Willingness to use PrEP among PrEP naïve men who have sex with men: a meta-analysis.

This study aimed to measure the pooled estimate of willingness to use HIV pre-exposure prophylaxis (PrEP) (WTUP) among PrEP-naïve United States (U.S.)-based men who have sex with men (MSM). PubMed, Embase, Web of Science, CINAHL, and PsycINFO were searched. The search strategy contained the keyword willingness and interest and the MeSH terms for HIV and PrEP. Articles were included if they were published between January 2005 and May 2022, reported quantitative data on WTUP among PrEP-naïve US-based MSM, and were available as full text in English. Meta-analysis was conducted to assess the pooled effect size of WTUP prevalence using a random-effects model, heterogeneity in the pooled estimate was assessed, and subgroup analyzes were conducted. Fifteen studies were included based on the inclusion and exclusion criteria. Meta-analysis revealed a pooled prevalence proportion for WTUP of 0.58 (95% CI 0.54-0.61) (or 58 out of 100) among PrEP-naïve MSM. High inter-study heterogeneity (Q = 548.10, df = 19, p < 0.01, I2 = 96.53, τ2 = 0.09) was observed. Age of the study sample and region where the data were collected significantly moderated the pooled WTUP estimate. Age-appropriate PrEP related messaging and a focus on HIV priority areas of the U.S. would be important strategies to improve WTUP among MSM in the U.S. moving forward.

Opioid Use for Adults with and without Systemic Autoimmune/Inflammatory Rheumatic Diseases: Analysis of 2006-2019 United States National Data.

OBJECTIVES: This study compared opioid prescribing among ambulatory visits with Systemic Autoimmune/Inflammatory Rheumatic Diseases (SARDs) or without, and assessed factors associated with opioid prescribing in SARDs. METHODS: This cross-sectional study used the National Ambulatory Medical Care Survey between 2006 and 2019. Adult (≥18) visits with a primary diagnosis of SARDs, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or systemic lupus erythematosus were included in the study. Opioid prescribing was compared between those with vs. without SARDs using multivariable logistic regression (MLR) accounting for the complex survey design and adjusting for predisposing, enabling, and need factors within Andersen's Behavioral Model of Health Services Use. Another MLR examined the predictors associated with opioid prescribing in SARDs. RESULTS: Annually, an average of 5.20 (95% CI 3.58-6.82) million visits were made for SARDs, whereas 780.14 (95% CI 747.56-812.72) million visits were made for non-SARDs. The SARDs group was more likely to be prescribed opioids (22.53%) than the non-SARDs group (9.83%) (aOR 2.65 [95% CI 1.68-4.18]). Among the SARDs visits, adults aged 50-64 (aOR 1.95 [95% CI 1.05-3.65] relative to ages 18-49) and prescribing of glucocorticoids (aOR 1.75 [95% CI 1.20-2.54]) were associated with an increased odd of opioid prescribing, whereas private insurance relative to Medicare (aOR 0.50 [95% CI 0.31-0.82]) was associated with a decreased odds of opioid prescribing. CONCLUSIONS: Opioid prescribing in SARDs was higher compared to non-SARDs. Concerted efforts are needed to determine the appropriateness of opioid prescribing in SARDs.

Preferences for a community pharmacy-based pre-exposure prophylaxis (PrEP) delivery program: A discrete choice experiment.

