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Background Adhesive capsulitis (AC) of the shoulder, also known as frozen shoulder, causes substantial pain and disability. In cases of secondary AC, the inflammation and fibrosis of the synovial joint can be triggered by trauma or surgery to the joint followed by extended immobility. However, for primary AC the inciting trigger is unknown. The burden of the disorder among the elderly is also unknown leading to this age group being left out of therapeutic research studies, potentially receiving delayed diagnoses, and unknown financial costs to the Medicare system. The purpose of this analysis was to describe the epidemiology of AC in individuals over the age of 65, an age group little studied for this disorder. The second purpose was to investigate whether specific medications, co-morbidities, infections, and traumas are risk factors or triggers for primary AC in this population. Methods We used Medicare claims data from 2010–2012 to investigate the prevalence of AC and assess comorbid risk factors and seasonality. Selected medications, distal trauma, and classes of infections as potential inflammatory triggers for primary AC were investigated using a case–control study design with patients with rotator cuff tears as the comparison group. Medications were identified from National Drug codes and translated to World Health Organization ATC codes for analysis. Health conditions were identified using ICD9-CM codes. Results We found a one-year prevalence rate of AC of approximately 0.35% among adults aged 65 years and older which translates to approximately 142,000 older adults in the United States having frozen shoulder syndrome. Diabetes and Parkinson’s disease were significantly associated with the diagnosis of AC in the elderly. Cases were somewhat more common from August through December, although a clear seasonal trend was not observed. Medications, traumas, and infections were similar for cases and controls. Conclusions This investigation identified the burden of AC in the US elderly population and applied case–control methodology to identify triggers for its onset in this population. Efforts to reduce chronic health conditions such as diabetes may reduce seemingly unrelated conditions such as AC. The inciting trigger for this idiopathic condition remains elusive.

Polypharmacy poses a significant risk for adverse reactions. While there are clinical decision support tools to assist clinicians in medication management, pharmacogenetic testing to identify potential drug–gene or drug–drug–gene interactions is not widely implemented in the clinical setting. A PRISMA-compliant scoping review was performed to determine if pharmacogenetic testing for absorption, distribution, metabolism, and excretion (ADME)-related genetic variants is associated with improved clinical outcomes in patients with polypharmacy. Six studies were reviewed. Five reported improved clinical outcomes, reduced side effects, reduction in the number of drugs used, or reduced healthcare utilization. The reviewed studies varied in methodological quality, risk of bias, and outcome measures. Age, diet, disease state, and treatment adherence also influence drug response, and may confound the relationship between genetic polymorphisms and treatment outcomes. Further studies using a randomized control design are needed. We conclude that pharmacogenetic testing represents an opportunity to improve health outcomes in patients exposed to polypharmacy, particularly in patients with psychiatric disorders and the elderly.

Introduction Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40 , a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging. Methods Using the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging. Results Twenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity. Discussions Our systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease. In an effort to better understand the functional landscape of the PMS region during normal neurodevelopment, we assessed RNA-sequencing (RNA-seq) expression data collected from post-mortem brain tissue from developmentally normal subjects over the course of prenatal to adolescent age and analyzed expression changes of 65 genes on 22q13. We found that the majority of genes within this region were expressed in the brain, with ATNX10, MLC1, MAPK8IP2, and SULT4A1 having the highest overall expression. Analysis of the temporal profiles of the highest expressed genes revealed a trend towards peak expression during the early post-natal period, followed by a drop in expression later in development. Spatial analysis revealed significant region specific differences in the expression of SHANK3, MAPK8IP2, and SULT4A1. Region specific expression over time revealed a consistently unique gene expression profile within the cerebellum, providing evidence for a distinct developmental program within this region. Exon-specific expression of SHANK3 showed higher expression within exons contributing to known brain specific functional isoforms. Overall, we provide an updated roadmap of the PMS region, implicating several genes and time periods as important during neurodevelopment, with the hope that this information can help us better understand the phenotypic heterogeneity of PMS.

