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.

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.

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.

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.

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.

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.

Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular adenosine triphosphate (ATP) derived from respiration, and that ATP levels could be restored with coenzyme Q10 (CoQ10 ) supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10 . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants.

FGF21 outperforms GDF15 as a diagnostic biomarker of mitochondrial disease in children.

Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD.

Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa.

BACKGROUND: The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care. RESULTS: As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) increased in subjects who were < 18 years of age at ERT initiation (mean change: +0.3 [0.1, 0.4] L and + 0.4 [0.3, 0.5] L; mean follow-up: ∼6 years; n = 82) and were stable in subjects ≥18 years (mean change: 0.0 [-0.0, 0.1] L and 0.0 [-0.1, 0.1] L; mean follow-up: 4.6 years; n = 38). Overall, 148 (47.1%) ERT-treated subjects experienced ≥1 adverse event (AE) and 110 subjects (35%) reported ≥1 serious AE. Drug-related AEs were reported in 39 (12.4%) subjects; the most common were hypersensitivity (9 subjects [2.9%]), urticaria (8 subjects [2.5%]), and pyrexia (7 subjects [2.2%]). CONCLUSIONS: MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

Financial toxicity and its impact on health outcomes and caregiver burden among adult cancer survivors in the USA.

Aim: To examine the association between cancer-related financial toxicity on cancer survivors' physical and mental health outcomes and caregiver burden. Materials & methods: 2016-2017 Medical Expenditure Panel Survey data were used to identify adult cancer survivors with cancer-related financial toxicity. Multivariable regression analyses were employed to examine the association between cancer-related financial toxicity and cancer survivors' self-reported physical and mental health outcomes and caregiver burden. Results: A total of 53.7% of adult cancer survivors reported experiencing financial toxicity. Those who experienced financial toxicity reported 14% greater pain, and poorer physical and mental health outcomes as compared to those who did not experience financial toxicity, ranging from 38% greater odds for activity limitations to 427% greater odds for mental task limitation. Moreover, cancer survivors with financial toxicity reported 206% greater odds for caregiver burden. Conclusions: Intervention programs for reducing financial toxicity among adult cancer survivors and their caregivers should be developed.

The cost of cancer care has increased substantially over the past decade imposing significant financial burden on cancer survivors, with a growing number of cancer survivors experiencing financial toxicity. Using the Cancer Self-Administered Questionnaire of the Medical Expenditure Panel Survey, this study estimated the impact of cancer-related financial toxicity on cancer survivors' self-reported health outcomes and caregiver burden. The results highlight the impact of financial toxicity on cancer survivors' physical health and mental health outcomes and caregiver burden in a nationally representative sample of noninstitutionalized adults in the USA. The study findings document the critical need to develop interventions and implement structural policy changes aimed at identifying and reducing financial toxicity among adult cancer survivors and their caregivers.

Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype.

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. We identified two patients with defective serum transferrin glycosylation and mutations in the MAGT1 gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability. MAGT1 has been described to be a subunit of the oligosaccharyltransferase (OST) complex and more specifically of the STT3B complex. However, it was also claimed that MAGT1 is a magnesium (Mg2+) transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg2+ homeostasis defect (XMEN). We compared the clinical and cellular phenotype of our two patients to that of an XMEN patient that we recently identified. All three patients have an N-glycosylation defect, as was shown by the study of different substrates, such as GLUT1 and SHBG, demonstrating that the posttranslational glycosylation carried out by the STT3B complex is dysfunctional in all three patients. Moreover, MAGT1 deficiency is associated with an enhanced expression of TUSC3, the homolog protein of MAGT1, pointing toward a compensatory mechanism. Hence, we delineate MAGT1-CDG as a disorder associated with two different clinical phenotypes caused by defects in glycosylation.

Food Insecurity in a Sample of Informal Caregivers in 4 Southern US States.

INTRODUCTION: Given the disproportionate burden of food insecurity in the southern US states and the high prevalence of caregiving in this area, we assessed caregiving-related predictors of food insecurity among caregivers in 4 southern US states. METHODS: We used data from the 2015 Behavioral Risk Factor Surveillance System (BRFSS) for individuals aged 18 years or older who resided in Alabama, Louisiana, Mississippi, and Tennessee to assess the association between caregiving status and food insecurity, accounting for the complex survey design of BRFSS. Caregiving-related predictors of food insecurity were identified by using multivariable logistic regression. RESULTS: Weighted counts of caregivers and noncaregivers were 356,198 and 652,737, respectively. Prevalence of food insecurity was higher among caregivers than noncaregivers (35.9% vs 25.9%). Adjusting for sociodemographic predictors, caregivers had 56% (95% CI, 1.30-1.87; P < .001) higher odds of food insecurity than noncaregivers. Among caregivers, those caring for a spouse or a partner (adjusted odds ratio [aOR] = 1.7; 95% CI, 1.02-2.85; P = .04) had significantly higher odds of food insecurity compared with those caring for parents or parents-in-law. Caregivers who had been caregiving for 6 months to 2 years had higher odds of food insecurity compared with those who had been caregiving for less than 6 months (aOR = 1.88; 95% CI, 1.12-3.16; P = .02). Caregivers who reported a need for support services had higher odds of food insecurity compared with those who did not (aOR = 3.38; 95% CI, 2.19-5.21; P < .001). Caregivers caring for people with musculoskeletal conditions, compared with people with neurologic conditions, had higher odds of food insecurity (aOR = 3.47; 95% CI, 1.52-7.91; P = .003). CONCLUSION: Caregiver screening for food insecurity in health care settings and linkage to appropriate food and caregiving support resources should be prioritized by future health policies.