BACKGROUND: Community pharmacies are ideal venues for pre-exposure prophylaxis (PrEP) delivery. Pharmacists and pharmacy-based PrEP delivery programs have the potential to improve access. OBJECTIVES: This study elicited preferences for attributes of a hypothetical community pharmacy-based PrEP delivery program among US men who have sex with men (MSM) and assessed predictors of their preferences. METHODS: Data were collected via a cross-sectional anonymous survey of US MSM, who were aged 18-65 years, not transgender, reported HIV status negative/unknown, and PrEP eligible. A discrete choice experiment was conducted with seven attributes of a pharmacy-based PrEP program: initial PrEP eligibility screening mode, location for human immunodeficiency virus (HIV) tests, timing for HIV test results, PrEP decision-making style, location of PrEP consultations, PrEP medication fill method, and mode for ongoing monitoring. Latent class analysis was performed to analyze preference heterogeneity. Multinomial logistic regression assessed predictors of latent class membership. RESULTS: This study included 390 MSM. Time to receive HIV test results was the most important attribute; receiving results on the same day had the highest preference. The next most important attribute was PrEP screening mode; online questionnaires were the most preferred. Respondents' preferences clustered into four classes: 1) "Same day results and online monitoring" (SDROM) group (63.1%), 2) "Consumerist decision-making" (CDM) group (16.2%), 3) "Self-screening (online questionnaire)" (SOQ) group (11.3%), and 4) "Same day results preferring" (SDRP) group (9.5%). Hispanic MSM (adjusted odds ratio [aOR] =0.31, 95% confidence interval [CI] [0.12-0.84], P = 0.020), MSM of other races (aOR=0.38, 95% CI [0.15-0.97], P = 0.044) vs. White MSM; and those having a sexually transmitted disease recently (aOR=0.37, 95% CI [0.16-0.85], P = 0.018), had lower odds of being in the CDM group vs. the SDROM group. CONCLUSIONS: MSM's preferences for a pharmacy-based PrEP program are heterogeneous. Same day results for HIV tests and online PrEP screening are key components when designing a community pharmacy-based PrEP program.

An assessment of the psychometric properties of the Coping Strategies Questionnaire - Sickle Cell Disease (CSQ-SCD) among adults in the United States.

BACKGROUND: Previous studies have reported conflicting factor structures of the Coping Strategies Questionnaire - Sickle Cell Disease (CSQ-SCD). This study examined the psychometric properties of the CSQ-SCD among adults with SCD in the United States. METHODS: This study implemented a cross-sectional study design with web-based self-administered surveys. Individuals with SCD were recruited via an online panel. Psychometric properties, including factorial and construct validity, and internal consistency reliability, of the CSQ-SCD were assessed. RESULTS: A total of 196 adults with SCD completed the survey. Confirmatory factor analysis (CFA), using maximum likelihood estimation and the 13 subscale scores as factor indicators, supported a three-factor model for the CSQ-SCD compared to a two-factor model. Model fit statistics for the three-factor model were: Chi-square [df] = 227.084 [62]; CFI = 0.817; TLI = 0.770; RMSEA [90% CI] = 0.117 [0.101-0.133]; SRMR = 0.096. All standardized factor loadings (except for the subscales isolation, resting, taking fluids, and praying and hoping) were > 0.5 and statistically significant, indicating evidence of convergent validity. Correlations between all subscales (except praying and hoping) were lower than hypothesized; however, model testing revealed that the three latent factors, active coping, affective coping, and passive adherence coping were not perfectly correlated, suggesting discriminant validity. Internal consistency reliabilities for the active coping factor (α = 0.803) and affective coping factor (α = 0.787) were satisfactory, however, reliability was inadequate for the passive adherence coping factor (α = 0.531). Given this overall pattern of results, a follow-up exploratory factor analysis (EFA) was also conducted. The new factor structure extracted by EFA supported a three-factor structure (based on the results of a parallel analysis), wherein the subscale of praying and hoping loaded on the active coping factor. CONCLUSIONS: Overall, the CSQ-SCD was found to have less than adequate psychometric validity in our sample of adults with SCD. These results provide clarification around the conflicting factor structure results reported in the literature and demonstrate a need for the future development of a SCD specific coping instrument.

