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This collection showcases journal articles, preprints, book chapters, and other publications and presentations produced by faculty, postdocs, and researchers at UMass Chan Medical School.

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Recently Published

  • Harmonizing the Generation and Pre-publication Stewardship of FAIR Image data [preprint]

    Bialy, Nikki; Alber, Frank; Andrews, Brenda; Angelo, Michael; Beliveau, Brian; Bintu, Lacramioara; Boettiger, Alistair; Boehm, Ulrike; Brown, Claire M; Maina, Mahmoud Bukar; et al. (2024-02-08)
    Together with the molecular knowledge of genes and proteins, biological images promise to significantly enhance the scientific understanding of complex cellular systems and to advance predictive and personalized therapeutic products for human health. For this potential to be realized, quality-assured image data must be shared among labs at a global scale to be compared, pooled, and reanalyzed, thus unleashing untold potential beyond the original purpose for which the data was generated. There are two broad sets of requirements to enable image data sharing in the life sciences. One set of requirements is articulated in the companion White Paper entitled "Enabling Global Image Data Sharing in the Life Sciences," which is published in parallel and addresses the need to build the cyberinfrastructure for sharing the digital array data (arXiv:2401.13023 [q-bio.OT], https://doi.org/10.48550/arXiv.2401.13023). In this White Paper, we detail a broad set of requirements, which involves collecting, managing, presenting, and propagating contextual information essential to assess the quality, understand the content, interpret the scientific implications, and reuse image data in the context of the experimental details. We start by providing an overview of the main lessons learned to date through international community activities, which have recently made considerable progress toward generating community standard practices for imaging Quality Control (QC) and metadata. We then provide a clear set of recommendations for amplifying this work. The driving goal is to address remaining challenges, and democratize access to common practices and tools for a spectrum of biomedical researchers, regardless of their expertise, access to resources, and geographical location.
  • Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during infection in the large intestine [preprint]

    Kellogg, Tasia D; Ceglia, Simona; Mortzfeld, Benedikt M; Zeamer, Abigail L; Foley, Sage E; Ward, Doyle V; Bhattarai, Shakti K; McCormick, Beth A; Reboldi, Andrea; Bucci, Vanni (2024-01-31)
    Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen Clostridioides difficile in the large intestine. To date, no research has shown the role of succinate in modulating TC dynamics in the large intestine, or the relevance of this immune pathway to C. difficile pathophysiology. Here we reveal the existence of a three-way circuit between commensal microbes, C. difficile and host epithelial cells which centers around succinate. Through selective microbiota depletion experiments we demonstrate higher levels of type 2 cytokines leading to expansion of TCs in the colon. We then demonstrate the causal role of the microbiome in modulating colonic TC abundance and subsequent type 2 cytokine induction using rational supplementation experiments with fecal transplants and microbial consortia of succinate-producing bacteria. We show that administration of a succinate-deficient Bacteroides thetaiotaomicron knockout (Δfrd) significantly reduces the enhanced type 2 immunity in mono-colonized mice. Finally, we demonstrate that mice prophylactically administered with the consortium of succinate-producing bacteria show reduced C. difficile-induced morbidity and mortality compared to mice administered with heat-killed bacteria or the vehicle. This effect is reduced in a partial tuft cell knockout mouse, Pou2f3+/-, and nullified in the tuft cell knockout mouse, Pou2f3-/-, confirming that the observed protection occurs via the TC pathway. Succinate is an intermediary metabolite of the production of short-chain fatty acids, and its concentration often increases during dysbiosis. The first barrier to enteric pathogens alike is the intestinal epithelial barrier, and host maintenance and strengthening of barrier integrity is vital to homeostasis. Considering our data, we propose that activation of TC by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.
  • Association of spatial proximity to fixed-site syringe services programs with HCV serostatus and injection equipment sharing practices among people who inject drugs in rural New England, United States