Rates of genetic testing in patients prescribed drugs with pharmacogenomic information in FDA-approved labeling.

This study examined rates of genetic testing in two cohorts of publicly insured individuals who have newly prescribed medication with FDA pharmacogenomic labeling guidance. Genetic testing was rare (4.4% and 10.5% in Medicaid and Medicare cohorts, respectively) despite the fact that all participants selected were taking medications that contained pharmacogenomic labeling information. When testing was conducted it was typically done before the initial use of a target medication. Factors that emerged as predictors of the likelihood of undergoing genetic testing included White ethnicity (vs. Black), female gender, and age. Cost analyses indicated higher expenditures in groups receiving genetic testing vs. matched comparators with no genetic testing, as well as disparities between proactively and reactively tested groups (albeit in opposite directions across cohorts). Results are discussed in terms of the possible reasons for the low base rate of testing, mechanisms of increased cost, and barriers to dissemination and implementation of these tests.

New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.

Carnitine acyl-carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long-chain fatty-acid transport. Most patients present in the first 2 days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Multi-centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Twenty-three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia. Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High-energy intake seems necessary to prevent decompensation. Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer-term outcomes.

Rare diseases research and policy in Australia: On the journey to equitable care.

Almost exactly 10 years after the publication of 'Call for a national plan for rare diseases' in this journal, the Federal Government launched the National Strategic Action Plan for Rare Diseases (the Action Plan) on the 26th of February 2020, in the lead up to Rare Disease Day on the 29th of February - a rare day for rare diseases. The Action Plan is the culmination of effective advocacy by Rare Voices Australia (RVA) and other stakeholders in the rare disease (RD) sector. RVA is the peak body for Australians living with a RD. The organisation works collaboratively with RD organisations, researchers and clinicians. Since the initial call for a RD plan, a number of health-care initiatives and policy changes have gathered apace including expanded antenatal and newborn screening, the increasing application of next generation sequencing and advances in gene and cell therapeutics. The development of new models of care, diagnostic and treatment pathways, and communities of practice have started to ease the considerable burden and inequitable access to care experienced by RD patients and their families. However, much work remains to be done. The Action Plan outlines the actions to bring about the best possible health and well-being outcomes for Australians living with RD. It is centred around three pillars - awareness and education, care and support, research and data - and will be delivered against the principles of person centredness, equity, and sustainable systems and workforce.

Investigating paediatric hypoglycaemia: Dynamic studies at a tertiary paediatric hospital.

AIM: Paediatric hypoglycaemia often requires specific investigations to determine aetiology. Samples from the time of hypoglycaemia may not be available and a diagnostic fasting test may be required. Additionally, fasting studies can determine safe fasting intervals and prolonged oral glucose challenges can assess hypoglycaemia due to abnormal post-prandial glucose handling. This audit reviewed the current utility and yield of fasting studies, prolonged oral glucose challenges and starch loads. METHODS: Retrospective audit of clinical record to determine purpose and outcome of tests performed at a Tertiary Paediatric Endocrine/Metabolic Testing Unit in Sydney, Australia, from 2013 to 2018 inclusive. RESULTS: One hundred and thirty-eight children (aged 3 weeks-17 years) underwent 170 tests: 122 fasting studies, 20 five-hour OGTTs, 22 uncooked corn starch loads and six modified waxy maize starch (Glycosade) loads. The majority were for diagnostic purposes (n = 113, 66%), with 57 (34%) to guide management in patients with known diagnoses. Following diagnostic studies, 35 (31%) patients received a pathological diagnosis, the most common of which (n = 19, 17%) was accelerated starvation. Hypoglycaemia developed in n = 15/113 (13%) during the diagnostic studies. Management studies helped determine length of safe fast, adjustment of medication or diet and document resolution of pathology. CONCLUSION: Fasting studies remain a safe and effective method to assist with diagnoses, confirm or exclude pathological causes of childhood hypoglycaemia and to guide management of known diagnoses in the paediatric population.

Does Transient Opioid Use Increase Risk of Short-Term Respiratory Exacerbation among Older Adults with Chronic Obstructive Pulmonary Disease?

The objective of this study was to examine the association between transient opioid use and acute respiratory exacerbations among older Medicare beneficiaries with COPD. This study was conducted using national Medicare 5% sample administrative claims data between 2012 and 2016 and employed a case-crossover design. The date of eligible COPD exacerbation events was defined as the index date and the presence of opioid prescriptions during a 7-day exposure window prior to index date was compared to a set of 10 control periods, each 7-days long. The association between opioid exposure and COPD exacerbation was estimated using a conditional logistic regression with robust sandwich estimators, after accounting for known time-varying confounders. Among 16,290 eligible COPD exacerbations included in the study sample, the average patient age was 77.08 years, and 64.2% of events occurred in women. Transient exposure to opioids was associated with a 76% increase in the odds of an acute COPD exacerbation (OR: 1.76, 95%CI: 1.67-1.84), and each 25 mg increase in morphine milligram equivalent dose was associated with a 18% increase in the odds of exacerbation (OR: 1.18, 95% CI: 1.15-1.21). Effect estimates were consistent across subgroup analyses conducted among events identified in the emergency department versus hospital, and among individuals with a single exacerbation event versus those with multiple exacerbations. Transient exposure to opioids was associated with an increased short-term risk of respiratory exacerbation among older adults with COPD. Treatment decisions for breathlessness among individuals with COPD need to account for the benefit-risk profile of opioids.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.2013460 .

The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease.

PURPOSE: The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated. METHODS: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants. RESULTS: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD. CONCLUSION: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.

PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. METHODS: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. RESULTS: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). CONCLUSION: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria.

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 µmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 µmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.