Exposure profiles of social-environmental neighborhood factors and psychotic-like experiences.

Importance: Recent research has demonstrated that domains of social determinants of health (SDOH) (e.g., air pollution and social context) are associated with psychosis. However, SDOHs have often been studied in isolation. Objective: To identify distinct exposure profiles, estimate their associations with persistent distressing psychotic-like experiences (PLE), and evaluate whether involvement with physical activities partially explains this association. Design Setting and Participants: This population-based study used data from the Adolescent Brain and Cognitive Development (ABCD) Study. Participants were recruited from 22 US sites between September 2016 and January 2022. Data from baseline and three follow-ups were included. Exposures: Area-level geocoded variables spanning various domains of SDOH, including socioeconomic status (SES), education, crime, built environment, social context, and crime, were clustered using a self-organizing map method to identify exposure profiles. Main Outcomes and Measures: Persistent distressing PLE was derived from the Prodromal Questionnaire-Brief Child Version across four years. Generalized linear mixed modeling tested the association between exposure profiles and persistent distressing PLE as well as physical activities (i.e., team and individual sports), adjusting for individual-level covariates including age, sex, race/ethnicity, highest level of parent education, family-relatedness, and study sites. Results: Among 8,145 participants (baseline mean [SD] age, 9.92 [0.63] years; 3,868 (47.5%) females; 5,566 (68.3%) White, 956 (11.7%) Black, 159 (2.0%) Asian, and 1,480 (18.4%) Hispanic participants), five exposure profiles were identified. Compared to the reference Profile 1 (suburban affluent areas, 2521 children, 30.9%), Profile 3 (rural areas with low walkability and high ozone; 1459 children, 17.9%; adjusted OR: 1.34, 95% CI: 1.09-1.64) and Profile 4 (urban areas with high SES deprivation, high crime, and high pollution; 715 children, 8.8%; adjusted OR: 1.40, 95% CI: 1.08-1.81), were associated with persistent distressing PLE. Team sports mediated 6.14% of the association for Profile 3. Conclusion and Relevance: This study found that neighborhoods characterized by rural areas with low walkability and urban areas with high socioeconomic deprivation, air pollutants, and crime were associated with persistent distressing PLE. Further research is needed to explore the pathways through which different environmental factors may impact the development of psychosis.

Women's experiences with continuity for effective coordination during maternal and neonatal continuum in Kenya: An interpretive phenomenology.

BACKGROUND:  Embracing women's experiences in decision-making is imperative for continuity in effective coordination of maternal and neonatal health (MNH); women are the end users within the care ecosystem. Through women's continuous feedback, skilled birth attendants (SBAs) and the healthcare system get to understand emerging issues based on their needs and preferences. AIM:  The purpose of this article is to describe women's experiences of continuity for effective coordination of care through the transitions in the MNH continuum in Kenya. SETTING:  The study was conducted in selected counties of Kenya based on birth rates per woman as follows: Wajir (7.8) Narok (6.0) Kirinyaga (2.3) and Nairobi (2.7) (1). The clients were interviewed concerning their experiences of the MNH continuum of care in English and Kiswahili. METHODS:  An interpretive hermeneutic phenomenological approach was used to construct the experiences of women of continuity during transitions in the MNH continuum for effective care coordination. Twelve participants were interviewed between January and April 2023. Atlas ti 22 software was used for data analysis. RESULTS:  Four women experiences were highlighted: Women unawareness of preconception care, use of prenatal care, labour, birthing and postpartum flow and the women's view on the MNH continuum. CONCLUSION:  The women reported their segmental and transitional experience of the MNH continuum as one that did not consistently meet their needs and preferences in order for them to fully agree that the continuum enhanced continuity for effective coordination. They felt that they experienced continuity in some segments while in some they did not.Contribution: The embrace of women's experience of their needs and preferences through the MNH continuum (segments and transitional segments) through the lens of continuity for effective coordination is timely towards the improvement of maternal and neonatal care by 2030.