    Romo, Eric; Stopka, Thomas J; Jesdale, Bill M; Wang, Bo; Mazor, Kathleen M; Friedmann, Peter D (2024-01-28)
    Background: Hepatitis C virus (HCV) disproportionately affects rural communities, where health services are geographically dispersed. It remains unknown whether proximity to a syringe services program (SSP) is associated with HCV infection among rural people who inject drugs (PWID). Methods: Data are from a cross-sectional sample of adults who reported injecting drugs in the past 30 days recruited from rural counties in New Hampshire, Vermont, and Massachusetts (2018-2019). We calculated the road network distance between each participant's address and the nearest fixed-site SSP, categorized as ≤ 1 mile, 1-3 miles, 3-10 miles, and > 10 miles. Staff performed HCV antibody tests and a survey assessed past 30-day injection equipment sharing practices: borrowing used syringes, borrowing other used injection equipment, and backloading. Mixed effects modified Poisson regression estimated prevalence ratios (aPR) and 95% confidence intervals (95% CI). Analyses were also stratified by means of transportation. Results: Among 330 PWID, 25% lived ≤ 1 mile of the nearest SSP, 17% lived 1-3 miles of an SSP, 12% lived 3-10 miles of an SSP, and 46% lived > 10 miles from an SSP. In multivariable models, compared to PWID who lived within 1 mile of an SSP, those who lived 3 to 10 miles away had a higher prevalence of HCV seropositivity (aPR: 1.25, 95% CI 1.06-1.46), borrowing other used injection equipment (aPR: 1.23, 95% CI 1.04-1.46), and backloading (aPR: 1.48, 95% CI 1.17-1.88). Similar results were observed for PWID living > 10 miles from an SSP: aPR [HCV]: 1.19, 95% CI 1.01-1.40; aPR [borrowing other used equipment]:1.45, 95% CI 1.29-1.63; and aPR [backloading]: 1.59, 95% CI 1.13-2.24. Associations between living 1 to 3 miles of an SSP and each outcome did not reach statistical significance. When stratified by means of transportation, associations between distance to SSP and each outcome (except borrowing other used injection equipment) were only observed among PWID who traveled by other means (versus traveled by automobile). Conclusions: Among PWID in rural New England, living farther from a fixed-site SSP was associated with a higher prevalence of HCV seropositivity, borrowing other used injection equipment, and backloading, reinforcing the need to increase SSP accessibility in rural areas. Means of transportation may modify this relationship.
  • Investigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencing

    Levine, Zoë C; Sene, Aita; Mkandawire, Winnie; Deme, Awa B; Ndiaye, Tolla; Sy, Mouhamad; Gaye, Amy; Diedhiou, Younouss; Mbaye, Amadou M; Ndiaye, Ibrahima M; et al. (2024-01-25)
    The worldwide decline in malaria incidence is revealing the extensive burden of non-malarial febrile illness (NMFI), which remains poorly understood and difficult to diagnose. To characterize NMFI in Senegal, we collected venous blood and clinical metadata in a cross-sectional study of febrile patients and healthy controls in a low malaria burden area. Using 16S and untargeted sequencing, we detected viral, bacterial, or eukaryotic pathogens in 23% (38/163) of NMFI cases. Bacteria were the most common, with relapsing fever Borrelia and spotted fever Rickettsia found in 15.5% and 3.8% of cases, respectively. Four viral pathogens were found in a total of 7 febrile cases (3.5%). Sequencing also detected undiagnosed Plasmodium, including one putative P. ovale infection. We developed a logistic regression model that can distinguish Borrelia from NMFIs with similar presentation based on symptoms and vital signs (F1 score: 0.823). These results highlight the challenge and importance of improved diagnostics, especially for Borrelia, to support diagnosis and surveillance.
  • Comparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positive

