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IntroductionAlthough hospitalisation remains the preferred management for neonatal sepsis, it is often not possible in resource-limited settings. The Home-Based Newborn Care (HBNC) study in Gadchiroli, India (1995–1998) was the first trial to demonstrate that neonatal sepsis can be managed in the community. HBNC continues to operate in Gadchiroli. In 2015, WHO recommended community-based management of neonatal sepsis when hospitalisation is not feasible but called for implementation research. We studied the implementation and effectiveness of home-based management of neonatal sepsis over 23 years in Gadchiroli.MethodsIn this cohort study (1996–2019), community health workers (CHWs) visited neonates at home in 39 villages in Gadchiroli, India. CHWs screened, diagnosed sepsis and offered home-based antibiotic treatment if hospitalisation was refused. We evaluated the implementation outcomes of coverage, diagnostic fidelity and adoption. We assessed the association between treatment type and odds of neonatal death using mixed effects logistic regression. Time trends were analysed using the Mann-Kendall test.ResultsCHWs screened 93.8% (17 700/18 874) of neonates (coverage) and correctly diagnosed 89% (1051/1177) of sepsis episodes (diagnostic fidelity). Home-based management was preferred by 88.4% (929/1051) of parents (adoption), with 5.6 percent of total neonates receiving antibioties at home. Compared with neonates treated at home, the adjusted odds of death was 5.27 (95% CI 1.91 to 14.58) times higher when parents refused all treatment, 2.17 (95% CI 1.07 to 4.41) times higher when CHWs missed the diagnosis and 5.45 (95% CI 2.74 to 10.87) times higher when parents accepted hospital referral. Implementation outcomes remained consistent over 23 years (coverage p=0.57; fidelity p=0.57; adoption p=0.26; mortality p=0.71). The rate of facility births increased (p<0.01) and the sepsis incidence decreased (p<0.05) over 23 years.ConclusionImplementation of home-based management of neonatal sepsis was sustainable and effective over 23 years. During this period, the need for home-based management in Gadchiroli is declining. Home-based management is advised where sepsis remains a major cause of neonatal mortality and hospital access is limited.

In 2018, Pakistan had the world's highest neonatal mortality rate. Within Pakistan, most neonatal deaths occur in rural areas where access to health facilities is limited, and robust vital registration systems are lacking. To improve newborn survival, there is a need to better understand the causes of neonatal death in high burden settings and engage caregivers in the promotion of newborn health. To describe the causes of neonatal death in a rural area in Pakistan and to estimate the effect of an integrated neonatal care kit (iNCK) on cause-specific neonatal mortality. We analyzed data from a community-based, cluster-randomized controlled trial of 5286 neonates in Rahim Yar Khan (RYK), Punjab, Pakistan between April 2014 and August 2015. In intervention clusters, Lady Health Workers (LHW) delivered the iNCK and education on its use to pregnant women while control clusters received the local standard of care. The iNCK included interventions to prevent and identify signs of infection, identify low birthweight (LBW), and identify and manage hypothermia. Verbal autopsies were attempted for all deaths. The primary outcome was cause-specific neonatal mortality. Verbal autopsies were conducted for 84 (57%) of the 147 reported neonatal deaths. The leading causes of death were infection (44%), intrapartum-related complications (26%) and prematurity/LBW (20%). There were no significant differences in neonatal mortality due to prematurity/LBW (RR 0.43; 95% CI 0.15-1.24), infection (RR 1.10; 95% CI 0.58-2.10) or intrapartum-related complications (RR 1.04; 95% CI 0.0.45-2.41) among neonates who died in the intervention arm compared to those who died in the control arm. The major causes of neonatal deaths in RYK, Pakistan mirror the global landscape of neonatal deaths. The iNCK did not significantly reduce any cause-specific neonatal mortality.