A novel expression domain of extradenticle underlies the evolutionary developmental origin of the chelicerate patella.

Neofunctionalization of duplicated gene copies is thought to be an important process underlying the origin of evolutionary novelty and provides an elegant mechanism for the origin of new phenotypic traits. One putative case where a new gene copy has been linked to a novel morphological trait is the origin of the arachnid patella, a taxonomically restricted leg segment. In spiders, the origin of this segment has been linked to the origin of the paralog dachshund-2, suggesting that a new gene facilitated the expression of a new trait. However, various arachnid groups that possess patellae do not have a copy of dachshund-2, disfavoring the direct link between gene origin and trait origin. We investigated the developmental genetic basis for patellar patterning in the harvestman Phalangium opilio, which lacks dachshund-2. Here, we show that the harvestman patella is established by a novel expression domain of the transcription factor extradenticle. Leveraging this definition of patellar identity, we surveyed targeted groups across chelicerate phylogeny to assess when this trait evolved. We show that a patellar homolog is present in Pycnogonida (sea spiders) and various arachnid orders, suggesting a single origin of the patella in the ancestor of Chelicerata. A potential loss of the patella is observed in Ixodida. Our results suggest that the modification of an ancient gene, rather than the neofunctionalization of a new gene copy, underlies the origin of the patella. Broadly, this work underscores the value of comparative data and broad taxonomic sampling when testing hypotheses in evolutionary developmental biology.

Accuracy of self-reported treated hypertension in the women's health initiative: Comparisons with medication inventories.

Few studies have reported on the accuracy of self-reported hypertension history among older postmenopausal women, which was this study's objective. Participants were postmenopausal women enrolled in the Osteoporosis and Periodontal Disease (OsteoPerio) study, an ancillary investigation of the Women's Health Initiative Observational Study (WHI-OS) at the Buffalo, New York, clinical site. Participants self-reported their history of physician diagnosed hypertension treated with medication at WHI-OS enrollment (1993-1998; n = 1342, mean age 63 years), then 3 years later at OsteoPerio enrollment (1997-2001; n = 1342), and again at OsteoPerio Year 5 follow-up (2002-2005; n = 1020). At each time point, medication inventories were recorded and served as the criterion with which self-report was compared in the present study. Physician diagnosed-treated hypertension was also self-reported annually on mailed health update questionnaires in the WHI-OS and were compared against medication inventory at the subsequent clinic exam. Of those participants who self-reported a history of hypertension at WHI enrollment, OsteoPerio enrollment, and OsteoPerio Year 5 follow-up, 41.2%, 90.3%, and 94.4%, respectively, had anti-hypertensive pills in their medication inventory. Across the three time points, sensitivity and specificity ranged from 0.72 to 0.98 and from 0.85 to 0.95, and kappa coefficients ranged from 0.52 to 0.79 when comparing self-report with medication inventory. For self-reported newly physician-diagnosed and treated hypertension on the annual health update questionnaire, 88.4% and 95.2% of those reporting hypertension had anti-hypertensive pills in the subsequent medication inventory. In general, sensitivity and kappa were lower in women aged ≥70 versus < 70 years and in those with history of cardiovascular disease and diabetes compared to those without these comorbidities. In this cohort of postmenopausal women, self-reported physician diagnosed and treated hypertension demonstrated moderate to high accuracy when compared against anti-hypertensive medication use documented by pill inventory, particularly for those who were younger and managing fewer comorbidities.

A Comparison of PROMIS Scores of Metatarsophalangeal Joint Arthrodesis and Polyvinyl Alcohol Hydrogel Implant Hemiarthroplasty for Hallux Rigidus.