    Harrold, Leslie R; Wittstock, Keith; Kelly, Sheila; Han, Xue; Zhuo, Joe; Schrader, Amy; Middaugh, Nicole; Moore, Page C; Khaychuk, Vadim (2024-01-19)
    Background: The HLA-DRB1 shared epitope (SE) is a risk factor for the development of rheumatoid arthritis (RA) and the production of anti-citrullinated protein antibodies (ACPAs) in RA patients. Our objective was to examine the real-world effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFi) in patients with RA who were SE and anti-cyclic citrullinated peptide antibody (anti-CCP3) positive. Methods: Abatacept or TNFi initiators who were SE + and anti-CCP3+ (> 20 U/mL) at or prior to treatment and had moderate or high CDAI score (> 10) at initiation were identified. The primary outcome was mean change in CDAI score over six months. Analyses were conducted in propensity score (PS)-trimmed and -matched populations overall and a biologic-experienced subgroup. Mixed-effects models were used. Results: In the overall PS-trimmed (abatacept, n = 170; TNFi, n = 157) and PS-matched cohorts (abatacept, n = 111; TNFi, n = 111), there were numerically greater improvements in mean change in CDAI between abatacept and TNFi but were not statistically significant. Similar trends were seen for biologic-experienced patients, except that statistical significance was reached for mean change in CDAI in the PS-trimmed cohort (abatacept, 12.22 [95% confidence interval (95%CI) 10.13 to 14.31]; TNFi, 9.28 [95%CI 7.08 to 11.48]; p = 0.045). Conclusion: In this real world cohort, there were numerical improvements in efficacy outcomes with abatacept over TNFi in patients with RA who were SE + and ACPA+, similar to results from a clinical trial population The only statistically significant finding after adjusting for covariates was greater improvement in CDAI with abatacept versus TNFi in the bio-experienced PS-trimmed cohort..
  • Dog size and patterns of disease history across the canine age spectrum: Results from the Dog Aging Project

    Nam, Yunbi; White, Michelle; Karlsson, Elinor K; Creevy, Kate E; Promislow, Daniel E L; McClelland, Robyn L (2024-01-17)
    Age in dogs is associated with the risk of many diseases, and canine size is a major factor in that risk. However, the size patterns are complex. While small size dogs tend to live longer, some diseases are more prevalent among small dogs. In this study we seek to quantify how the pattern of disease history varies across the spectrum of dog size, dog age, and their interaction. Utilizing owner-reported data on disease history from a substantial number of companion dogs enrolled in the Dog Aging Project, we investigate how body size, as measured by weight, associates with the lifetime prevalence of a reported condition and its pattern across age for various disease categories. We found significant positive associations between dog size and the lifetime prevalence of skin, bone/orthopedic, gastrointestinal, ear/nose/throat, cancer/tumor, brain/neurologic, endocrine, and infectious diseases. Similarly, dog size was negatively associated with lifetime prevalence of ocular, cardiac, liver/pancreas, and respiratory disease categories. Kidney/urinary disease prevalence did not vary by size. We also found that the association between age and lifetime disease prevalence varied by dog size for many conditions including ocular, cardiac, orthopedic, ear/nose/throat, and cancer. Controlling for sex, purebred vs. mixed-breed status, and geographic region made little difference in all disease categories we studied. Our results align with the reduced lifespan in larger dogs for most of the disease categories and suggest potential avenues for further examination.
  • Do organisms need an impact factor? Citations of key biological resources including model organisms reveal usage patterns and impact [preprint]

    Piekniewska, Agata; Anderson, Nathan; Roelandse, Martijn; Lloyd, K C Kent; Korf, Ian; Voss, S Randal; de Castro, Giovanni; Magnani, Diogo M; Varga, Zoltan; James-Zorn, Christina; et al. (2024-01-16)
    Research resources like transgenic animals and antibodies are the workhorses of biomedicine, enabling investigators to relatively easily study specific disease conditions. As key biological resources, transgenic animals and antibodies are often validated, maintained, and distributed from university based stock centers. As these centers heavily rely largely on grant funding, it is critical that they are cited by investigators so that usage can be tracked. However, unlike systems for tracking the impact of papers, the conventions and systems for tracking key resource usage and impact lag behind. Previous studies have shown that about 50% of the resources are not findable, making the studies they are supporting irreproducible, but also makes tracking resources difficult. The RRID project is filling this gap by working with journals and resource providers to improve citation practices and to track the usage of these key resources. Here, we reviewed 10 years of citation practices for five university based stock centers, characterizing each reference into two broad categories: findable (authors could use the RRID, stock number, or full name) and not findable (authors could use a nickname or a common name that is not unique to the resource). The data revealed that when stock centers asked their communities to cite resources by RRID, in addition to helping stock centers more easily track resource usage by increasing the number of RRID papers, authors shifted from citing resources predominantly by nickname (~50% of the time) to citing them by one of the findable categories (~85%) in a matter of several years. In the case of one stock center, the MMRRC, the improvement in findability is also associated with improvements in the adherence to NIH rigor criteria, as determined by a significant increase in the Rigor and Transparency Index for studies using MMRRC mice. From this data, it was not possible to determine whether outreach to authors or changes to stock center websites drove better citation practices, but findability of research resources and rigor adherence was improved.
  • Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders

    Daci, Rrita; Flotte, Terence R (2024-01-15)
    Genetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic disorders. Owing to the intricacy of the human CNS and the blood-brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development. In this review, we analyzed delivery methods for AAV-mediated gene therapy in past and current clinical trials. The delivery routes analyzed were direct intraparenchymal (IP), intracerebroventricular (ICV), intra-cisterna magna (CM), lumbar intrathecal (IT), and intravenous (IV). The results demonstrated that the dose used in these routes varies dramatically. The average total doses used were calculated and were 1.03 × 1013 for IP, 5.00 × 1013 for ICV, 1.26 × 1014 for CM, and 3.14 × 1014 for IT delivery. The dose for IV delivery varies by patient weight and is 1.13 × 1015 IV for a 10 kg infant. Ultimately, the choice of intervention must weigh the risk of an invasive surgical procedure to the toxicity and immune response associated with a high dose vector.
  • Hypertension among persons living with HIV/AIDS and its association with HIV-related health factors

    Denu, Mawulorm K I; Revoori, Ritika; Buadu, Maame Araba E; Oladele, Oluwakemi; Berko, Kofi Poku (2024-01-11)
    Background: Human Immunodeficiency Virus (HIV) infection remains a public health concern in many countries. The increased life expectancy in the post-Antiretroviral Therapy (ART) era has led to an increased risk of cardiovascular disease and death among Persons Living with HIV (PLHIV). Hypertension remains a significant risk factor for cardiovascular disease among PLHIV. Some studies have suggested associations between hypertension among PLHIV and HIV-related health factors. Objective: To determine the prevalence of hypertension among PLHIV on antiretroviral medications and examine its association with HIV-related health factors. Methods: A cross-sectional study was conducted among attendants at an adult HIV clinic. 362 study participants were selected by systematic sampling. Data on hypertension diagnosis, HIV-related health factors, sociodemographic and other traditional cardiovascular risk factors were collected using a standardized questionnaire and patient chart review. Multivariate logistic regression model was used to determine the association between hypertension and HIV-related factors, adjusting for other risk factors for hypertension. Results: The mean age of participants was 47.9 years and majority of participants were female (77.1%). 42% of study participants had been on antiretroviral medications for > 10 years. The prevalence of hypertension was 17.4%. Age > 50 years was associated with higher odds of hypertension (aOR: 3.75, 95%CI 1.68, 8.55, p-value: 0.002). BMI in overweight and obese categories, and a history of comorbid medical conditions (diabetes, hyperlipidemia) were also associated with higher odds of hypertension (aOR: 3. 76, 95%CI 1.44, 9.81, p-value: 0.007), (aOR: 3.17, 95%CI 1.21, 8.32, p-value: 0.019) and (aOR: 14.25, 95%CI 7.41, 27.41, p-value: < 0.001) respectively. No HIV-related health factors were associated with hypertension. Conclusion: Hypertension was a common condition among PLHIV on antiretroviral medications. No HIV-related health factors were associated with hypertension. Traditional risk factors associated with hypertension were increased age > 50 years, increased BMI, and a history of comorbid medical conditions.
  • Opioid Overdose Recognition: A Survey of Perceived Preparedness and Desire for Curricular Integration Among Current US Medical Students

