Weight, habitual fibre intake, and microbiome composition predict tolerance to fructan supplementation.

Fructans are commonly used as dietary fibre supplements for their ability to promote the growth of beneficial gut microbes. However, fructan consumption has been associated with various dosage-dependent side effects. We characterised side effects in an exploratory analysis of a randomised trial in healthy adults (n = 40) who consumed 18 g/day inulin or placebo. We found that individuals weighing more or habitually consuming higher fibre exhibited the best tolerance. Furthermore, we identified associations between gut microbiome composition and host tolerance. Specifically, higher levels of Christensenellaceae R-7 group were associated with gastrointestinal discomfort, and a machine-learning-based approach successfully predicted high levels of flatulence, with [Ruminococcus] torques group and (Oscillospiraceae) UCG-002 sp. identified as key predictive taxa. These data reveal trends that can help guide personalised recommendations for initial inulin dosage. Our results support prior ecological findings indicating that fibre supplementation has the greatest impact on individuals whose baseline fibre intake is lowest.

A Case of Osseous Metaplasia in a Juvenile Rectal Polyp.

Rectal mucosal prolapse is uncommon in children. While most patients present with rectal bleeding and constipation, the occurrence of osseous metaplasia within the prolapsed mucosa is extremely rare. Overlapping clinical, gross, and histological features between rectal mucosal prolapse polyps and malignancy pose a challenge for diagnoses. We describe a case of a 16-year-old male who had a rectal mucosal prolapsed polyp with osseous metaplasia. He initially presented due to periumbilical pain with a sore throat and fever. Incidentally, during the workup of his periumbilical pain, he was found to have a soft tissue mass in his rectum on a CT scan, with a biopsy confirming the diagnosis. The case was complicated by the development of sepsis. The patient was treated with empiric antibiotics and was discharged without further complications.

Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice.

Previous studies have shown that ligands that bind to sigma-2 receptor/TMEM97 (s2R/TMEM97), a transmembrane protein, have anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest in s2R/TMEM97, little affective and pain behavioral characterization has been done using transgenic mice, which limits the development of s2R/TMEM97 as a viable therapeutic target. Using wild-type (WT) and global Tmem97 knock-out (KO) mice, we sought to identify the contribution of Tmem97 in modulating affective and pain-like behaviors using a battery of affective and pain assays, including open field, light/dark preference, elevated plus maze, forced swim test, tail suspension test, and the mechanical sensitivity tests. Our results demonstrate that female Tmem97 KO mice show less anxiety-like and depressive-like behaviors in light/dark preference and tail suspension tests but not in an open field, elevated plus maze, and forced swim tests at baseline. We next performed spared nerve injury in WT and Tmem97 KO mice to assess the role of Tmem97 in neuropathic pain-induced anxiety and depression. WT mice, but not Tmem97 KO mice, developed a prolonged neuropathic pain-induced depressive-like phenotype when tested 10 weeks after nerve injury in females. Our results show that Tmem97 plays a role in modulating anxiety-like and depressive-like behaviors in naive animals with a significant change in the presence of nerve injury in female mice. Overall, these data demonstrate that Tmem97 could be a target to alleviate affective comorbidities of pain disorders.

Clinician-perceived barriers to cervical cancer screening before and during the COVID-19 pandemic at three US healthcare systems.

Introduction: The COVID-19 pandemic posed serious challenges to cancer screening delivery, including cervical cancer. While the impact of the pandemic on deferred screening has been documented, less is known about how clinicians experienced barriers to screening delivery, and, in particular, the role of pre-pandemic barriers to changes reported during the pandemic. Methods: Survey of clinicians who performed ≥ 10 cervical cancer screening tests in 2019 from Mass General Brigham, Kaiser Permanente Washington, and Parkland Health, the healthcare systems participating in the Population-based Research to Optimize the Screening Process (PROSPR II) consortium (administered 10/2020-12/2020, response rate 53.7 %). Results: Prior to the pandemic, clinicians commonly noted barriers to the delivery of cervical cancer screening including lack of staff support (57.6%), interpreters (32.5%), resources to support patients with social barriers to care (61.3%), and discrimination or bias in interactions between staff and patients (31.2%). Clinicians who reported experiencing a given barrier to care before the pandemic were more likely than those who did not experience one to report worsening during the pandemic: lack of staff support (odds ratio 4.70, 95% confidence interval 2.94-7.52); lack of interpreters (8.23, 4.46-15.18); lack of resources to support patients in overcoming social barriers (7.65, 4.41-13.27); and discrimination or bias (6.73, 3.03-14.97). Conclusions: Clinicians from three health systems who deliver cervical cancer screening commonly reported barriers to care. Barriers prior to the pandemic were associated with worsening of barriers during the pandemic. Addressing barriers to cervical cancer screening may promote resilience of care delivery during the next public health emergency.