Background: The current literature shows similar clinical outcomes between first metatarsophalangeal (MTP) joint arthrodesis and synthetic cartilage implant (SCI) hemiarthroplasty in the treatment of hallux rigidus; however, prior studies have not reported validated patient-reported outcome measures (PROMs). To our knowledge, this is the first study to compare PROMs using 6 domains of the validated Patient-Reported Outcomes Measurement Information System (PROMIS) in patients treated for hallux rigidus with MTP joint arthrodesis and with SCI hemiarthroplasty. In addition, this novel study provides comparative data on the complication and revision rates for each procedure. Methods: A single-center, retrospective registry search identified all patients with preoperative PROMIS scores who underwent MTP joint arthrodesis or SCI hemiarthroplasty for hallux rigidus between February 2016 and June 2021. The study aimed to determine if the 2 procedures showed statistically or clinically equivalent PROMIS scores in 6 domains: physical function, pain interference, pain intensity, global physical health, global mental health, and depression. A multivariable linear regression analysis was performed to compare adjusted 1-year postoperative PROMIS scores between the 2 cohorts. Complication and revision rates were also compared. Results: The study included 82 patients who underwent SCI hemiarthroplasty and 101 who underwent MTP joint arthrodesis. Demographic data and preoperative hallux rigidus severity showed no significant differences between the cohorts. PROMIS scores were mostly comparable between the 2 groups, except for the pain intensity domain. The patients who underwent MTP joint arthrodesis exhibited significantly better pain relief at 1 and 2 years postoperatively, which was supported by adjusted postoperative PROMIS scores. At 2 years, the SCI group had worse pain intensity scores and lower global physical health scores. There were no differences between the cohorts in additional PROMIS scores or complication data. Conclusions: While outcomes in most of the domains were similar, MTP joint arthrodesis was more effective at mitigating pain intensity compared with SCI hemiarthroplasty. This information can guide patient counseling and decision-making when considering surgical intervention for hallux rigidus. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Validation of clinically related aging models based on enamel wear.

PURPOSE: Physiological and erosive wear reported in clinical studies were reviewed, and in vitro aging models were developed to simulate and compare the effect of aging on human teeth with the review data obtained from clinical studies. METHODS: A review of clinical studies and randomized clinical trials that quantify enamel wear was performed in the PubMed database. The first in vitro analysis evaluated the effect of mechanical chewing simulation only. Enamel specimens were aged in the chewing simulator (up to 1.2 million cycles) with two occlusal loads (30 and 50 N). In the second in vitro analysis, specimens were aged in two aging models. The first model (MT) simulated mechanical and thermal oral challenges: MT1- 240,000 chewing and 10,000 thermal cycles, MT2- 480,000 chewing and 20,000 thermal cycles, MT3- 1.2 million chewing and 50,000 thermal cycles. The second model (MTA) simulated mechanical, thermal, and acidic oral challenges as follows: MTA1- 240,000 chewing, 10,000 thermal and 3-h acidic cycles; MTA2: 480,000 chewing, 20,000 thermal and 6-h acidic cycles, MTA3- 1.2 million chewing, 50,000 thermal and 15-h acidic cycles. RESULTS: The review included 13 clinical studies evaluating tooth wear (eight physiological and five erosive). The results estimated the annual average physiological wear as 38.4 µm (9.37-51). In comparison, the MT1 showed wear of 60 (24) µm. Also, the average annual erosive wear in the literature was 179.5 µm (70-265) compared to MTA1-induced wear of 209 (14) µm. CONCLUSION: There was wide variation in tooth wear reported in clinical studies, suggesting a critical need for more accurate studies, possibly based on scanning technologies. Despite this, the data reported using the novel aging models are within a range to be considered consistent with and to simulate tooth wear measured in vivo.

Biosensors for Parkinson's Disease: Where Are We Now, and Where Do We Need to Go?

Parkinson's Disease is the second most common neurological disease in the United States, yet there is no cure, no pinpointed cause, and no definitive diagnostic procedure. Parkinson's is typically diagnosed when patients present with motor symptoms such as slowness of movement and tremors. However, none of these are specific to Parkinson's, and a confident diagnosis of Parkinson's is typically only achieved when 60-80% of dopaminergic neurons are no longer functioning, at which point much of the damage to the brain is irreversible. This Perspective details ongoing efforts and accomplishments in biosensor research with the goal of overcoming these issues for Parkinson's diagnosis and care, with a focus on the potential impact of early diagnosis and associated opportunities to pinpoint a cause and a cure. We critically analyze the strengths and shortcomings of current technologies and discuss the ideal characteristics of a diagnostic technology toolbox to guide future research decisions in this space. Finally, we assess what role biosensors can play in facilitating precision medicine for Parkinson's patients.