Incidence and risk factors of immune-related adverse events induced by immune checkpoint inhibitors among older adults with non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) treatment has been linked to a variety of immune-related adverse events (irAEs), which can affect any organ system. The incidence and risk factors of irAEs have not been adequately evaluated among older adults with NSCLC. METHODS: A cohort study was conducted using 1999-2019 SEER-Medicare data among beneficiaries aged ≥65 years with a diagnosis of NSCLC who received nivolumab, pembrolizumab, or atezolizumab. Incident irAEs were identified post-ICI initiation. Demographic, cancer-related characteristics, and clinical history risk factors of irAEs were evaluated with competing events considered. RESULTS: A total of 8175 older NSCLC patients were included (with 46.8% experiencing irAEs). Pneumonitis (16.5%), hypothyroidism (10.5%), arrhythmia (11.18%), and acute kidney injury (AKI) (5.8%) were the most common irAEs. The median time to first irAE was 82 days (IQR: 29-182 days). The earliest onset of irAE occurrence was for hematologic irAEs, while the latest were gastrointestinal, dermatologic, and musculoskeletal irAEs. Fine-Gray regression modeling revealed significantly greater hazards of irAE occurrence in patients who received pembrolizumab at index, did not have CNS metastases, had a history of autoimmune disorder, and had chemotherapy in combination with ICI. Race, socioeconomic status, previous radiation therapy, and comorbidity burden were found to be associated with the occurrence of certain type of irAEs. CONCLUSION: A significant proportion of older patients with NSCLC develop an irAE after receiving ICI treatment. Factors related to cancer and treatment as well as demographics contribute to the increased risk of irAEs. Close monitoring and prediction of irAE among older patients receiving ICI is warranted.

Risk Factors for Severe Maternal Morbidity Among Women Enrolled in Mississippi Medicaid.

Importance: Mississippi has one of the highest rates of severe maternal morbidity (SMM) in the US, and SMMs have been reported to be more frequent among Medicaid-insured women. A substantial proportion of pregnant women in Mississippi are covered by Medicaid; hence, there is a need to identify potential risk factors for SMM in this population. Objective: To examine the associations of health care access and clinical and sociodemographic characteristics with SMM events among Mississippi Medicaid-enrolled women who had a live birth. Design, Setting, and Participants: A nested case-control study was conducted using 2018 to 2021 Mississippi Medicaid administrative claims database. The study included Medicaid beneficiaries aged 12 to 55 years who had a live birth and were continuously enrolled throughout their pregnancy period and 12 months after delivery. Individuals in the case group had SMM events and were matched to controls on their delivery date using incidence density sampling. Data analysis was performed from June to September 2022. Exposure: Risk factors examined in the study included sociodemographic factors (age and race), health care access (distance from delivery center, social vulnerability index, and level of maternity care), and clinical factors (maternal comorbidity index, first-trimester pregnancy-related visits, and postpartum care). Main Outcomes and Measures: The main outcome of the study was an SMM event. Adjusted odds ratio (aORs) and 95% CIs were calculated using conditional logistic regression. Results: Among 13 485 Mississippi Medicaid-enrolled women (mean [SD] age, 25.0 [5.6] years; 8601 [63.8%] Black; 4419 [32.8%] White; 465 [3.4%] other race [American Indian, Asian, Hispanic, multiracial, and unknown]) who had a live birth, 410 (3.0%) were in the case group (mean [SD] age, 26.8 [6.4] years; 289 [70.5%] Black; 112 [27.3%] White; 9 [2.2%] other race) and 820 were in the matched control group (mean [SD] age, 24.9 [5.7] years; 518 [63.2%] Black; 282 [34.4%] White; 20 [2.4%] other race). Black individuals (aOR, 1.44; 95% CI, 1.08-1.93) and those with higher maternal comorbidity index (aOR, 1.27; 95% CI, 1.16-1.40) had higher odds of experiencing SMM compared with White individuals and those with lower maternal comorbidity index, respectively. Likewise, an increase of 100 miles (160 km) in distance between beneficiaries' residence to the delivery center was associated with higher odds of experiencing SMM (aOR, 1.14; 95% CI, 1.07-1.20). Conclusions and Relevance: The study findings hold substantial implications for identifying high-risk individuals within Medicaid programs and call for the development of targeted multicomponent, multilevel interventions for improving maternal health outcomes in this highly vulnerable population.

