Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

The human cerebral cortex is a complex network of functionally specialized regions interconnected by axonal fibers, but the organizational principles underlying cortical connectivity remain unknown. Here, we report evidence that one such principle for functional cortical networks involves finding a balance between maximizing communication efficiency and minimizing connection cost, referred to as optimization of network cost-efficiency. We measured spontaneous fluctuations of the blood oxygenation level-dependent signal using functional magnetic resonance imaging in healthy monozygotic (16 pairs) and dizygotic (13 pairs) twins and characterized cost-efficient properties of brain network functional connectivity between 1041 distinct cortical regions. At the global network level, 60% of the interindividual variance in cost-efficiency of cortical functional networks was attributable to additive genetic effects. Regionally, significant genetic effects were observed throughout the cortex in a largely bilateral pattern, including bilateral posterior cingulate and medial prefrontal cortices, dorsolateral prefrontal and superior parietal cortices, and lateral temporal and inferomedial occipital regions. Genetic effects were stronger for cost-efficiency than for other metrics considered, and were more clearly significant in functional networks operating in the 0.09 -0.18 Hz frequency interval than at higher or lower frequencies. These findings are consistent with the hypothesis that brain networks evolved to satisfy competitive selection criteria of maximizing efficiency and minimizing cost, and that optimization of network cost-efficiency represents an important principle for the brain's functional organization.

COVID-19 can cause deadly healthcare-associated outbreaks. In a major London teaching hospital, 66/435 (15%) of COVID-19 inpatient cases between 2 March and 12 April 2020 were definitely or probably hospital-acquired, through varied transmission routes. The case fatality was 36%. Nosocomial infection rates fell following comprehensive infection prevention and control measures.

ObjectiveTo conduct a systematic review to identify drivers of, and barriers to, help seeking behaviour in people with new onset RA. MethodsQualitative peer-reviewed publications discussing primary data on the drivers of, and barriers to, seeking help at RA onset in adults were included. One thousand and fifty-eight abstracts were searched. Fifty-three articles were read to identify relevant publications which were assessed for quality and subjected to analysis informed by thematic and grounded theory frameworks. ResultsTwenty-one publications were included in the final analysis. Several interacting themes were identified. These included the early experience of RA symptoms; making sense of early symptom experience and prototypes of RA; minimising the impact of symptoms; speaking to others, gathering information and seeking alternative treatments; and issues related to accessing health services and attitudes towards healthcare professionals. Many people suggested that they had little knowledge of RA before diagnosis, often believing RA to be a mild condition caused by wear and tear which affected the elderly. These misperceptions made correct symptom interpretation unlikely. Instead, RA symptoms were attributed to causes such as injuries. Normalising and ignoring the presence of symptoms helped people to cope and delay for longer. However, when symptoms impacted on daily activities these coping mechanisms became inadequate and help was sought. ConclusionsIndividual interpretations of symptoms are both drivers of and barriers to help seeking.Interpretations are informed by symptom onset, sources of information and coping mechanisms. 4Targeted public health interventions are required to inform symptom interpretation and reduce delays. 5 BACKGROUND

Severe Acute Respiratory Syndrome (SARS) emerged recently as a new infectious disease that was transmitted efficiently in the healthcare setting and particularly affected healthcare workers (HCWs), patients and visitors. The efficiency of transmission within healthcare facilities was recognised following significant hospital outbreaks of SARS in Canada, China, Hong Kong, Singapore, Taiwan and Vietnam. The causative agent of SARS was identified as a novel coronavirus, the SARS coronavirus. This was largely spread by direct or indirect contact with large respiratory droplets, although airborne transmission has also been reported. High infection rates among HCWs led initially to the theory that SARS was highly contagious and the concept of 'super-spreading events'. Such events illustrated that lack of infection control (IC) measures or failure to comply with IC precautions could lead to large-scale hospital outbreaks. SARS was eventually contained by the stringent application of IC measures that limited exposure of HCWs to potentially infectious individuals. As the 'global village' becomes smaller and other microbial threats to health emerge, or re-emerge, there is an urgent need to develop a global strategy for infection control in hospitals. This paper provides an overview of the main IC practices employed during the 2003 SARS outbreak, including management measures, dedicated SARS hospitals, personal protective equipment, isolation, handwashing, environmental decontamination, education and training. The psychological and psychosocial impact on HCWs during the outbreak are also discussed. Requirements for IC programmes in the post-SARS period are proposed based on the major lessons learnt from the SARS outbreak.

Background: Reducing the need for antibiotics is crucial in addressing the global threat of antimicrobial resistance. Catheter-associated urinary tract infection (CAUTI) is one of the most frequent device-related infections that may be amenable to prevention. Interventions implemented nationally in England target behaviours related to catheter insertion, maintenance and removal, but the extent to which they target barriers to and facilitators of these behaviours is unclear. This strategic behavioural analysis applied behavioural science frameworks to (i) identify barriers to and facilitators of behaviours that lead to CAUTI (CAUTI-related behaviours) in primary, community and secondary care and nursing homes; (ii) describe the content of nationally adopted interventions; and (iii) assess the extent to which intervention content is theoretically congruent with barriers and facilitators. Methods: A mixed-methods, three-phased study: (1) systematic review of 25 studies to identify (i) behaviours relevant to CAUTI and (ii) barriers to and facilitators of CAUTI-related behaviours, classified using the COMB model and Theoretical Domains Framework (TDF); (2) content analysis of nationally adopted CAUTI interventions in England identified through stakeholder consultation, classified using the Behaviour Change Wheel (BCW) and Behaviour Change Techniques Taxonomy (BCTTv1); and (3) findings from 1 and 2 were linked using matrices linking COMB and TDF to BCW/BCTTv1 in order to signpost to intervention design and refinement. Results: The most frequently reported barriers to and facilitators of CAUTI-related behaviours related to 'environmental context and resources'; 'knowledge'; 'beliefs about consequences'; 'social influences'; 'memory, attention and decision processes'; and 'social professional role and identity.' Eleven interventions aiming to reduce CAUTI were identifed. Interventions were primarily guidelines and included on average 2.3 intervention functions (1-5) and six BCTs (2-11), most frequently 'education', 'training' and 'enablement.' The most frequently used BCT was 'information about health consequences' which was used in almost all interventions. Social professional role and identity and environmental context and resources were

This study has objectively identified the transitional care workload facing paediatric and adult rheumatologists in terms of disease-related, self-advocacy and vocational issues. Outcome data following the implementation of a coordinated transitional care programme are awaited.