Effects of Aging, Fitness, and Cerebrovascular Status on White Matter Microstructural Health.

White matter (WM) microstructural health declines with increasing age, with evidence suggesting that improved cardiorespiratory fitness (CRF) may mitigate this decline. Specifically, higher fit older adults tend to show preserved WM microstructural integrity compared to their lower fit counterparts. However, the extent to which fitness and aging independently impact WM integrity across the adult lifespan is still an open question, as is the extent to which cerebrovascular health mediates these relationships. In a large sample (N = 125, aged 25-72), we assessed the impact of age and fitness on fractional anisotropy (FA, derived using diffusion weighted imaging, DWI) and probed the mediating role of cerebrovascular health (derived using diffuse optical tomography of the cerebral arterial pulse, pulse-DOT) in these relationships. After orthogonalizing age and fitness and computing a PCA on whole brain WM regions, we found several WM regions impacted by age that were independent from the regions impacted by fitness (hindbrain areas, including brainstem and cerebellar tracts), whereas other areas showed interactive effects of age and fitness (midline areas, including fornix and corpus callosum). Critically, cerebrovascular health mediated both relationships suggesting that vascular health plays a linking role between age, fitness, and brain health. Secondarily, we assessed potential sex differences in these relationships and found that, although females and males generally showed the same age-related FA declines, males exhibited somewhat steeper declines than females. Together, these results suggest that age and fitness impact specific WM regions and highlight the mediating role of cerebrovascular health in maintaining WM health across adulthood.

The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis and maintain translational repression of maternal mRNA and oocyte quality.

The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination of in vitro condensation assays and the in vivo C. elegans oogenesis model to characterize the properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and three other translational regulators. We demonstrate that MEX-3 undergoes phase separation and appears to have intrinsic gel-like properties in vitro. We also identify novel roles for the CCT chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. The CCT chaperonin and actin also oppose the expansion of ER sheets that may promote ectopic condensation of RNA-binding proteins. These novel regulators of condensation are also required for the translational repression of maternal mRNA which is essential for oocyte quality and fertility. The identification of this regulatory network may also have implications for understanding the role of hMex3 phase transitions in cancer.

Comparison of Minimally Invasive Chevron Akin and Open Lapidus Surgery in Older Patients at a Minimum 1-Year Follow-Up.

Background: Hallux valgus deformity affects more than 35% of people aged ≥65 years. Surgical correction in this population can be more complicated because of poor bone quality, worse deformity, and postoperative recovery challenges. The purpose of this study was to compare the radiographic and clinical outcomes of patients aged ≥65 years who underwent either open Lapidus or minimally invasive chevron Akin osteotomy for bunion correction. Methods: A retrospective review identified 62 patients aged ≥65 years who were treated surgically for hallux valgus with at least 1-year postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores (physical function and pain interference). Preoperative and at least 6-month postoperative radiographs were measured for the hallux valgus angle and intermetatarsal angle. PROMIS scores were obtained preoperatively and at 1 and/or 2 years postoperatively. Differences in demographic, clinical, and radiographic outcomes were assessed using the Mann Whitney U test and P values were adjusted for a false discovery rate of 5%. Results: There was no difference between the MIS and open cohorts in pre- or postoperative radiographic measurements or clinical outcomes at any time point. At 1 year postoperatively, both groups had statistically significant improvements in the PROMIS pain interference domain but only the MIS group had a statistically significant improvement in the PROMIS physical function domain. Clinical significance was equivocal. At 2 years postoperatively, there were clinically and statistically significant improvements in the PROMIS pain interference and physical function domains for the open and MIS groups. Conclusion: Patients in both surgical groups had improvement in radiographic measurements and 2-year PROMIS scores, although there was no clinical or statistical difference found between groups. MIS and open surgical techniques appear to be safe and effective in correcting hallux valgus in older patients; however, patients may need to be counseled that maximum improvement after surgery may take more than 1 year. Level of Evidence: Level III, retrospective cohort study.