Sentinel Enhanced Dengue Surveillance System - Puerto Rico, 2012-2022.

Problem/Condition: Dengue is the most prevalent mosquitoborne viral illness worldwide and is endemic in Puerto Rico. Dengue's clinical spectrum can range from mild, undifferentiated febrile illness to hemorrhagic manifestations, shock, multiorgan failure, and death in severe cases. The disease presentation is nonspecific; therefore, various other illnesses (e.g., arboviral and respiratory pathogens) can cause similar clinical symptoms. Enhanced surveillance is necessary to determine disease prevalence, to characterize the epidemiology of severe disease, and to evaluate diagnostic and treatment practices to improve patient outcomes. The Sentinel Enhanced Dengue Surveillance System (SEDSS) was established to monitor trends of dengue and dengue-like acute febrile illnesses (AFIs), characterize the clinical course of disease, and serve as an early warning system for viral infections with epidemic potential. Reporting Period: May 2012-December 2022. Description of System: SEDSS conducts enhanced surveillance for dengue and other relevant AFIs in Puerto Rico. This report includes aggregated data collected from May 2012 through December 2022. SEDSS was launched in May 2012 with patients with AFIs from five health care facilities enrolled. The facilities included two emergency departments in tertiary acute care hospitals in the San Juan-Caguas-Guaynabo metropolitan area and Ponce, two secondary acute care hospitals in Carolina and Guayama, and one outpatient acute care clinic in Ponce. Patients arriving at any SEDSS site were eligible for enrollment if they reported having fever within the past 7 days. During the Zika epidemic (June 2016-June 2018), patients were eligible for enrollment if they had either rash and conjunctivitis, rash and arthralgia, or fever. Eligibility was expanded in April 2020 to include reported cough or shortness of breath within the past 14 days. Blood, urine, nasopharyngeal, and oropharyngeal specimens were collected at enrollment from all participants who consented. Diagnostic testing for dengue virus (DENV) serotypes 1-4, chikungunya virus, Zika virus, influenza A and B viruses, SARS-CoV-2, and five other respiratory viruses was performed by the CDC laboratory in San Juan. Results: During May 2012-December 2022, a total of 43,608 participants with diagnosed AFI were enrolled in SEDSS; a majority of participants (45.0%) were from Ponce. During the surveillance period, there were 1,432 confirmed or probable cases of dengue, 2,293 confirmed or probable cases of chikungunya, and 1,918 confirmed or probable cases of Zika. The epidemic curves of the three arboviruses indicate dengue is endemic; outbreaks of chikungunya and Zika were sporadic, with case counts peaking in late 2014 and 2016, respectively. The majority of commonly identified respiratory pathogens were influenza A virus (3,756), SARS-CoV-2 (1,586), human adenovirus (1,550), respiratory syncytial virus (1,489), influenza B virus (1,430), and human parainfluenza virus type 1 or 3 (1,401). A total of 5,502 participants had confirmed or probable arbovirus infection, 11,922 had confirmed respiratory virus infection, and 26,503 had AFI without any of the arboviruses or respiratory viruses examined. Interpretation: Dengue is endemic in Puerto Rico; however, incidence rates varied widely during the reporting period, with the last notable outbreak occurring during 2012-2013. DENV-1 was the predominant virus during the surveillance period; sporadic cases of DENV-4 also were reported. Puerto Rico experienced large outbreaks of chikungunya that peaked in 2014 and of Zika that peaked in 2016; few cases of both viruses have been reported since. Influenza A and respiratory syncytial virus seasonality patterns are distinct, with respiratory syncytial virus incidence typically reaching its annual peak a few weeks before influenza A. The emergence of SARS-CoV-2 led to a reduction in the circulation of other acute respiratory viruses. Public Health Action: SEDSS is the only site-based enhanced surveillance system designed to gather information on AFI cases in Puerto Rico. This report illustrates that SEDSS can be adapted to detect dengue, Zika, chikungunya, COVID-19, and influenza outbreaks, along with other seasonal acute respiratory viruses, underscoring the importance of recognizing signs and symptoms of relevant diseases and understanding transmission dynamics among these viruses. This report also describes fluctuations in disease incidence, highlighting the value of active surveillance, testing for a panel of acute respiratory viruses, and the importance of flexible and responsive surveillance systems in addressing evolving public health challenges. Various vector control strategies and vaccines are being considered or implemented in Puerto Rico, and data from ongoing trials and SEDSS might be integrated to better understand epidemiologic factors underlying transmission and risk mitigation approaches. Data from SEDSS might guide sampling strategies and implementation of future trials to prevent arbovirus transmission, particularly during the expansion of SEDSS throughout the island to improve geographic representation.