    Walsh, Lindsay; Chapman, Brittany; Carey, Jennifer; Loycano, Kayla; Carreiro, Stephanie (2024-01-10)
    Objectives: Opioid overdose deaths remain a major health issue in the United States (US). As future physicians, medical students must receive comprehensive training to recognize and manage opioid overdoses. This study aimed to highlight training gaps at the medical student level and understand students' attitudes toward patients with opioid use disorder (OUD). Methods: We assessed baseline knowledge of and attitudes toward the management of opioid overdoses and naloxone administration among medical students in the US. Two validated survey tools (Opioid Overdose Knowledge Scale and Opioid Overdose Attitude Scale) were administered to medical students training at accredited institutions along with supplemental questions measuring knowledge and attitudes towards opioid overdose management, naloxone administration, and prior training. Results: The final sample had N = 73 participants from US medical schools with a mean age of 25.3 (range of 22-37): 72.6% of respondents were female. Although most respondents reported personal/professional experience with OUD before medical school, they expressed interest in additional training. Knowledge surrounding opioid overdoses increased insignificantly over the 4 years of medical school. However, there was a significant increase in both perceived competence in overdose recognition/management and in concerns about intervening from the first to fourth year of medical school. Female respondents had significantly lower perceived competence and readiness to intervene sub-scores than male counterparts; however, there was no significant difference in overall attitude and knowledge scores when stratified by sex. Incorporating opioid overdose prevention training (OOPT) into early medical education was favorable among respondents, who expressed an overwhelming interest in learning and supporting patients with OUD. Conclusions: Given the ongoing opioid crisis, medical students are ideally placed to identify and manage opioid overdoses. Medical students are ready to receive this training, thus strengthening the argument for OOPT integration into early medical student curricula.
  • The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy

    Muntoni, Francesco; Byrne, Barry J; McMillan, Hugh J; Ryan, Monique M; Wong, Brenda L; Dukart, Juergen; Bansal, Amita; Cosson, Valerie; Dreghici, Roxana; Guridi, Maitea; et al. (2024-01-08)
    Introduction: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice. Methods: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686). Results: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score). Conclusions: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events. Trial registration: NCT02145234, NCT02515669, NCT03039686.
  • mRNA initiation and termination are spatially coordinated [preprint]

    Calvo-Roitberg, Ezequiel; Carroll, Christine L; Venev, Sergey V; Kim, GyeungYun; Mick, Steven T; Dekker, Job; Fiszbein, Ana; Pai, Athma A (2024-01-07)
    The expression of a precise mRNA transcriptome is crucial for establishing cell identity and function, with dozens of alternative isoforms produced for a single gene sequence. The regulation of mRNA isoform usage occurs by the coordination of co-transcriptional mRNA processing mechanisms across a gene. Decisions involved in mRNA initiation and termination underlie the largest extent of mRNA isoform diversity, but little is known about any relationships between decisions at both ends of mRNA molecules. Here, we systematically profile the joint usage of mRNA transcription start sites (TSSs) and polyadenylation sites (PASs) across tissues and species. Using both short and long read RNA-seq data, we observe that mRNAs preferentially using upstream TSSs also tend to use upstream PASs, and congruently, the usage of downstream sites is similarly paired. This observation suggests that mRNA 5' end choice may directly influence mRNA 3' ends. Our results suggest a novel "Positional Initiation-Termination Axis" (PITA), in which the usage of alternative terminal sites are coupled based on the order in which they appear in the genome. PITA isoforms are more likely to encode alternative protein domains and use conserved sites. PITA is strongly associated with the length of genomic features, such that PITA is enriched in longer genes with more area devoted to regions that regulate alternative 5' or 3' ends. Strikingly, we found that PITA genes are more likely than non-PITA genes to have multiple, overlapping chromatin structural domains related to pairing of ordinally coupled start and end sites. In turn, PITA coupling is also associated with fast RNA Polymerase II (RNAPII) trafficking across these long gene regions. Our findings indicate that a combination of spatial and kinetic mechanisms couple transcription initiation and mRNA 3' end decisions based on ordinal position to define the expression mRNA isoforms.
  • Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy

    Bettio, Cinzia; Banchelli, Federico; Salsi, Valentina; Vicini, Roberto; Crisafulli, Oscar; Ruggiero, Lucia; Ricci, Giulia; Bucci, Elisabetta; Angelini, Corrado; Berardinelli, Angela; et al. (2024-01-05)
    Background: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). Methods: People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. Results: 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73-0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51-0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). Conclusions: PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.
  • A Burden of Rare Copy Number Variants in Obsessive-Compulsive Disorder [preprint]