Opioid tapering and mental health crisis in older adults.

BACKGROUND: Opioid tapering and discontinuation have increased in recent years with the implementation of national prescribing guidelines. This study aimed to examine the relationship between opioid tapering velocity and mental health crisis events in older Medicare beneficiaries. METHODS: A nested case-control study was conducted using the 2012-2018, 5% national Medicare claims data. Older adults with chronic non-cancer pain (CNCP) who were receiving long-term opioid therapy (LTOT) were included in the study. Cases were defined as individuals experiencing mental health crisis events; controls were identified using incidence density sampling. The opioid tapering velocity was measured in the 120-day hazard period that yielded a monthly percentage of dose change. Conditional logistic regression was used to assess the relationship of interest. RESULTS: A total of 42 091 older adults with CNCP were eligible for the study. Cases (n = 952) were matched with controls in a 1:2 ratio based on age (±1 year) and time of cohort entry (±30 days). A higher percentage of controls (67.65%) were on steady dose compared with cases (59.03%). In the adjusted model, tapering (aOR = 1.36; 95% CI: 1.02-1.83), rapid tapering (aOR = 1.45; 95% CI: 1.11-1.91), and dose escalation (aOR = 1.78; 95% CI: 1.32-2.39) were significantly associated with the mental health crisis, compared with steady dose. CONCLUSION: Both opioid tapering and dose escalation are associated with mental health crisis events. Patient-driven and gradual dose tapering, as recommended by prescribing guidelines, should be promoted to prevent mental health crisis events among older adults on LTOT.

Association of antecedent statin use on 30-day, 60-day and 90-day mortality among Mississippi Medicaid beneficiaries diagnosed with COVID-19.

OBJECTIVE: To assess if the antecedent statin use was associated with all-cause death among COVID-19 patients enrolled in Medicaid. DESIGN: Cohort study. SETTING: Mississippi Medicaid population. PARTICIPANTS: This study included 10 792 Mississippi Medicaid-enrolled patients between 18 and 64 years of age with a confirmed COVID-19 diagnosis from March 2020 to June 2021. INTERVENTION: Antecedent statin use, which was determined by a record of statin prescription in the 90-day period prior to the COVID diagnosis. MAIN OUTCOME MEASURES: The outcomes of interest included mortality from all cause within 30 days, 60 days and 90 days after index. RESULTS: A total of 10 792 patients with COVID-19 met the inclusion and exclusion criteria, with 13.1% of them being antecedent statin users. Statin users were matched 1:1 with non-users based on age, sex, race, comorbidities and medication use by propensity score matching. In total, the matched cohort consisted of 1107 beneficiaries in each group. Multivariable logistic regression showed that statin users were less likely to die within 30 days (adjusted OR: 0.51, 95% CI: 0.32 to 0.83), 60 days (OR: 0.56, 95% CI: 0.37 to 0.85) and 90 days (OR: 0.55, 95% CI: 0.37 to 0.82) after diagnosis of COVID-19. Those with low-intensity/moderate-intensity statin use had significantly lower mortality risk in the 60-day and the 90-day follow-up period, while the high intensity of statin use was only found to be significantly associated with a lower odd of mortality within 30 days post index. CONCLUSION: After COVID infection, Medicaid beneficiaries who had taken statins antecedently could be at lower risk for death. For patients with chronic conditions, continuity of care is crucial when interruptions occur in their medical care. Further research is required to further investigate the potential mechanisms and optimal use of statins in COVID-19 treatment.

Characterizing Common Phenotypes Across the Childhood Dementia Disorders: A Cross-sectional Study From Two Australian Centers.