Background Primary adhesive capsulitis (AC) is not well understood, and controversy remains about the most effective treatment approaches. Even less is known about the treatment of AC in the Medicare population. We aimed to fully characterize initial treatment for AC in terms of initial treatment utilization, timing of initial treatments and treatment combinations. Methods Using United States Medicare claims from 2010–2012, we explored treatment utilization and patient characteristics associated with initial treatment for primary AC among 7,181 Medicare beneficiaries. Patients with primary AC were identified as patients seeking care for a new shoulder complaint in 2011, with the first visit related to shoulder referred to as the index date, an x-ray or MRI of the shoulder region, and two separate diagnoses of AC (ICD-9-CM codes: 726.00). The treatment period was defined as the 90 days immediately following the index shoulder visit. A multivariable logistic model was used to assess baseline patient factors associated with receiving surgery within the treatment period. Results Ninety percent of beneficiaries with primary AC received treatment within 90 days of their index shoulder visit. Physical therapy (PT) alone (41%) and injection combined with PT (34%) were the most common treatment approaches. Similar patient profiles emerged across treatment groups, with higher proportions of racial minorities, socioeconomically disadvantaged and more frail patients favoring injections or watchful waiting. Black beneficiaries (OR = 0.37, [0.16, 0.86]) and those residing in the northeast (OR = 0.36, [0.18, 0.69]) had significantly lower odds of receiving surgery in the treatment period. Conversely, younger beneficiaries aged 66–69 years (OR = 6.75, [2.12, 21.52]) and 70–75 years (OR = 5.37, [1.67, 17.17]) and beneficiaries with type 2 diabetes had significantly higher odds of receiving surgery (OR = 1.41, [1.03, 1.92]). Conclusions Factors such as patient baseline health and socioeconomic characteristics appear to be important for physicians and Medicare beneficiaries making treatment decisions for primary AC.

Background Anorexia nervosa has one of the highest mortality rates of all mental illnesses. For those who survive, less than 70% fully recover, with many going on to develop a more severe and enduring phenotype. Research now suggests that genetics plays a role in the development and persistence of anorexia nervosa. Inclusion of participants with more severe and enduring illness in genetics studies of anorexia nervosa is critical. Objective The primary goal of this review was to assess the inclusion of participants meeting the criteria for the severe enduring anorexia nervosa phenotype in genetics research by (1) identifying the most widely used defining criteria for severe enduring anorexia nervosa and (2) performing a review of the genetics literature to assess the inclusion of participants meeting the identified criteria. Methods Searches of the genetics literature from 2012 to 2023 were performed in the PubMed, PsycINFO, and Web of Science databases. Publications were selected per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The criteria used to define the severe and enduring anorexia nervosa phenotype were derived by how often they were used in the literature since 2017. The publications identified through the literature search were then assessed for inclusion of participants meeting these criteria. Results most prevalent criteria used to define severe enduring anorexia nervosa in the literature were an illness duration of ≥ 7 years, lack of positive response to at least two previous evidence-based treatments, a body mass index meeting the Diagnostic and Statistical Manual of Mental Disorders-5 for extreme anorexia nervosa, and an assessment of psychological and/or behavioral severity indicating a significant impact on quality of life. There was a lack of consistent identification and inclusion of those meeting the criteria for severe enduring anorexia nervosa in the genetics literature. Discussion This lack of consistent identification and inclusion of patients with severe enduring anorexia nervosa in genetics research has the potential to hamper the isolation of risk loci and the development of new, more effective treatment options for patients with anorexia nervosa. Plain English Summary Anorexia nervosa (AN) is a serious illness with a high death rate. Many of those with AN do not recover and have continuing severe psychological and physical symptoms that greatly impact their quality of life. Research has shown that genetics plays an important role, along with environment, in the development and persistence of AN. This review highlights the continued lack of consensus on defining criteria for severe and enduring AN in the literature and the continued focus on younger females with shorter illness durations in AN genetics research. Greater efforts are needed to include older participants with severe AN of longer duration in genetics research in hopes of developing more effective treatments for this underrepresented group.