    Halvorsen, Matthew; de Schipper, Elles; Boberg, Julia; Strom, Nora; Hagen, Kristen; Lindblad-Toh, Kerstin; Karlsson, Elinor K; Pedersen, Nancy; Bulik, Cynthia; Fundín, Bengt; et al. (2024-01-03)
    Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from large, rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2,248 deeply phenotyped OCD cases and 3,608 unaffected controls from Sweden and Norway. We found that in general cases carry an elevated burden of large (>30kb, at least 15 probes) CNVs (OR=1.12, P=1.77×10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P=2.58×10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR=1.19, P=3.08×10-4), particularly deletions impacting loss-of-function intolerant genes (pLI>0.995, OR=4.12, P=2.54×10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60×10-3). In cases where sufficient clinical data were available (n=1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P<0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P=0.02). The results demonstrate a contribution of large, rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.
  • Moving Beyond the 2018 Minimum International Care Considerations for Osteoporosis Management in Duchenne Muscular Dystrophy (DMD): Meeting Report from the 3rd International Muscle-Bone Interactions Meeting 7th and 14th November 2022

    Phung, Kim; Crabtree, Nicola; Connolly, Anne M; Furlong, Pat; Hoffman, Eric P; Jackowski, Stefan A; Jayash, Soher Nagi; Johnson, Alex; Koujok, Khaldoun; Munns, Craig F; et al. (2024-01-02)
    This current manuscript summarizes the proceedings of the “Third Muscle-bone interactions in Duchenne Muscular Dystrophy Symposium: Moving Beyond the 2018 Minimum International Standards of Care for Osteoporosis Management”, an event co-organized by the World Duchenne Organization (www.worldduchenne.org) and the International Conference on Children’s Bone Health (www.theiscbh.org). This virtual symposium, held on November 7th and 14th 2022, brought together a total of 385 delegates representing 55 countries registered for the symposium, which included 239 clinicians, 70 researchers, 40 patient representatives and others from pharmaceutical companies and regulators. This symposium aimed to review the evidence base that informed the 2018 international minimum Care Considerations, best practices for implementation of these Care Considerations, and emerging knowledge that has arisen from research since the 2018 Care Considerations that shines light on the path forward.
  • Effectiveness of two systems-level interventions to address perinatal depression in obstetric settings (PRISM): an active-controlled cluster-randomised trial

    Byatt, Nancy; Brenckle, Linda; Sankaran, Padma; Flahive, Julie; Ko, Jean Y; Robbins, Cheryl L; Zimmermann, Martha; Allison, Jeroan J.; Person, Sharina D.; Moore Simas, Tiffany A (2024-01-01)
    Background: Perinatal depression is a common and undertreated condition, with potential deleterious effects on maternal, obstetric, infant, and child outcomes. We aimed to compare the effectiveness of two systems-level interventions in the obstetric setting-the Massachusetts Child Psychiatry Access Program (MCPAP) for Moms and the PRogram In Support of Moms (PRISM)-in improving depression symptoms and participation in mental health treatment among women with perinatal depression. Methods: In this cluster-randomised, active-controlled trial, obstetric practices across Massachusetts (USA) were allocated (1:1) via covariate adaptive randomisation to either continue participating in the MCPAP for Moms intervention, a state-wide, population-based programme, or to participate in the PRISM intervention, which involved MCPAP for Moms plus a proactive, multifaceted, obstetric practice-level intervention with intensive implementation support. English-speaking women (aged ≥18 years) who screened positive for depression (Edinburgh Postnatal Depression Scale [EPDS] score ≥10) were recruited from the practices. Patients were followed up at 4-25 weeks of gestation, 32-40 weeks of gestation, 0-3 months postpartum, 5-7 months postpartum, and 11-13 months postpartum via telephone interview. Participants were masked to the intervention; investigators were not masked. The primary outcome was change in depression symptoms (EPDS score) between baseline assessment and 11-13 months postpartum. Analysis was done by intention to treat, fitting generalised linear mixed models adjusting for age, insurance status, education, and race, and accounting for clustering of patients within practices. This trial is registered with ClinicalTrials.gov, NCT02760004. Findings: Between July 29, 2015, and Sept 20, 2021, ten obstetric practices were recruited and retained; five (50%) practices were randomly allocated to MCPAP for Moms and five (50%) to PRISM. 1265 participants were assessed for eligibility and 312 (24·7%) were recruited, of whom 162 (51·9%) were enrolled in MCPAP for Moms practices and 150 (48·1%) in PRISM practices. Comparing baseline to 11-13 months postpartum, EPDS scores decreased by 4·2 (SD 5·2; p<0·0001) among participants in MCPAP for Moms practices and by 4·3 (SD 4.5; p<0·0001) among those in PRISM practices (estimated difference between groups 0·1 [95% CI -1·2 to 1·4]; p=0·87). Interpretation: Both the MCPAP for Moms and PRISM interventions were equally effective in improving depression symptoms. This finding is important because the 4-point decrease in EPDS score is clinically significant, and MCPAP for Moms has a lower intensity and greater population-based reach than does PRISM. Funding: US Centers for Disease Control and Prevention.
  • Unintentional Ketamine Overdose Via Telehealth