BACKGROUND: Childhood dementias are a group of rare pediatric conditions characterized by progressive neurocognitive decline. Quantifying and characterising phenotypes to identify similarities between specific conditions is critical to inform opportunities to optimize care and advance research. METHODS: This cross-sectional study recruited primary caregivers of children (<18 years) living with a dementia syndrome from neurology and metabolic clinics in Sydney and Adelaide, Australia. Sociodemographic and clinical data were collated. Behavior, eating, sleep, pain, and neurological disability were assessed using validated tools, including Strengths and Difficulties, Child Eating Behaviour, and Children's Sleep Habits questionnaires and visual analog of pain and modified Rankin scales. Data were analyzed with descriptive statistics. RESULTS: Among 45 children with 23 different dementia syndromes, the modified Rankin Scale demonstrated at least moderate neurological disability and functional dependence in 82% (37/45). Families reported delays in receiving an accurate diagnosis following initial symptoms (mean: 1.6 ± 1.4 years, range: 0-5 years). The most prevalent phenotypes included communication, comprehension, or recall difficulties (87%, 39/45); disturbances in sleep (80%, 36/45); appetite changes (74%, 29/39); mobility issues (53%, 24/45); and hyperactive behavior (53%, 21/40). Behavioral problems had a "high" or "very high" impact on everyday family life in 73% (24/33). CONCLUSIONS: Childhood dementia disorders share substantial behavioral, motor, sensory, and socioemotional symptoms, resulting in high care needs, despite their vast heterogeneity in age of onset and progression. Considering their unifying characteristics under one collective term is an opportunity to improve treatment, provide quality care, and accelerate research.

The psychosocial impact of childhood dementia on children and their parents: a systematic review.

BACKGROUND: Childhood dementias are a group of rare and ultra-rare paediatric conditions clinically characterised by enduring global decline in central nervous system function, associated with a progressive loss of developmentally acquired skills, quality of life and shortened life expectancy. Traditional research, service development and advocacy efforts have been fragmented due to a focus on individual disorders, or groups classified by specific mechanisms or molecular pathogenesis. There are significant knowledge and clinician skill gaps regarding the shared psychosocial impacts of childhood dementia conditions. This systematic review integrates the existing international evidence of the collective psychosocial experiences of parents of children living with dementia. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched four databases to identify original, peer-reviewed research reporting on the psychosocial impacts of childhood dementia, from the parent perspective. We synthesised the data into three thematic categories: parents' healthcare experiences, psychosocial impacts, and information and support needs. RESULTS: Nineteen articles met review criteria, representing 1856 parents. Parents highlighted extensive difficulties connecting with an engaged clinical team and navigating their child's rare, life-limiting, and progressive condition. Psychosocial challenges were manifold and encompassed physical, economic, social, emotional and psychological implications. Access to coordinated healthcare and community-based psychosocial supports was associated with improved parent coping, psychological resilience and reduced psychological isolation. Analysis identified a critical need to prioritize access to integrated family-centred psychosocial supports throughout distinct stages of their child's condition trajectory. CONCLUSION: This review will encourage and guide the development of evidence-based and integrated psychosocial resources to optimise quality of life outcomes for of children with dementia and their families.

Diagnosis and management of children with McArdle Syndrome (GSD V) in New South Wales.

Glycogen storage type V (GSD V-McArdle Syndrome) is a rare neuromuscular disorder characterised by severe pain early after the onset of physical activity. A recent series indicated a diagnostic delay of 29 years; hence reports of children affected by the disorder are uncommon (Lucia et al., 2021, Neuromuscul Disord, 31, 1296-1310). This paper presents eight patients with a median onset age of 5.5 years and diagnosis of 9.5 years. Six patients had episodes of rhabdomyolysis with creatine kinase elevations >50 000 IU/L. Most episodes occurred in relation to eccentric non-predicted activities rather than regular exercise. One of the patients performed a non-ischaemic forearm test. One patient was diagnosed subsequent to a skeletal muscle biopsy, and all had confirmatory molecular genetic diagnosis. Three were homozygous for the common PYGM:c.148C > T (p.Arg50*) variant. All but one patient had truncating variants. All patients were managed with structured exercise testing to help them identify 'second-wind', and plan an exercise regimen. In addition all also had an exercise test with 25 g maltodextrin which had statistically significant effect on ameliorating ratings of perceived exertion. GSD V is under-recognised in paediatric practice. Genetic testing can readily diagnose the condition. Careful identification of second-wind symptomatology during exercise with the assistance of a multi-disciplinary team, allows children to manage activities and tolerate exercise. Maltodextrin can be used for structured exercise, but excessive utilisation may lead to weight gain. Early intervention and education may improve outcomes into adult life.