Neurodynamical Computing at the Information Boundaries of Intelligent Systems.

Artificial intelligence has not achieved defining features of biological intelligence despite models boasting more parameters than neurons in the human brain. In this perspective article, we synthesize historical approaches to understanding intelligent systems and argue that methodological and epistemic biases in these fields can be resolved by shifting away from cognitivist brain-as-computer theories and recognizing that brains exist within large, interdependent living systems. Integrating the dynamical systems view of cognition with the massive distributed feedback of perceptual control theory highlights a theoretical gap in our understanding of nonreductive neural mechanisms. Cell assemblies-properly conceived as reentrant dynamical flows and not merely as identified groups of neurons-may fill that gap by providing a minimal supraneuronal level of organization that establishes a neurodynamical base layer for computation. By considering information streams from physical embodiment and situational embedding, we discuss this computational base layer in terms of conserved oscillatory and structural properties of cortical-hippocampal networks. Our synthesis of embodied cognition, based in dynamical systems and perceptual control, aims to bypass the neurosymbolic stalemates that have arisen in artificial intelligence, cognitive science, and computational neuroscience.

Hyperglycemia sensitizes female mice to stress-induced depressive-like behavior in an inflammation-independent manner.

BACKGROUND: Depression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia. METHODS: To this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21). RESULTS: Our results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior. CONCLUSION: We interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization.

The role of body image dissatisfaction in the relationship between body size and disordered eating and self-harm: complimentary Mendelian randomization and mediation analyses.

Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored. Employing data from two large population-based cohorts, the UK Biobank and the Avon Longitudinal Study of Parents And Children (ALSPAC), we conducted bidirectional Mendelian randomization (MR) to determine the causal direction of effect between genetically predicted prepubertal body size and two measures of BID indicating (i) desire to be smaller, and (ii) desire to be larger. We then used multivariable regression followed by counterfactual mediation analyses. Bidirectional MR indicated robust evidence that increased genetically predicted prepubertal body size increased desire to be smaller and decreased desire to be larger. Evidence for the reverse causal direction was negligible. These findings remained very similar across sensitivity analyses. In females and males, multivariable regression analyses demonstrated that being overweight increased the risk of disordered eating (risk ratio (RR), 95% confidence interval (CI): 1.19, 1.01 to 1.40 and 1.98, 1.28 to 3.05, respectively) and self-harm (RR, 95% CI: 1.35, 1.04 to 1.77 and 1.55, 0.86 to 2.81, respectively), while being underweight was protective against disordered eating (RR, 95% CI: 0.57, 0.40 to 0.81 and 0.81, 0.38 to 1.73, respectively). There was weak evidence of an increase in the risk of self-harm among underweight individuals. Mediation analyses indicated that the relationship between being overweight and subsequent disordered eating was largely mediated by the desire to be smaller. Our research carries important public health implications, suggesting distinct risk profiles for self-harm and disordered eating in relation to weight and body image. In addition, a better understanding of genetically predicted prepubertal BID may be valuable in the prevention and treatment of disordered eating and self-harm in adolescence.

Red cell exchange modulates neutrophil degranulation responses in sickle cell disease.

