The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate–activated protein kinase)–dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.

The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. Individuals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD⁺ levels through perturbed NAD⁺ biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.

Summary: Objective  Following the severe acute respiratory syndrome (SARS) outbreak, many survivors were observed to suffer from psychosomatic symptoms reminiscent of various endocrine disorders. Hence, we sought to determine the existence of any chronic endocrine sequelae in SARS survivors.Design, patients, measurements  Sixty‐one survivors of SARS prospectively recruited were analysed for hormonal derangements 3 months following recovery. Patients with pre‐existing endocrine disorders were excluded. Any endocrine abnormalities diagnosed were investigated and treated where indicated up to a year. Serial evaluation facilitated characterization of trends and prognostication of any endocrinological aberrations.Results  Twenty‐four (39·3%) patients had evidence of hypocortisolism. The hypothalamic–pituitary–adrenal (HPA) axis dysfunction of the majority resolved within a year. Two (3·3%) of the hypocortisolic cohort had transient subclinical thyrotoxicosis. Four (6·7%) were biochemically hypothyroid, being comprised of three with central hypothyroidism and one with primary hypothyroidism. Two of the three with central hypothyroidism had concomitant central hypocortisolism. Eight had subnormal DHEAS levels.Conclusions  These preliminary findings highlight a possible aetiologic role of SARS‐associated coronavirus in causing a reversible hypophysitis or direct hypothalamic effect, with the HPA axis affected more frequently than the HPT axis.

Medical apps are widely available, increasingly used by patients and clinicians, and are being actively promoted for use in routine care. However, there is little systematic evidence exploring possible risks associated with apps intended for patient use. Because self-medication errors are a recognized source of avoidable harm, apps that affect medication use, such as dose calculators, deserve particular scrutiny. We explored the accuracy and clinical suitability of apps for calculating medication doses, focusing on insulin calculators for patients with diabetes as a representative use for a prevalent long-term condition. We performed a systematic assessment of all English-language rapid/short-acting insulin dose calculators available for iOS and Android. Searches identified 46 calculators that performed simple mathematical operations using planned carbohydrate intake and measured blood glucose. While 59% (n = 27/46) of apps included a clinical disclaimer, only 30% (n = 14/46) documented the calculation formula. 91% (n = 42/46) lacked numeric input validation, 59% (n = 27/46) allowed calculation when one or more values were missing, 48% (n = 22/46) used ambiguous terminology, 9% (n = 4/46) did not use adequate numeric precision and 4% (n = 2/46) did not store parameters faithfully. 67% (n = 31/46) of apps carried a risk of inappropriate output dose recommendation that either violated basic clinical assumptions (48%, n = 22/46) or did not match a stated formula (14%, n = 3/21) or correctly update in response to changing user inputs (37%, n = 17/46). Only one app, for iOS, was issue-free according to our criteria. No significant differences were observed in issue prevalence by payment model or platform. The majority of insulin dose calculator apps provide no protection against, and may actively contribute to, incorrect or inappropriate dose recommendations that put current users at risk of both catastrophic overdose and more subtle harms resulting from suboptimal glucose control. Healthcare professionals should exercise substantial caution in recommending unregulated dose calculators to patients and address app safety as part of self-management education. The prevalence of errors attributable to incorrect interpretation of medical principles underlines the importance of clinical input during app design. Systemic issues affecting the safety and suitability of higher-risk apps may require coordinated surveillance and action at national and international levels involving regulators, health agencies and app stores.

Objective: Although more children are surviving critical illness, little is known about long-term physical impairment. This scoping review aims to critically appraise existing literature on functional outcome measurement tools, prevalence, and risk factors for physical impairments in pediatric critical care survivors. Data Sources: PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature, using a combination of MeSH terms and keywords (critical illness, intensive care, and functional outcomes/status). Study Selection: All human studies reporting functional outcomes in children 0–18 years old admitted to the PICU. Non-English language, adult and preterm infant studies were excluded. Data Synthesis: Three global assessment tools and eight multidimensional measures were used to measure functional outcome in pediatric survivors of critical illness. Rates of acquired functional impairment in a general pediatric intensive care cohort ranged from 10% to 36% at discharge and 10% to 13% after more than 2 years. Risk factors for acquired functional impairment include illness severity, the presence of organ dysfunction, length of ICU stay, and younger age. There is some evidence that physical impairment may be more severe and persistent than psychosocial components. Conclusions: Functional impairment may be persistent in pediatric survivors of critical care. Unfortunately, studies varied largely in measurement timing and tools used. The lack of differentiation between impairment in different functional domains limited the generalizability of data. Further studies using a combination of standardized measures at various time points of the disease process can help establish more comprehensive rates of physical impairment.

The aim of this study was to investigate pulmonary function and exercise capacity in a group of survivors of the severe acute respiratory syndrome (SARS).At 3 months after hospital discharge, 46 survivors of SARS underwent the following evaluation: spirometry, static lung volumes and carbon monoxide transfer factor (T_L,CO). In total, 44 of these patients underwent cardiopulmonary exercise testing.No abnormalities were detected in the pulmonary function tests in 23 (50%) of the patients. Abnormalities of forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), FEV₁/FVC andT_L,COwere detected in seven (15%), 12 (26%), one (2%) and 18 (39%) patients, respectively. All of these abnormalities were mild except in one case. In 18 patients (41%), the maximum aerobic capacity was below the lower limit of the normal range. Breathing reserve was low in four patients and significant oxygen desaturation was detected in a further four patients. Comparison of the measured exercise capacity with resting pulmonary function tests showed many cases of discordance in impairment.In conclusion, pulmonary function defects were detected in half of the recovered severe acute respiratory syndrome patients 3 months after hospital discharge, but the impairment was mild in almost all cases. Many patients had reduced exercise capacity that cannot be accounted for by impairment of pulmonary function.