Reducing risk behaviours after stroke: An overview of reviews interrogating primary study data using the Theoretical Domains Framework.

BACKGROUND: Lifestyle changes, in addition to preventive medications, optimise stroke secondary prevention. Evidence from systematic reviews support behaviour-change interventions post-stroke to address lifestyle-related risk. However, understanding of the theory-driven mediators that affect behaviour-change post-stroke is lacking. METHODS: Electronic databases MEDLINE, Embase, Epistemonikos and Cochrane Library of Systematic Reviews were searched to March 2023 for systematic reviews addressing behaviour-change after stroke. Primary studies from identified systematic reviews were interrogated for evidence supporting theoretically-grounded interventions. Data were synthesized in new meta-analyses examining behaviour-change domains of the Theoretical Domains Framework (TDF) and secondary prevention outcomes. RESULTS: From 71 identified SRs, 246 primary studies were screened. Only 19 trials (N = 2530 participants) were identified that employed theoretically-grounded interventions and measured associated mediators for behaviour-change. Identified mediators mapped to 5 of 14 possible TDF domains. Trial follow-up ranged between 1-12 months and no studies addressed primary outcomes of recurrent stroke or cardiovascular mortality and/or morbidity. Lifestyle interventions targeting mediators mapped to the TDF Knowledge domain may improve the likelihood of medication adherence (OR 6.08 [2.79, 13.26], I2 = 0%); physical activity participation (OR 2.97 [1.73, 5.12], I2 = 0%) and smoking cessation (OR 10.37 [3.22, 33.39], I2 = 20%) post-stroke, supported by low certainty evidence; Lifestyle interventions targeting mediators mapping to both TDF domains of Knowledge and Beliefs about Consequences may improve medication adherence post-stroke (SMD 0.36 [0.07, 0.64], I2 = 13%, very low certainty evidence); Lifestyle interventions targeting mediators mapped to Beliefs about Capabilities and Emotions domains may modulate low mood post-stroke (SMD -0.70 [-1.28, -0.12], I2 = 81%, low certainty evidence). CONCLUSION: Limited theory-based research and use of behaviour-change mediators exists within stroke secondary prevention trials. Knowledge, Beliefs about Consequences, and Emotions are the domains which positively influence risk-reducing behaviours post-stroke. Behaviour-change interventions should include these evidence-based constructs known to be effective. Future trials should address cardiovascular outcomes and ensure adequate follow-up time.

Effectiveness of behavior change and self-management theoretically-informed telehealth interventions for stroke secondary prevention: An overview of systematic reviews.

INTRODUCTION: Despite the increased use of telehealth interventions, low-level evidence supports their use for behavior change and self-management in stroke secondary prevention. Therefore, this overview of systematic reviews (SRs) critically appraises and consolidates the evidence about theoretically-informed telehealth interventions in stroke secondary prevention. METHODS: Two phases were conducted independently by two reviewers. Phase-1 included SRs contemplating randomized controlled trials (RCTs) implementing telehealth interventions with individuals post-stroke, targeting cardiovascular events, risk-reducing health behaviors or physiological risk factors. Phase-2 interrogated RCTs from these SRs that implemented theoretically-informed interventions. Best-evidence synthesis of published meta-analyses and new meta-analyses of theoretically-informed interventions were conducted. GRADE evidence was applied. RESULTS: In Phase-1 (15 SRs), best-evidence synthesis identified telehealth interventions as effective in reducing recurrent angina and recurrent stroke rates (both with very low GRADE), improving medication adherence (low GRADE), physical activity participation (very low GRADE), and blood pressure targets (very low GRADE), reducing systolic blood pressure (SBP) (moderate GRADE) and low-density lipoprotein levels (very low GRADE). In Phase-2 (14 RCTs), new meta-analyses identified theoretically-informed telehealth interventions as effective in improving medication adherence (SMD: 0.38; 95%CI: 0.13-0.64; I²: 72%, low GRADE) and healthy eating (SMD: 0.38; 95%CI: 0.15-0.60; I²: 38%, low GRADE), and decreasing SBP (MD: -9.19; 95%CI: -5.49 to -12.89; I²: 0%, moderate GRADE). DISCUSSION: Telehealth demonstrates utility in stroke secondary prevention, notably in SBP reduction. High-quality RCTs are required given the lack of current evidence supporting theoretically-informed telehealth interventions addressing primary outcomes of secondary prevention, and the low certainty evidence identified for health behavior change.