BACKGROUND: Neutrophils in sickle cell disease (SCD) are activated, contributing to disease. Red cell exchange (RCE), with the goal of lowering hemoglobin S (HbS), is an important part of therapy for many SCD patients. Whether RCE impacts neutrophil reactivity is unknown. STUDY DESIGN AND METHODS: To determine the effect of RCE on neutrophil activation, SCD patients undergoing RCE in steady-state were enrolled. Neutrophil degranulation responses were examined before/after RCE. Kinetic studies were completed to determine the duration of the effect of RCE on neutrophil function. Degranulation results were examined in relation to white blood cell count, neutrophil count, and HbS levels. The effect of RCE on RBC phosphatidylserine (PS) exposure was examined as a possible contributor to modulation of neutrophil function by RCE. RESULTS: Twenty-two patients with SCD, genotype SS, who underwent RCE (average pre-RCE HbS 33 ± 14%) were included for the study. RCE significantly decreased neutrophil degranulation responses. The effect of RCE on neutrophil activation was unrelated to cell count and instead directly correlated with HbS. The effect of RCE on neutrophil activation was sustained over several days post-apheresis. Furthermore, while increased RBC PS exposure results in increased neutrophil degranulation, RCE decreases RBC PS exposure. DISCUSSION: To our knowledge, this is the first study demonstrating that RCE significantly decreases neutrophil activation in a sustained HbS-dependent manner. Modulation of PS exposure by RCE may be a contributing mechanism by which RCE modulates neutrophil activation. These studies raise the possibility that modulation of neutrophil activation contributes significantly to the therapeutic effect of RCE.

Reflections on the Advisory Committee on Immunization Practices During the COVID-19 Pandemic.

Pediatricians and primary care providers serve an important role in building trust with families and communities. To support the critical role of front-line providers, this perspective seeks to reflect on the work of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices to support COVID-19 pandemic response efforts. Although Advisory Committee on Immunization Practice (ACIP) recommends vaccines for all age groups, this perspective focuses on the pediatric lens and is tailored to Academic Pediatrics. ACIP adapted from in-person meetings 3 times yearly to virtual meetings on an emergency basis to ensure a thorough review and presentation of all the components of the evidence to recommendation framework, including explicit consideration of equity in the decision-making process. The need for diverse enrollment in clinical trials was highlighted as critical for supporting recommendations and enhancing trust. Near real-time vaccine safety surveillance was implemented at scale and emphasized the importance of collaboration between federal partners engaged in vaccine safety in the United States and extended to other countries with similar safety surveillance systems to enable early recognition and response to safety concerns. A key equity opportunity for future pandemics is to shorten the time between vaccines being available for adults and young children.

SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity.

The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.

Natural Variation in HIV-1 Entry Kinetics Map to Specific Residues and Reveal an Interdependence Between Attachment and Fusion.

HIV-1 entry kinetics reflect the fluid motion of the HIV envelope glycoprotein through at least three major structural configurations that drive virus-cell membrane fusion. The lifetime of each state is an important component of potency for inhibitors that target them. We used the time-of-addition inhibitor assay and a novel analytical strategy to define the kinetics of pre-hairpin exposure (using T20) and co-receptor engagement (via. maraviroc), through a characteristic delay metric, across a variety of naturally occurring HIV Env isolates. Among 257 distinct HIV-1 envelope isolates we found a remarkable breadth of T20 and maraviroc delays ranging from as early as 30 seconds to as late as 60 minutes. The most extreme delays were observed among transmission-linked clade C isolates. We identified four single-residue determinants of late T20 and maraviroc delays that are associated with either receptor engagement or gp41 function. Comparison of these delays with T20 sensitivity suggest co-receptor engagement and fusogenic activity in gp41 act cooperatively but sequentially to drive entry. Our findings support current models of entry where co-receptor engagement drives gp41 eclipse and have strong implications for the design of entry inhibitors and antibodies that target transient entry states. Author Summary: The first step of HIV-1 infection is entry, where virus-cell membrane fusion is driven by the HIV-1 envelope glycoprotein through a series of conformational changes. Some of the most broadly active entry inhibitors work by binding conformations that exist only transiently during entry. The lifetimes of these states and the kinetics of entry are important elements of inhibitor activity for which little is known. We demonstrate a remarkable range of kinetics among 257 diverse HIV-1 isolates and find that this phenotype is highly flexible, with multiple single-residue determinants. Examination of the kinetics of two conformational landmarks shed light on novel kinetic features that offer new details about the role of co-receptor engagement and provide a framework to explain entry inhibitor synergy.