A Randomized Trial of Inspiratory Training in Children and Adolescents With Obesity.

Introduction: Children with obesity suffer excess dyspnea that contributes to sedentariness. Developing innovative strategies to increase exercise tolerance and participation in children with obesity is a high priority. Because inspiratory training (IT) has reduced dyspnea, we sought to assess IT in children with obesity. Methods: We conducted a 6-week randomized IT trial involving 8- to 17-year-olds with obesity. Participants were randomized 1:1 to either high [75% of maximal inspiratory pressure (MIP)] or low resistance control (15% of MIP) three times weekly. Assessments included adherence, patient satisfaction, and changes in inspiratory strength and endurance, dyspnea scores and total activity level. Results: Among 27 randomized, 24 (89%) completed the intervention. Total session adherence was 72% which did not differ between treatment groups. IT was safe, and more than 90% felt IT benefitted breathing and general health. IT led to a mean improvement (95% CI) in inspiratory strength measured by MIP of 10.0 cm H2O (-3.5, 23.6; paired t-test, p = 0.139) and inspiratory endurance of 8.9 (1.0, 16.8; paired t-test, p = 0.028); however, there was no significant difference between high- and low-treatment groups. IT led to significant reductions in dyspnea with daily activity (p < 0.001) and in prospectively reported dyspnea during exercise (p = 0.024). Among the high- versus low-treatment group, we noted a trend for reduced dyspnea with daily activity (p = 0.071) and increased daily steps (865 vs. -51, p = 0.079). Discussion: IT is safe and feasible for children with obesity and holds promise for reducing dyspnea and improving healthy activity in children with obesity. Breathe-Fit trial NCT05412134.

G-protein-coupled receptor 84 regulates acute inflammation in normal and diabetic skin wounds.

Lipids have emerged as potent regulators of immune cell function. In the skin, adipocyte lipolysis increases the local pool of free fatty acids and is essential for coordinating early macrophage inflammation following injury. Here, we investigate G-protein-coupled receptor 84 (GPR84), a medium-chain fatty acid (MCFA) receptor, for its potential to propagate pro-inflammatory signaling after skin injury. GPR84 signaling was identified as a key component of regulating myeloid cell numbers and subsequent tissue repair through in vivo administration of a pharmacological antagonist and the MCFA decanoic acid. We found that impaired injury-induced dermal adipocyte lipolysis is a hallmark of diabetes, and lipidomic analysis demonstrated that MCFAs are significantly reduced in diabetic murine wounds. Furthermore, local administration of decanoic acid rescued myeloid cell numbers and tissue repair during diabetic wound healing. Thus, GPR84 is a readily targetable lipid signaling pathway for manipulating injury-induced tissue inflammation with beneficial effects on acute diabetic healing.

Interplay between particle size and microbial ecology in the gut microbiome.

Physical particles can serve as critical abiotic factors that structure the ecology of microbial communities. For non-human vertebrate gut microbiomes, fecal particle size (FPS) has been known to be shaped by chewing efficiency and diet. However, little is known about what drives FPS in the human gut. Here, we analyzed FPS by laser diffraction across a total of 76 individuals and found FPS to be strongly individualized. Surprisingly, a behavioral intervention with 41 volunteers designed to increase chewing efficiency did not impact FPS. Dietary patterns could also not be associated with FPS. Instead, we found evidence that mammalian and human gut microbiomes shaped FPS. Fecal samples from germ-free and antibiotic-treated mice exhibited increased FPS relative to colonized mice. In humans, markers of longer transit time were correlated with smaller FPS. Gut microbiota diversity and composition were also associated with FPS. Finally, ex vivo culture experiments using human fecal microbiota from distinct donors showed that differences in microbiota community composition can drive variation in particle size. Together, our results support an ecological model in which the human gut microbiome plays a key role in reducing the size of food particles during digestion, and that the microbiomes of individuals vary in this capacity. These new insights also suggest FPS in humans to be governed by processes beyond those found in other mammals and emphasize the importance of gut microbiota in shaping their own abiotic environment.

Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.

Multiple Prenatal Exposures and Acute Care Clinical Encounters for Asthma among Children Born to Mothers Living near a Superfund Site.

Prenatal exposures are associated with childhood asthma, and risk may increase with simultaneous exposures. Pregnant women living in lower-income communities tend to have elevated exposures to a range of potential asthma risk factors, which may interact in complex ways. We examined the association between prenatal exposures and the risk of childhood asthma acute care clinical encounters (hospitalization, emergency department visit, observational stay) using conditional logistic regression with a multivariable smooth to model the interaction between continuous variables, adjusted for maternal characteristics, and stratified by sex. All births near the New Bedford Harbor (NBH) Superfund site (2000-2006) were followed through 2011 using the Massachusetts Pregnancy to Early Life Longitudinal data system to identify children ages 5-11 with asthma acute care clinical encounters (265 cases among 7,787 with follow-up). Hazard ratios (HRs) were higher for children living closer to the NBH with higher cord blood Pb levels than children living further away from the NBH with lower Pb levels (P<0.001). HRs were highest for girls (HR=4.17, 95% CI: 3.60, 4.82) compared to boys (HR=1.72, 95% CI: 1.46, 2.02). Our results suggest that prenatal Pb exposure in combination with residential proximity to the NBH is associated with childhood asthma acute care clinical encounters.

Elder abuse geriatrics: describing an important new medical specialist.

Elder mistreatment, including elder abuse and neglect, is a difficult diagnosis to make and manage for most providers. To address this, two elder abuse consultation teams were developed for patients in the hospital and emergency department settings. As these teams have developed, the providers involved have obtained specialized training and experience that we believe contributes to a new field of elder abuse geriatrics, a corollary to the well-established field of child abuse pediatrics. Providers working in this field require specialized training and have a specialized scope of practice that includes forensic evaluation, evaluation of cognition and capacity, care coordination and advocacy for victims of abuse, and collaboration with protective services and law enforcement. Here we describe the training, scope of practice, ethical role, and best practices for elder mistreatment medical consultation. We hope this will serve as a starting point for this new and important medical specialty.

People perceive parasocial relationships to be effective at fulfilling emotional needs.

People regularly form one-sided, "parasocial" relationships (PSRs) with targets incapable of returning the sentiment. Past work has shown that people engage with PSRs to support complex psychological needs (e.g., feeling less lonely after watching a favorite movie). However, we do not know how people rate these relationships relative to traditional two-sided relationships in terms of their effectiveness in supporting psychological needs. The current research (Ntotal = 3085) examined how PSRs help people fulfil emotion regulation needs. In Studies 1 and 2, participants felt that both their YouTube creator and non-YouTube creator PSRs were more effective at fulfilling their emotional needs than in-person acquaintances, albeit less effective than close others. In Study 3, people with high self-esteem thought PSRs would be responsive to their needs when their sociometer was activated, just as they do with two-sided relationships.

Storylines of family medicine VI: ways of being-in the office with patients.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'VI: ways of being-in the office with patients', authors address the following themes: 'Patient-centred care-cultivating deep listening skills', 'Doctor as witness', 'Words matter', 'Understanding others-metaphor and its use in medicine', 'Communicating with patients-making good use of time', 'The patient-centred medical home-aspirations for the future', 'Routine, ceremony or drama?' and 'The life course'. May readers better appreciate the nuances of patient care through these essays.

Diving into the proteomic atlas of SARS-CoV-2 infected cells.

The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome_App/ ) to enrich and expand this knowledgebase.

ED/hospital program contributions to community multi-disciplinary team meetings: Different models.

Elder mistreatment (EM) is a complex problem, with response and prevention requiring contributions from professionals from many disciplines. Community-based multi-disciplinary teams (MDTs) that conduct meetings to discuss challenging cases and coordinate services are a common strategy to ensure effective collaboration. Though they play an important role in EM identification, intervention, and prevention, hospitals and hospital-based healthcare professionals have been particularly difficult to engage in MDTs. Two hospitals in different communities recently launched Emergency Department (ED)/hospital-based response teams to consult in cases of potential EM, and both participate in MDTs. We explored similarities and differences between the MDTs in these communities including in the role of the ED/hospital-based response team. The comparison demonstrates both core common features as well as large variations. These differences reflect different circumstances in the models on which they were based, on MDT development in these communities, available resources and infrastructure, and the ED/hospital program's role.

De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features.

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.