SLC6A8 creatine transporter deficiency can be detected by plasma creatine and creatinine concentrations.

Creatine transporter deficiency has been described with normal or uninformative levels of creatine and creatinine in plasma, while urine has been the preferred specimen type for biochemical diagnosis. We report a cohort of untreated patients with creatine transporter deficiency and abnormal plasma creatine panel results, characterized mainly by markedly decreased plasma creatinine. We conclude that plasma should be considered a viable specimen type for the biochemical diagnosis of this disorder, and abnormal results should be followed up with further confirmatory testing.

Retrospective Review of Positive Newborn Screening Results for Isovaleric Acidemia and Development of a Strategy to Improve the Efficacy of Newborn Screening in the UK.

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0-9.6) and 4.0 (1.8->70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in 'asymptomatic' individuals (n = 17), demonstrating a median (range) C5C of 3.0 (1.8-7.1) whilst 'clinically affected' patients (n = 7), showed a median (range) C5C of 13.9 (7.7-70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and <5.0 µmol/L prompting second-tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder.

Newborn Screening for Krabbe Disease: Status Quo and Recommendations for Improvements.

Krabbe disease (KD) is part of newborn screening (NBS) in 11 states with at least one additional state preparing to screen. In July 2021, KD was re-nominated for addition to the federal Recommended Uniform Screening Panel (RUSP) in the USA with a two-tiered strategy based on psychosine (PSY) as the determinant if an NBS result is positive or negative after a first-tier test revealed decreased galactocerebrosidase activity. Nine states currently screening for KD include PSY analysis in their screening strategy. However, the nomination was rejected in February 2023 because of perceived concerns about a high false positive rate, potential harm to newborns with an uncertain prognosis, and inadequate data on presymptomatic treatment benefit or harm. To address the concern about false positive NBS results, a survey was conducted of the eight NBS programs that use PSY and have been screening for KD for at least 1 year. Seven of eight states responded. We found that: (1) the use of PSY is variable; (2) when modeling the data based on the recommended screening strategy for KD, and applying different cutoffs for PSY, each state could virtually eliminate false positive results without major impact on sensitivity; (3) the reason for the diverse strategies appears to be primarily the difficulty of state programs to adjust screening algorithms due to the concern of possibly missing even an adult-onset case following a change that focuses on infantile and early infantile KD. Contracts with outside vendors and the effort/cost of making changes to a program's information systems can be additional obstacles. We recommend that programs review their historical NBS outcomes for KD with their advisory committees and make transparent decisions on whether to accept false positive results for such a devastating condition or to adjust their procedures to ensure an efficient, effective, and manageable NBS program for KD.

Interventions for Behaviour Change and Self-Management of Risk in Stroke Secondary Prevention: An Overview of Reviews.

