUSION: QMUS is able to detect abnormal architecture of submental and masticatory muscles in children with spastic CP, but the interpretation of abnormalities in relation to the severity of mastication and swallowing problems needs further investigation.

Geographic Disparities in Availability of General and Specialized Pediatricians in the US and Prevalence of Childhood Neurodevelopmental Disorders.

General pediatricians and those specialized in developmental-behavioral and neurodevelopmental disabilities support children with neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We identified substantial geographic disparities in pediatrician availability (eg, urban > rural areas), as well as regions with low pediatrician access but high ASD/ADHD prevalence estimates (eg, the US Southeast).

MDFit: automated molecular simulations workflow enables high throughput assessment of ligands-protein dynamics.

Molecular dynamics (MD) simulation is a powerful tool for characterizing ligand-protein conformational dynamics and offers significant advantages over docking and other rigid structure-based computational methods. However, setting up, running, and analyzing MD simulations continues to be a multi-step process making it cumbersome to assess a library of ligands in a protein binding pocket using MD. We present an automated workflow that streamlines setting up, running, and analyzing Desmond MD simulations for protein-ligand complexes using machine learning (ML) models. The workflow takes a library of pre-docked ligands and a prepared protein structure as input, sets up and runs MD with each protein-ligand complex, and generates simulation fingerprints for each ligand. Simulation fingerprints (SimFP) capture protein-ligand compatibility, including stability of different ligand-pocket interactions and other useful metrics that enable easy rank-ordering of the ligand library for pocket optimization. SimFPs from a ligand library are used to build & deploy ML models that predict binding assay outcomes and automatically infer important interactions. Unlike relative free-energy methods that are constrained to assess ligands with high chemical similarity, ML models based on SimFPs can accommodate diverse ligand sets. We present two case studies on how SimFP helps delineate structure-activity relationship (SAR) trends and explain potency differences across matched-molecular pairs of (1) cyclic peptides targeting PD-L1 and (2) small molecule inhibitors targeting CDK9.

Clinical features, haemodynamics, and outcomes of heart failure with preserved ejection fraction in coarctation of aorta.

AIMS: There are similarities in the pathogenesis of cardiac remodelling and dysfunction in heart failure with preserved ejection fraction (HFpEF) and coarctation of aorta (COA). We hypothesized that clinical HFpEF would be highly prevalent in adults with COA, and that the presence of HFpEF would increase the risk of mortality in this population. The aim of this study was to define the clinical features, haemodynamics, and prognostic implications of HFpEF in COA. METHODS AND RESULTS: Consecutive adults with repaired COA that underwent right heart catheterization were identified retrospectively. HFpEF was defined as heart failure symptoms (exertional dyspnoea or fatigue), preserved left ventricular ejection fraction ≥50%, and pulmonary artery wedge pressure at rest >15 mmHg. Of 99 COA patients, 32 (32%) had HFpEF. The correlates of HFpEF were obesity (adjusted odds ratio [OR] 4.15, 95% confidence interval [CI] 1.31-13.2), atrial fibrillation (adjusted OR 3.13, 95% CI 1.00-10.7), total arterial compliance index (adjusted OR 0.12, 95% CI 0.06-0.41 per 1 ml/mmHg*m2), and pulmonary artery compliance index (adjusted OR 0.36, 95% CI 0.15-0.56 per 1 ml/mmHg*m2). Of 99 patients, 24 (24%) died and 5 (5%) underwent heart transplant. The 10-year cumulative incidence of death/transplant was higher in COA patients with HFpEF compared with patients without HFpEF (39% vs. 12%, p = 0.001). The presence of HFpEF was associated with increased risk of death/transplant (adjusted hazard ratio 1.68, 95% CI 1.16-3.11). CONCLUSIONS: Heart failure with preserved ejection fraction is common in adults with COA and is associated with greater risk of death/transplant, emphasizing a pressing need for interventions to prevent and treat HFpEF in COA.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Spatiotemporal congruency modulates weighting of visuotactile information in displacement judgments.

Combining or integrating information from multiple senses often provides richer and more reliable estimates for the perception of objects and events. In daily life, sensory information from the same source often is in close spatiotemporal proximity. This can be an important determinant of whether and how multisensory signals are combined. The introduction of advanced technical display systems allows to present multisensory information in virtual environments. However, technical displays can lack the spatiotemporal fidelity of the real world due the rendering delays. Thus, any spatiotemporal incongruency could alter how information is combined. In the current study we tested this by investigating if and how spatially and temporally discrepant tactile displacement cues can supplement imprecise visual displacement cues. Participants performed a visual displacement task with visual and tactile displacement cues under spatial and temporal incongruency conditions. We modelled how participants combined visual and tactile information in visuotactile condition using their performance in visual only condition. We found that temporal incongruency lead to an increase in tactile weights although they were correlated with the congruency condition. In contrast, the spatial incongruency led to individual differences altering cue combination strategies. Our results illustrate the importance of spatiotemporal congruency for combining tactile and visual cues when making visual displacement judgments. Given the altered cue combination strategies and individual differences, we recommend developers to adopt individual spatiotemporal calibration procedures to improve the efficiency of the sensory augmentation.