    Johnson, Brett E; Borges, Eric S; Gaspari, Romolo J; Galletta, Gayle M; Lai, Jeffrey T (2024-01-01)
    The use of ketamine in psychiatry has expanded to at-home ketamine-assisted therapy (KAT) via telemedicine. We report a case of massive unintentional ketamine overdose during at-home KAT resulting in hypoxemic respiratory failure, successfully treated with atropine.
  • Change in Sexual and Reproductive Health Knowledge among Young Women Using the Conversational Agent "Nthabi" in Lesotho: A Clinical Trial [preprint]

    Nkabane-Nkholongo, Elizabeth; Mokgatle, Mathildah; Bickmore, Timothy; Julce, Clevanne; Thompson, David; Jack, Brian (2023-12-28)
    Background: Young women worldwide face problems like unwanted pregnancy and sexually transmitted infections. Providing sexual and reproductive health education to this population remains a priority. It is unknown if using digital health interventions to deliver health education in human resource-constrained settings is effective. Methods: We conducted a clinical trial of the Nthabi intervention to determine participant's knowledge before and after discussion of family planning, folic acid and healthy eating among young women aged 18-28 years in two rural districts of Lesotho who used the Nthabi conversational agent system on either smartphones or tablets for up to six weeks. The number of correct pre- and post-test responses were compared using generalized linear models that directly estimated the proportions and percentages of correct responses. Results: Of the 172 participants enrolled, the mean age was 22.5 years, 91% were unmarried, 69% completed high school, 23% were unemployed and 66% were students. The mean number of interactions with Nthabi was Family planning was chosen to be discussed by 82 (52.2%), of the 172 participants and of those, 49 (59.8%) completed the content on this topic, and 26 (53.1%) completed the post-test. For the 11 questions about family planning, there were 717 (76.6%) correct responses on the pre-test and 320 (89.9%) on the post-test (p = 0.0233). Folic acid was chosen to be discussed by 74 (47.1%) of 172 participants, and of those, 27 (36.5%) completed the content on this topic, and all 27 (100%) completed the post-test. For the 5 questions about folic acid use, there were 181 (45.3%) correct responses on the pre-test and 111 (71.6%) on the post-test (p < 0.0001). The number of correct responses on the post-test was positively associated with the number of sessions that the participant engaged with Nthabi. Conclusion: The Nthabi conversational agent system increased knowledge of family planning methods and folic acid use among young women in Lesotho. Digital health interventions like Nthabi offer new opportunities to deliver reproductive health information in countries that have limited human resources for health. Trial registration: ClinicalTrials.gov ID: NCT04354168.
  • Stem cells and pain

    da Silva, Matheus Deroco Veloso; Piva, Maiara; Martelossi-Cebinelli, Geovana; Stinglin Rosa Ribas, Mariana; Hoffmann Salles Bianchini, Beatriz; Heintz, Olivia K; Casagrande, Rubia; Verri, Waldiceu A (2023-12-26)
    Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.
  • Intraflagellar transport: A critical player in photoreceptor development and the pathogenesis of retinal degenerative diseases

    Gupta, Mohona; Pazour, Gregory J (2023-12-23)
    In vertebrate vision, photons are detected by highly specialized sensory cilia called outer segments. Photoreceptor outer segments form by remodeling the membrane of a primary cilium into a stack of flattened disks. Intraflagellar transport (IFT) is critical to the formation of most types of eukaryotic cilia including the outer segments. This review covers the state of knowledge of the role of IFT in the formation and maintenance of outer segments and the human diseases that result from mutations in genes encoding the IFT complex and associated motors.

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