INTRODUCTION: Optimised secondary prevention strategies that include lifestyle change are recommended after stroke. While multiple systematic reviews (SRs) address behaviour change interventions, intervention definitions, and associated outcomes differ between reviews. This overview of reviews addresses the pressing need to synthesise high-level evidence for lifestyle-based behavioural and/or self-management interventions to reduce risk in stroke secondary prevention in a structured, consistent way. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria were applied to meta-analyses, demonstrating statistically significant effect sizes to establish the certainty of existing evidence. Electronic databases MEDLINE, Embase, Epistemonikos, and the Cochrane Library of Systematic Reviews were systematically searched, current to March 2023. RESULTS: Fifteen SRs were identified following screening, with moderate overlap of primary studies demonstrated (5.84% degree of corrected covered area). Interventions identified could be broadly categorised as multimodal; behavioural change; self-management; psychological talk therapies, albeit with overlap between some theoretical domains. Seventy-two meta-analyses addressing twenty-one preventive outcomes of interest were reported. Best-evidence synthesis identifies that for primary outcomes of mortality and future cardiovascular events post-stroke, moderate certainty GRADE evidence supports multimodal interventions to reduce cardiac events, with no available evidence for outcomes of mortality (all-cause or cardiovascular) or recurrent stroke events. For secondary outcomes addressing risk-reducing behaviours, best-evidence synthesis identifies moderate certainty GRADE evidence for multimodal lifestyle-based interventions to increase physical activity participation, and low certainty GRADE evidence for behavioural change interventions to improve healthy eating post-stroke. Similarly, low certainty GRADE evidence supports self-management interventions to improve preventive medication adherence. For mood self-management post-stroke, moderate GRADE evidence supports psychological therapies for remission and/or reduction of depression and low/very low certainty GRADE evidence for reduction of psychological distress and anxiety. Best-evidence for outcomes addressing proxy physiological measures identified low GRADE evidence supporting multimodal interventions to improve blood pressure, waist circumference, and LDL cholesterol. CONCLUSION: Effective strategies to redress risk-related health behaviours are required in stroke survivors to complement current pharmacological secondary prevention. Inclusion of multimodal interventions and psychological talk therapies in evidence-based stroke secondary prevention programmes is warranted given the moderate GRADE of evidence that supports their role in risk reduction. Given the overlap in primary studies across reviews, often with overlapping theoretical domains between broad intervention categories, further research is required to identify optimal intervention behavioural change theories and techniques employed in behavioural/self-management interventions.

Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency: Family Impact and Perspectives.

Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is a fatty acid oxidation disorder characterized by the decreased ability of the enzyme very-long-chain acyl-CoA dehydrogenase to break down fatty acids with 14 to 20-long carbon chains. The resulting clinical manifestations are variable in severity and include hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. Treatment can consist of limiting the dietary intake of long-chain fatty acids, the prevention of fasting, and the supplementation of medium-chain fats. This study, conducted in the context of a 5-year long-term follow-up on VLCADD, evaluates how the diagnosis of this fatty acid disorder impacts the family, specifically as it relates to the medical diet and barriers to care. Caregivers (n = 10) of individuals with VLCADD responded to a survey about how VLCADD potentially impacts their family. The review included the clinical outcomes of the patients (n = 11), covering instances of rhabdomyolysis, cardiomyopathy, and hospitalizations related to VLCADD. Families affected by VLCADD experience barriers to care, including difficulties with finances, ability to work, and access to nutrition.

Medics as influencers: a historical analysis of British Army military medical exercises in Kenya over two decades.

INTRODUCTION: Annual British Army medical training exercises have run in Kenya since the early 1990s, initially with a dual purpose-to deliver the Kenyan Extended Programme of Immunisation (in remote locations) and to undertake austere training. This provided a specific response to a capability gap request from the partner nation, but as this gap closed, the exercise changed in various ways. This study aimed to qualitatively explore the impact of these exercises on the Kenyan healthcare system and the influence and relationships between the nations. METHODS: Semistructured interviews were conducted for 10 former senior commanders and medical officers who had deployed in key command and clinical positions from 1993 to 2019. Three researchers conducted thematic content analysis on the key-informant interviews. RESULTS: Five domains with 18 subdomains formed the study's analysis framework. 16 recurring themes were identified and placed into four categories that denote if they were of benefit to the engagement, enabled success, had the potential to cause harm or were a barrier to successful engagement. Three distinct phases of the exercise were identified: supporting Kenyan vaccinations, direct clinical care, training and education. CONCLUSIONS: This is the first qualitative analysis of the impact of a British Defence Engagement (Health) on the partner nation and UK influence gained through it. It has identified factors which may improve outcomes, namely, ensuring sustainability and continuity between iterations; maintaining enduring stakeholder relationships; responding to a capability gap request; intelligence-led planning with incorporated assessment, monitoring and evaluation; adapting to changes in needs or contextual settings; while ensuring mutual benefit in objective setting. These may be used as the basis for a conceptual framework supporting the planning and execution of high-quality, mutually beneficial Defence Engagement (Health) activities in future. This framework and future research would also benefit from gaining perspectives from the partner nation.

MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype.

Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5 µM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5-OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false-positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT-ATP6, low citrulline, elevated C3, and/or elevated C5-OH. All molecularly confirmed individuals (n = 17) with either no symptoms (n = 12), migraines (n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile-lethal Leigh syndrome had a B haplogroup.

Measuring wet bulb globe temperatures at point-of-exertion in worldwide UK military settings: a longitudinal observational study determining the accuracy of a portable WBGT monitor.

INTRODUCTION: Heat illness among the UK Armed Forces is usually exertional, and therefore preventable, yet the incidence has not reduced since 2011. JSP 539 explicitly states that wet bulb globe temperature (WBGT) should be measured 'at the location of greatest heat risk', not 'that of most convenience'. A handheld WBGT tracker used at point-of-exertion could reduce this incidence if proven to be as accurate as the current in-service device. METHODS: Longitudinal observational comparison and equipment feasibility study of the Kestrel 5400 and QUESTemp 34 (QT-34) in worldwide firm base and deployed UK Armed Forces locations. The locations chosen were Kenya, South Sudan, Belize, Tidworth, Aldershot and Brecon. Paired data points of WBGT readings were collected from November 2017 to August 2018 in all weather conditions. RESULTS: WBGT readings were comparable between the QT-34 and Kestrel 5400 across the UK and overseas. In addition, there was no change in accuracy between readings taken from the Kestrel 5400 when tripod-mounted and handheld. The Kestrel was easy to set up and far less susceptible to resupply or power supply limitations, as it requires no user input for wet bulb temperature, and runs on AA batteries. CONCLUSION: This equipment feasibility study has shown that the Kestrel 5400 gives an acceptable accuracy and is easier to use than the QT-34. The authors recommend that the Kestrel 5400 is introduced as an adjunct to the QT-34, and its use within the military setting monitored through ongoing comparative data collection in a large-scale proof-of-concept study.

A protocol to evaluate the impact of embedding Public and Patient Involvement in a structured PhD program for stroke care.

Background: Embedding Public and Patient Involvement (PPI) in postgraduate research has been recognized as an important component of post-graduate training, providing research scholars with an awareness and a skillset in an area which prepares them for future roles as healthcare researchers. Improving Pathways for Acute STroke And Rehabilitation (iPASTAR) is a structured PhD training program [Collaborative Doctoral Award (CDA)] which aims to design a person-centered stroke pathway throughout the trajectory of stroke care, to optimize post-stroke health and wellbeing. PPI is embedded at all stages. Purpose: The iPASTAR research programme was strongly informed by a round-table PPI consultation process with individuals who experienced stroke and who provided broad representation across ages, gender, geographical locations (urban and rural) and the PhD themed areas of acute care, early supported discharge and lifestyle-based interventions after stroke. Four PhD scholars taking part in the CDA-iPASTAR now work collaboratively with four stroke champions, supported by a wider PPI advisory panel. Methods: This study will evaluate the process and impact of embedding PPI during a PhD program. We will conduct a longitudinal mixed-methods evaluation, conducting focus groups at 24, 36, and 48 months to explore the experiences of the key stakeholders involved. The participants will include PhD scholars, PPI partners (PPI Advisory Group and PPI Champions), PhD supervisors and a PPI manager. An independent researcher will conduct the evaluation. We will include focus groups, individual interviews and participant reflections. Qualitative data will be analyzed using thematic and content analysis, quantitative data will be analyzed using descriptive statistics. Discussion: PPI and patient voice initiatives bring together researchers, family, and people with health care issues into meaningful dialogue and allow the development of a patient-voice learning network. Embedding PPI training within a PhD program can build meaningful capacity in PPI partnerships in stroke research.