Coprescribing of opioids and psychotropic medications among Medicare-enrolled older adults on long-term opioid therapy.

BACKGROUND: Pressures to reduce opioid prescribing have potential to incentivize coprescribing of opioids (at lower dose) with psychotropic medications. Evidence concerning the extent of the problem is lacking. This study assessed trends in coprescribing and characterized coprescribing patterns among Medicare-enrolled older adults with chronic noncancer pain (CNCP) receiving long-term opioid therapy (LTOT). METHODS: A cohort study was conducted using 2012-2018 5% National Medicare claims data. Eligible beneficiaries were continuously enrolled and had no claims for cancer diagnoses or hospice use, and ≥ 2 claims with diagnoses for CNCP conditions within a 30-day period in the 12 months before the index date (LTOT initiation). Coprescribing was defined as an overlap between opioids and any class of psychotropic medication (antidepressants, benzodiazepines, antipsychotics, anticonvulsants, muscle relaxants, and nonbenzodiazepine hypnotics) based on their prescription fill dates and days of supply in a given year. The occurrence of coprescribing, coprescribing intensity, and number of days of overlap with psychotropic medications were calculated for each calendar year. RESULTS: The eligible study population of individuals on LTOT ranged from 2038 in 2013 to 1751 in 2018. The occurrence of coprescribing among eligible beneficiaries decreased from 73.41% in 2013 to 70.81% in 2015 and then increased slightly to 71.22% in 2018. Among eligible beneficiaries with at least one overlap day, the coprescribing intensity with any class of psychotropic medications showed minimal variation throughout the study period: 74.73% in 2013 and 72.67% in 2018. Across all the years, the coprescribing intensity was found to be highest with antidepressants (2013, 49.90%; 2018, 50.33%) followed by benzodiazepines (2013, 25.42%; 2018, 19.95%). CONCLUSION: Coprescribing was common among older adults with CNCP who initiated LTOT but did not rise substantially in the period studied. Future research should investigate drivers behind coprescribing and safety of various patterns of use.

Exercise testing and prescription in patients with inborn errors of muscle energy metabolism.

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies.

Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.

Realization of the immense therapeutic potential of epigenetic editing requires development of clinically predictive model systems that faithfully recapitulate relevant aspects of the target disease pathophysiology. In female patients with ornithine transcarbamylase (OTC) deficiency, an X-linked condition, skewed inactivation of the X chromosome carrying the wild-type OTC allele is associated with increased disease severity. The majority of affected female patients can be managed medically, but a proportion require liver transplantation. With rapid development of epigenetic editing technology, reactivation of silenced wild-type OTC alleles is becoming an increasingly plausible therapeutic approach. Toward this end, privileged access to explanted diseased livers from two affected female infants provided the opportunity to explore whether engraftment and expansion of dissociated patient-derived hepatocytes in the FRG mouse might produce a relevant model for evaluation of epigenetic interventions. Hepatocytes from both infants were successfully used to generate chimeric mouse-human livers, in which clusters of primary human hepatocytes were either OTC positive or negative by immunohistochemistry (IHC), consistent with clonal expansion from individual hepatocytes in which the mutant or wild-type OTC allele was inactivated, respectively. Enumeration of the proportion of OTC-positive or -negative human hepatocyte clusters was consistent with dramatic skewing in one infant and minimal to modest skewing in the other. Importantly, IHC and fluorescence-activated cell sorting analysis of intact and dissociated liver samples from both infants showed qualitatively similar patterns, confirming that the chimeric mouse-human liver model recapitulated the native state in each infant. Also of importance was the induction of a treatable metabolic phenotype, orotic aciduria, in mice, which correlated with the presence of clonally expanded OTC-negative primary human hepatocytes. We are currently using this unique model to explore CRISPR-dCas9-based epigenetic targeting strategies in combination with efficient adeno-associated virus (AAV) gene delivery to reactivate the silenced functional OTC gene on the inactive X chromosome.