ObjectiveTo determine the feasibility of adapting Family Integrated Care to a neonatal hospital unit in a low-income country.DesignSingle-centre, pre/post-pilot study of an adapted Family Integrated Care programme in Uganda (UFICare).SettingSpecial Care Nursery at a Ugandan hospital.PatientsSingleton, inborn neonates with birth weight ≥2 kg.InterventionsAs part of UFICare, mothers weighed their infant daily, assessed for severe illness (‘danger signs’) twice daily and tracked feeds.Main outcome measuresFeasibility outcomes included maternal proficiency and completion of monitoring tasks. Secondary outcomes included maternal stress, discharge readiness and post-discharge healthcare seeking.ResultsFifty-three mother–infant dyads and 51 mother–infant dyads were included in the baseline and intervention groups, respectively. Most mothers were proficient in the tasks 2–4 days after training (weigh 43 of 51; assess danger signs 49 of 51; track feeds 49 of 51). Mothers documented their danger sign assessments 82% (IQR 71–100) of the expected times and documented feeds 83% (IQR 71–100) of hospital days. In the baseline group, nurses weighed babies 29% (IQR 18–50) of hospitalised days, while UFICare mothers weighed their babies 71% (IQR 57–80) of hospitalised days (p<0.001). UFICare mothers had higher Readiness for Discharge scores compared with the baseline group (baseline 6.8; UFICare 7.9; p<0.001). There was no difference in maternal stress scores or post-discharge healthcare seeking.ConclusionsUgandan mothers can collaborate in the medical care of their hospitalised infant. By performing tasks identified as important for infant care, mothers felt more prepared to care for their infant at discharge.

Skeletal muscle formation occurs through fusion of myoblasts to form multinucleated myofibers. From a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screen for genes required for myoblast fusion and myogenesis, we discovered an 84–amino acid muscle-specific peptide that we call Myomixer. Myomixer expression coincides with myoblast differentiation and is essential for fusion and skeletal muscle formation during embryogenesis. Myomixer localizes to the plasma membrane, where it promotes myoblast fusion and associates with Myomaker, a fusogenic membrane protein. Myomixer together with Myomaker can also induce fibroblast-fibroblast fusion and fibroblast-myoblast fusion. We conclude that the Myomixer-Myomaker pair controls the critical step in myofiber formation during muscle development.

Homeothermic vertebrates produce heat in cold environments through thermogenesis, in which brown adipose tissue (BAT) increases mitochondrial oxidation along with uncoupling of the electron transport chain and activation of uncoupling protein 1 (UCP1). Although the transcription factors regulating the expression of UCP1 and nutrient oxidation genes have been extensively studied, only a few other proteins essential for BAT function have been identified. We describe the discovery of FAM195A, a BAT-enriched RNA binding protein, which is required for cold-dependent thermogenesis in mice. FAM195A knockout (KO) mice display whitening of BAT and an inability to thermoregulate. In BAT of FAM195A KO mice, enzymes involved in branched-chain amino acid (BCAA) metabolism are down-regulated, impairing their response to cold. Knockdown of FAM195A in brown adipocytes in vitro also impairs expression of leucine oxidation enzymes, revealing FAM195A to be a regulator of BCAA metabolism and a potential target for metabolic disorders.

Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve–muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age. We show that ZFP106 is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes. Upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Muscle and spinal cord of Zfp106 knockout mice displayed a gene expression signature of neuromuscular degeneration. Strikingly, altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle of Zfp106 knockout mice resulted in ectopic expression of NOGO-A, the neurite outgrowth factor that inhibits nerve regeneration and destabilizes neuromuscular junctions. These findings reveal a central role for Zfp106 in the maintenance of nerve–muscle signaling, and highlight the involvement of aberrant RNA processing in neuromuscular disease pathogenesis.

ObjectiveWe analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 & Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor α (TNFα)-dependent animal models of the disease.MethodsSynovial tissues of patients with RA and osteoarthritis (OA) as well as hind paw sections from arthritic human TNFα transgenic (hTNFtg) mice and synovial fibroblasts from these were analysed. The effects of cytokines on the expression of FHL2 and disease-relevant matrixmetalloproteases (MMPs) were determined. Analyses of human tissue specimens from patients treated with anti-TNFα as well as anti-TNFα treatment of hTNFtg mice were performed to substantiate the TNFα effects on FHL2 levels. FHL2−/− mice and hTNFtg mice (with constitutive or inducible transgene expression) were crossbred to generate TNFα overexpressing FHL2-deficient animals. Signalling pathways were analysed in cells from these mice and in human cells after knock down of FHL2 by western blot.ResultsFHL2 levels were higher in RA than in OA and in hTNFtg than in wild-type mice. Surprisingly, while transforming growth factor (TGF)β-induced FHL2 expression, TNFα suppressed FHL2. In vivo, anti-TNFα treatment led to higher FHL2 levels both in RA patients and hTNFtg mice. The loss of FHL2 increased joint destruction in hTNFtg mice, which was accompanied by elevated MMP-13. In vitro, TNFα-mediated MMP-13 was significantly higher in FHL2−/− cells and after knock down of FHL2, which was caused by prolonged p38 MAPK activation.ConclusionsThese data suggest that FHL2 serves as a protective factor and that, rather than promoting the pathology, the upregulation of FHL2 in RA occurs in frame of a regenerative attempt.