Utilizing augmented artificial intelligence for aminoacidopathies using collaborative laboratory integrated reporting- A cross-sectional study.

Introduction: Plasma amino acids profiling can aid in the screening and diagnosis of aminoacidopathies. The goal of the current study was to analyze and report the metabolic profiles of plasma amino acid (PAA) and additionally to compare PAA-reference intervals (RI) from Pakistan with more countries utilizing Clinical Laboratory Integrated Reports (CLIR). Methods: This was a cross sectional prospective single center study. Twenty-two amino acids were analyzed in each sample received for one year at the clinical laboratory. Data was divided into reference and case data files after interpretation by a team of pathologists and technologists. All PAA samples were analyzed using ion-exchange high-performance chromatography. The CLIR application of Amino Acid in Plasma (AAQP) was used for statistical analysis for both data sets and post-analytical interpretive tools using a single condition tool was applied. Result: The majority of 92% (n = 1913) of PAA profiles out of the total 2081 tests run were non-diagnostic; the PAA values were within the age-specific RI. The PAA median was in close comparison close to the 50th percentile of reference data available in CLIR software. Out of the total 2081 tests run, one hundred and sixty-eight had abnormal PAA levels; 27.38% were labeled as non-fasting samples, and the main aminoacidopathies identified were Phenylketonuria and Maple Syrup Urine Disorder. Conclusion: An agreement of >95% was observed between the reporting done by the pathologists and technologists' team and then after the application of CLIR. Augmented artificial intelligence using CLIR can improve the accuracy of reporting rare aminoacidopathies in a developing country like ours.

Proximal urea cycle defects are challenging to detect with newborn screening: Results of a prospective pilot study using post-analytical tools.

The purpose of this pilot project was to evaluate the efficacy of the Collaborative Integrated Laboratory Reports (CLIR) postanalytical tools from Mayo Clinic for detection of newborns with proximal urea cycle disorders (PUCD) in the Georgia newborn screening program that uses the underivatized Neobase2 kit (Perkin Elmer). We evaluated 138,560 newborn screening (NBS) samples (between 125,000 and 130,000 children) and used the CLIR result interpretation guidelines to stratify results. Children at higher risk of having a PUCD received follow-up services including confirmatory lab testing (ammonia, plasma amino acids, urine orotic acid) or a repeat NBS sample. We made multiple adjustments to our CLIR PUCD tool and to our follow-up algorithms in order to reduce false positives. Regardless, a high number of NBS samples resulted with false positives in part due to the glutamine peak also containing lysine. No children were diagnosed with a PUCD during our study period, and the Emory Genetics Metabolic Center is unaware of any children diagnosed outside of the NBS system during that time. Based on our experience, PUCD is not suitable for statewide NBS using Neobase2 and CLIR. Other methodologies that can separate glutamine from other amino acids may have better performance.

An Innovative Model of Pediatric Emergency Department Mental Health Care: Protocol for a Multicenter Type 1 Effectiveness-Implementation Cluster Randomized Trial.