Correction: Burden of disease and risk factors for mortality amongst hospitalized newborns in Nigeria and Kenya.

[This corrects the article DOI: 10.1371/journal.pone.0244109.].

Safety of a Novel Upper Esophageal Sphincter Balloon Dilator.

OBJECTIVE: The shape of esophageal dilators has not changed in over 350 years. Clinical and animal research suggests that the upper esophageal sphincter (UES) is not round but approximates a kidney shape and that cylindrical dilators may be suboptimal. The Infinity UES Dilation System has been developed specifically for the anatomic configuration of the UES. This study evaluates the safety of the UES-specific Infinity Dilation System. METHODS: All patients undergoing dilation of the UES between January 1, 2022 and September 1, 2023 were included. Demographics, procedure indication, dilator type, minor adverse events, and major complications were abstracted. Minor adverse events, complications, and maximum dilation dimension (mm) were compared between groups. RESULTS: A total of 477 patients were included. Eight hundred and seventy-three total UES dilations were performed. The primary indications for UES dilation were cricopharyngeus muscle dysfunction (43%) and stenosis from radiation toxicity (40%). Twenty-three percent (202/873) of dilations were performed with an Infinity balloon, 31% (270/873) were performed using two conventional balloons placed side by side, and 46% (401/873) were performed with one singleton conventional balloon. The average maximum dilation dimension was 33 (±4.7) mm for Infinity balloons, 32 (±3.8) mm for two side-by-side balloons, and 18 (±3.4) mm for singleton balloons. There were three major complications with conventional balloons and none with Infinity balloons. There were no significant differences in minor adverse events between groups. CONCLUSIONS: A UES-specific esophageal dilator provides a greater maximum dilation dimension and appears to be at least as safe as dilation with a single cylindrical balloon designed to dilate the esophagus. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.

Prediction of post-hemorrhagic ventricular dilatation trajectory using a growth mixture model in preterm infants.

BACKGROUND: Early intervention for post-hemorrhagic ventricular dilatation (PHVD), guided by ventricular size measurements from cranial ultrasound (cUS), is associated with improved neurodevelopmental outcomes in preterm infants but benefits must be balanced against intervention risks. METHODS: Anterior horn width (AHW) and ventricular index (VI) were measured from cUS for preterm infants (<29 weeks) with intraventricular hemorrhage admitted from 2010-2018. PHVD was defined as AHW > 6 mm or VI >97th percentile for postmenstrual age. Individual ventricular size trajectories were plotted, and a growth mixture model (GMM) used to identify latent trajectory classes and compare these to predetermined outcome of neurosurgical intervention. RESULTS: Measurements were obtained from 1543 cUS in 249 infants, of whom 39 had PHVD without and 17 PHVD with neurosurgical intervention based on signs of raised intracranial pressure. The GMM predicted trajectory identified: 93.3% of infants without PHVD, 88.2% and 30.8% of infants with PHVD with and without intervention using AHW; 100% of infants without PHVD, 52.9% and 59.0% of infants with PHVD with and without intervention using VI. CONCLUSIONS: The AHW GMM identified a significant proportion of infants with severe PHVD. Model refinement offers a promising approach for identifying differences in PHVD trajectory at an early stage to guide management. IMPACT: It is difficult to distinguish the trajectory of PHVD in the early stage of development, in particular PHVD that spontaneously arrests from slowly progressive PHVD which eventually requires intervention. We report the first modeling-based evaluation of PHVD trajectory for the prediction of short-term outcome of PHVD progression and neurosurgical intervention. With additional clinical validation and optimization to increase accuracy, predictive modeling has the potential to identify important differences in PHVD trajectory at an early stage in the clinical course, allowing for more individualized data-driven risk-benefit assessments to guide decisions on early intervention.