Treatment of HMG-CoA Lyase Deficiency-Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases.

3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) deficiency can be a very severe disorder that typically presents with acute metabolic decompensation with features of hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis. A retrospective chart and literature review of Australian patients over their lifespan, incorporating acute and long-term dietary management, was performed. Data from 10 patients contributed to this study. The index case of this disorder was lost to follow-up, but there is 100% survival in the remainder of the cases despite several having experienced life-threatening episodes. In the acute setting, five of nine patients have used 900 mg/kg/day of sodium D,L 3-hydroxybutyrate in combination with intravenous dextrose-containing fluids (delivering glucose above estimated basal utilization requirements). All patients have been on long-term protein restriction, and those diagnosed more recently have had additional fat restriction. Most patients take L-carnitine. Three children and none of the adults take nocturnal uncooked cornstarch. Of the cohort, there were two patients that presented atypically-one with fulminant liver failure and the other with isolated developmental delay. Dietary management in patients with HMGCL deficiency is well tolerated, and rapid institution of acute supportive metabolic treatment is imperative to optimizing survival and improve outcomes in this disorder.

Continuity of opioid prescribing among older adults on long-term opioids.

OBJECTIVES: To describe the continuity of opioid prescribing and prescriber characteristics among older adults with chronic noncancer pain (CNCP) who are on long-term opioid therapy (LTOT) and to evaluate the association of continuity of opioid prescribing and prescriber characteristics with the risk of opioid-related adverse events. STUDY DESIGN: Nested case-control design. METHODS: This study employed a nested case-control design using a 5% random sample of the national Medicare administrative claims data for 2012-2016. Eligible individuals experiencing a composite outcome of opioid-related adverse events were defined as cases and matched to controls using incidence density sampling. Continuity of opioid prescribing (operationalized using the Continuity of Care Index) and prescriber specialty were assessed among all eligible individuals. Conditional logistic regression was conducted to assess the relationships of interest after accounting for known confounders. RESULTS: Individuals with low (odds ratio [OR], 1.45; 95% CI, 1.08-1.94) and medium (OR, 1.37; 95% CI, 1.04-1.79) continuity of opioid prescribing were found to have greater odds of experiencing a composite outcome of opioid-related adverse events compared with individuals with high prescribing continuity. Fewer than 1 in 10 (9.2%) older adults starting a new LTOT episode received at least 1 prescription from a pain specialist. Receiving a prescription from a pain specialist was not significantly associated with the outcome in adjusted analyses. CONCLUSIONS: We found that higher continuity of opioid prescribing, but not provider specialty, was significantly associated with fewer opioid-related adverse outcomes among older adults with CNCP.

Examining the context, logistics, and outcomes of food prescription programs: A scoping review.

BACKGROUND: Obesity and associated metabolic conditions are endemic. Finding new strategies to mitigate the impact on wellbeing and healthcare systems is critical. Food prescription programs (FPPs) have been promoted as one route to address this problem in a way that simultaneously addresses the socio-cultural context of obesity. Yet, little is known about the standard practices and logistics of using food prescription programs as an effective intervention. OBJECTIVES: To 1) identify the context in which food prescription programs are used; 2) identify implementation logistics of food prescription program; and 3) understand the scope of food prescription program outcomes. METHODS: A scoping review was conducted from October 2019 to May 2020 using Google Scholar, EBSCOhost, and AcademicOne Search to identify research articles focused on the implementation of prescription food programs in the US. Updates to articles were made in May of 2021 and May of 2022 to ensure the most up-to-date sample for analysis. There was no publication date restriction for article inclusion. RESULTS: A total of 213 articles were identified for abstract review via the search strategy, and 30 articles were included for analysis following article exclusion. Overall, there was little consistency among included articles regarding the target population, participant recruitment, delivery, and evaluation of the food prescription programs implemented. Most food prescription programs studied were associated with farmers markets, lasted less than 6 months, and utilized produce consumption and biometric data as primary outcomes measures. CONCLUSION: Significant gaps in the literature concerning the long-term effectiveness, impact on health behaviors, screening of eligible participants, and logistics for implementation were identified. Future research should focus on addressing these shortcomings in the current literature to improve the implementation, sustainability, and scaling of food prescription programs.