Over the past decade, visits to American and Canadian emergency departments (EDs) for child and youth mental health care have increased substantially.1,2 Acute mental health crises can occur as a result of a variety of concerns, including those that are life threatening (eg, suicide attempts), pose safety concerns (eg, suicidal intentions, aggressive behaviors, alcohol and other drug use), and are physically distressing to the child or youth (eg, panic attacks). ED health care providers play a vital role in assessing the safety and well-being of the child or youth and referring them to services for ongoing care.3,4 During the ED visit, assessment and care should pinpoint risks, inform treatment, and consider family needs and preferences as part of a patient-centered approach. Yet, this approach to care is not widely adopted in EDs. Most EDs do not require the use of pediatric-specific mental health tools to guide assessments or have patient-centered procedures in place to guide the care of patients with mental health emergencies.5-7 Our team believes these limitations have led to the provision of acute mental health care that can lack sufficient quality and efficiency. This study protocol describes a trial designed to evaluate if a novel mental health care bundle that was co-designed with parents and youth results in greater improvements in the well-being of children and youth 30 days after seeking ED care for mental health and/or substance misuse concerns compared with existing care protocols. We hypothesize that the bundle will positively impact child and youth well-being, while also providing cost-effective health care system benefits.

A Scoping Review of Non-Pharmacological, Non-Surgical Secondary Prevention Strategies in Ischaemic Stroke and TIA in National Stroke Guidelines and Clinical Audit Documents.

The Stroke Action Plan for Europe (2018-2030) calls for national-level secondary prevention plans that address lifestyle, in addition to prevention medications and surgical interventions. This scoping review examines national stroke care guideline and audit documents across WHO regions to identify non-pharmacological, non-surgical stroke secondary prevention recommendations and associated performance indicators. Using a snowballing methodology, 27 guideline documents met the inclusion criteria. Sixteen (59%) detailed, non-pharmacological, non-surgical stroke secondary prevention-addressing known, modifiable population attributable risk factors, of physical inactivity (N = 11), smoking (N = 11), unsafe alcohol consumption (N = 10), diet (N = 8), weight (N = 5), stress (N = 4) and depression (N = 2). Strategies recommended to address these risk factors were: assessment of stroke risk/risk factors (N = 4); provision of advice and information on reducing lifestyle related risk (N = 16); education and counselling for lifestyle behaviour change (N = 8) and onward referral for specialist management of risk (N = 4). Of the nine stroke audits/registries identified, only three (33%) included non-pharmacological, non-surgical quality indicators of documented provision of advice or information on the following: general lifestyle (N = 2); smoking cessation for current smokers (N = 2); reduction in alcohol consumption, where relevant (N = 1), exercise participation (N = 1) and diet (N = 1). Preventive quality indicators addressing the management of weight, stress or depression were absent. This review highlights current gaps in optimal stroke secondary prevention recommendations and their implementation.

Whole-Genome Sequencing to Identify Missed Rifampicin and Isoniazid Resistance Among Tuberculosis Isolates-Chennai, India, 2013-2016.

India has a high burden of drug-resistant tuberculosis (DR TB) and many cases go undetected by current drug susceptibility tests (DSTs). This study was conducted to identify rifampicin (RIF) and isoniazid (INH) resistance associated genetic mutations undetected by current clinical diagnostics amongst persons with DR TB in Chennai, India. Retrospectively stored 166 DR TB isolates during 2013-2016 were retrieved and cultured in Löwenstein-Jensen medium. Whole genome sequencing (WGS) and MGIT DST for RIF and INH were performed. Discordant genotypic and phenotypic sensitivity results were repeated for confirmation and the discrepant results considered final. Further, drug resistance-conferring mutations identified through WGS were analyzed for their presence as targets in current WHO-recommended molecular diagnostics. WGS detected additional mutations for rifampicin and isoniazid resistance than WHO-endorsed line probe assays. For RIF, WGS was able to identify an additional 10% (15/146) of rpoB mutant isolates associated with borderline rifampicin resistance compared to MGIT DST. WGS could detect additional DR TB cases than commercially available and WHO-endorsed molecular DST tests. WGS results reiterate the importance of the recent WHO revised critical concentrations of current MGIT DST to detect low-level resistance to rifampicin. WGS may help inform effective treatment selection for persons at risk of, or diagnosed with, DR TB.

The low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses.

BACKGROUND: Glutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical "low-excretor" (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation. METHODS: Samples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated. RESULTS: Five LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five GCDH variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype. CONCLUSIONS: The data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result.