Background: Phelan–McDermid syndrome (PMS), caused by SHANK3 variants or 22q13.3 deletions, often includes systemic features such as gastrointestinal and hepatic abnormalities. This study highlights the overlap between PMS and metabolic-associated steatotic liver disease (MASLD), focusing on PNPLA3 variants and underscoring the need for structured metabolic monitoring. Methods: We describe a 25-year-old male with PMS due to a 22q13.33 microdeletion involving SHANK3. He exhibited developmental delay, seizures, and hypotonia. Genetic testing revealed homozygosity for the PNPLA3 p.I148M variant. Clinical, anthropometric, biochemical, imaging, and metabolic investigations were performed, including liver ultrasound and metabolic profiling of lymphoblastoid cell lines. Results: Ultrasound revealed moderate hepatic steatosis consistent with MASLD. After ursodeoxycholic acid treatment and a Mediterranean-style diet, steatosis improved to mild. Metabolic profiling demonstrated increased nicotinamide adenine dinucleotide generation under metabolic stimuli, suggesting altered energy homeostasis. Conclusions: We highlight the contribution of PNPLA3 to MASLD in PMS and support systematic hepatic monitoring. Genotype–phenotype associations in PMS may provide insights relevant to MASLD research and clinical management.

Phelan–McDermid syndrome (PMS) is a multi-systemic disorder characterized by both genetic and phenotypic variability. Genetic abnormalities causing PMS span from pathogenic variants of the SHANK3 gene to chromosomal rearrangements affecting the 22q13 region and leading to the loss of up to over nine megabases. The clinical presentation of individuals with PMS includes intellectual disability, neonatal hypotonia, delayed or absent speech, developmental delay, and minor dysmorphic facial features. Several other features may present with differences in age of onset and/or severity: seizures, autism, regression, sleep disorders, gastrointestinal problems, renal disorders, dysplastic toenails, and disrupted thermoregulation. Among the causes of this phenotypic variability, the size of the 22q13 deletion has effects that may be influenced by environmental factors interacting with haploinsufficiency or hemizygous variants of certain genes. Another mechanism linking environmental factors and phenotypic variability in PMS involves the loss of one copy of genes like BRD1 or CYP2D6, located at 22q13 and involved in the regulation of genomic methylation or pharmacokinetics, which are also influenced by external agents, such as diet and drugs. Overall, several non-mutually exclusive genetic and epigenetic mechanisms interact with environmental factors and may contribute to the clinical variability observed in individuals with PMS. Characterization of such factors will help to better manage this disorder.

Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials.

Introduction MEF2C‐related disorders are characterized by developmental and cognitive delay, limited language and walking, hypotonia, and seizures. A recent systematic review identified 117 patients with MEF2C‐related disorders across 43 studies. Despite these reports, the disorder is not easily recognized and assessments are hampered by small sample sizes. Our objective was to gather developmental and clinical information on a large number of patients. Methods We developed a survey based on validated instruments and subject area experts to gather information from parents of children with this condition. No personal identifiers were collected. Surveys and data were collected via REDCap and analyzed using Excel and SAS v9.4. Results Seventy‐three parents completed the survey, with 39.7% reporting a MEF2C variant and 54.8% reporting a deletion involving MEF2C. Limited speech (82.1%), seizures (86.3%), bruxism (87.7%), repetitive movements (94.5%), and high pain tolerance (79.5%) were some of the prominent features. Patients with MEF2C variants were similarly affected as those with deletions. Female subjects showed higher verbal abilities. Conclusion This is the largest natural history study to date and establishes a comprehensive review of developmental and clinical features for MEF2C‐related disorders. This data can help providers diagnose patients and form the basis for longitudinal or genotype–phenotype studies. MEF2C‐related disorders are characterized by developmental and cognitive delay, limited language and walking, hypotonia, and seizures; however, the disorder is not easily recognized and assessments are hampered by small sample sizes. We developed a survey based on validated instruments and subject area experts to gather information from parents of children with this condition. This is the largest MEF2C natural history study to date with 73 parents completing the survey, establishing a comprehensive review of developmental and clinical features that can help providers diagnose patients and form the basis for longitudinal or genotype–phenotype studies.