Intronic variants in inborn errors of metabolism: Beyond the exome.

Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availability of next generation sequencing, variants in non-coding regions are often considered when no causative exonic changes have been identified. There is still a lack of understanding of normal human variation in non-coding areas. As a result, potentially pathogenic non-coding variants are initially classified as variants of uncertain significance or are even overlooked during genomic analysis. In most cases where the phenotype is non-specific, clinical suspicion is not sufficient to warrant further exploration of these changes, partly due to the magnitude of non-coding variants identified. In contrast, inborn errors of metabolism (IEMs) are one group of genetic disorders where there is often high phenotypic specificity. The clinical and biochemical features seen often result in a narrow list of diagnostic possibilities. In this context, there have been numerous cases in which suspicion of a particular IEM led to the discovery of a variant in a non-coding region. We present four patients with IEMs where the molecular aetiology was identified within non-coding regions. Confirmation of the molecular diagnosis is often aided by the clinical and biochemical specificity associated with IEMs. Whilst the clinical severity associated with a non-coding variant can be difficult to predict, obtaining a molecular diagnosis is crucial as it ends diagnostic odysseys and assists in management.

A narrative review of metabolomics in the era of "-omics": integration into clinical practice for inborn errors of metabolism.

Background and Objective: Traditional targeted metabolomic investigations identify a pre-defined list of analytes in samples and have been widely used for decades in the diagnosis and monitoring of inborn errors of metabolism (IEMs). Recent technological advances have resulted in the development and maturation of untargeted metabolomics: a holistic, unbiased, analytical approach to detecting metabolic disturbances in human disease. We aim to provide a summary of untargeted metabolomics [focusing on tandem mass spectrometry (MS-MS)] and its application in the field of IEMs. Methods: Data for this review was identified through a literature search using PubMed, Google Scholar, and personal repositories of articles collected by the authors. Findings are presented within several sections describing the metabolome, the current use of targeted metabolomics in the diagnostic pathway of patients with IEMs, the more recent integration of untargeted metabolomics into clinical care, and the limitations of this newly employed analytical technique. Key Content and Findings: Untargeted metabolomic investigations are increasingly utilized in screening for rare disorders, improving understanding of cellular and subcellular physiology, discovering novel biomarkers, monitoring therapy, and functionally validating genomic variants. Although the untargeted metabolomic approach has some limitations, this "next generation metabolic screening" platform is becoming increasingly affordable and accessible. Conclusions: When used in conjunction with genomics and the other promising "-omic" technologies, untargeted metabolomics has the potential to revolutionize the diagnostics of IEMs (and other rare disorders), improving both clinical and health economic outcomes.

3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis.

3-Methylglutaconyl-CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate. It is an ultra-rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention. We reviewed the collective Australian experience of patients with confirmed MGA1, four of whom were diagnosed when asymptomatic through newborn screening (NBS). When our cohort is considered alongside the broader literature, there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder. Some patients have non-specific clinical features (such as autism spectrum disorder [ASD]); however, there are also other family members with ASD in the absence of MGA1, suggesting a multifactorial aetiology. Importantly, all four patients diagnosed through NBS (including three with over 18 years of clinical follow-up) remain asymptomatic in the absence of treatment. Based on the available literature, we suggest that MGA1 represents a biochemical phenotype, with an absence of a childhood clinical phenotype. The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance. Longer-term follow-up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy.