Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q(10) deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q(10) biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q(10) deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q(10) biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast Saccharomyces cerevisiae abolished respiratory growth.

The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.

ObjectiveInflammation has been implicated in the aetiology of mental illness. We conducted the first systematic review and meta-analysis of the association between peripheral markers of inflammation and generalised anxiety disorder (GAD).DesignSystematic review and meta-analysis of studies measuring peripheral cytokine levels in people with GAD compared with controls.Data sourcesMEDLINE (1950–), EMBASE (1947–), PsycINFO (1872–) and Web of Science (1945–) databases up until January 2018.Eligibility criteriaPrimary, quantitative research studies of people with a diagnosis of GAD assessed using a standardised clinical interview that measured peripheral inflammatory markers.Data extraction and synthesisTwo independent reviewers extracted data and assessed study quality. Meta-analysis using a random-effects model was conducted for individual cytokines where data from three or more studies were available.Results14 of 1718 identified studies met the inclusion criteria, comprising 1188 patients with GAD and 10 623 controls. In total 16 cytokines were evaluated. Significantly raised levels of C reactive protein (CRP), interferon-γ and tumour necrosis factor-α were reported in patients with GAD compared with controls in two or more studies. Ten further proinflammatory cytokines were reported to be significantly raised in GAD in at least one study. However, 5 of 14 studies found no difference in the levels of at least one cytokine. Only CRP studies reported sufficient data for meta-analysis. CRP was significantly higher in people with GAD compared with controls, with a small effect size (Cohen’s d=0.38, 0.06–0.69), comparable with that reported in schizophrenia. However, heterogeneity was high (I2=75%), in keeping with meta-analyses of inflammation in other psychiatric conditions and reflecting differences in participant medication use, comorbid depression and cytokine sampling methodology.ConclusionThere is preliminary evidence to suggest an inflammatory response in GAD, but it remains unclear whether inflammatory cytokines play a role in the aetiology. GAD remains a poorly studied area of neuroinflammation compared with other mental disorders, and further longitudinal studies are required.

Background:Care home staff stress and burnout may be related to high turnover and associated with poorer quality care. We systematically reviewed and meta-analyzed studies reporting stress and burnout and associated factors in staff for people living with dementia in long-term care.Methods:We searched MEDLINE, PsycINFO, Web of Science databases, and CINAHL database from January 2009 to August 2017. Two raters independently rated study validity using standardized criteria. We meta-analyzed burnout scores across comparable studies using a random effects model.Results:17/2854 identified studies met inclusion criteria. Eight of the nine studies reporting mean Maslach Burnout Inventory (MBI) scores found low or moderate burnout levels. Meta-analysis of four studies using the 22-item MBI (n = 598) found moderate emotional exhaustion levels (mean 18.34, 95% Confidence Intervals 14.59–22.10), low depersonalization (6.29, 2.39–10.19), and moderate personal accomplishment (33.29, 20.13–46.46). All three studies examining mental health-related quality of life reported lower levels in carer age and sex matched populations. Staff factors associated with higher burnout and stress included: lower job satisfaction, lower perceived adequacy of staffing levels, poor care home environment, feeling unsupported, rating home leadership as poor and caring for residents exhibiting agitated behavior. There was preliminary evidence that speaking English as a first language and working shifts were associated with lower burnout levels.Conclusions:Most care staff for long-term care residents with dementia experience low or moderate burnout levels. Prospective studies of care staff burnout and stress are required to clarify its relationship to staff turnover and potentially modifiable risk factors.

Summary To date, there have been no detailed reports of patients developing persistent psychotic symptoms following Coronavirus disease 2019 (COVID-19) infection. There have been reports of patients developing transient delirium (with and without hypoxia) after COVID-19 infection as well as other neurological manifestations. We report on a female patient who, post-COVID-19 infection, developed an initial delirium followed by persistent and florid psychotic symptoms consisting of persecutory delusion, complex visual and auditory hallucinations and Capgras phenomenon in the absence of hypoxia but elevated tumour necrosis factor (TNF)-α. The psychotic symptoms persisted for about 40 days. Her magnetic resonance imaging brain scan, electroencephalogram, cerebrospinal fluid examination and extensive autoimmune panel did not show any abnormalities. The cause of the psychotic symptoms in this patient were not ascertained but we propose either an inflammatory state, characterised by the patient's elevated TNF-alpha levels as a possible contributing mechanism for her psychosis in line with the proinflammatory changes observed in some cases of psychosis. Or, an alternative, but unproven, hypothesis is one of an antibody-mediated encephalitic event induced by viral infection.

Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.

Background: The mitochondrial DNA mutation m.1555A>G predisposes to permanent idiosyncratic aminoglycoside-induced deafness that is independent of dose. Research suggests that in some families, m.1555A>G may cause non-syndromic deafness, without aminoglycoside exposure, as well as reduced hearing thresholds with age (age-related hearing loss).Objectives: To determine whether adults with m.1555A>G have impaired hearing, a factor that would inform the costebenefit argument for genetic testing prior to aminoglycoside administration.Design: Population-based cohort study. Setting: UK. Participants: Individuals from the British 1958 birth cohort.Measurements: Hearing thresholds at 1 and 4 kHz at age 44e45 years; m.1555A>G genotyping.Results: 19 of 7350 individuals successfully genotyped had the m.1555A>G mutation, giving a prevalence of 0.26% (95% CI 0.14% to 0.38%) or 1 in 385 (95% CI 1 in 714 to 1 in 263). There was no significant difference in hearing thresholds between those with and without the mutation. Single-nucleotide polymorphism analysis indicated that the mutation has arisen on a number of different mitochondrial haplogroups.Limitations: No data were collected on aminoglycoside exposure. For three subjects, hearing thresholds could not be predicted because information required for modelling was missing.Conclusions: In this cohort, hearing in those with m.1555A>G is not significantly different from the general population and appears to be preserved at least until 44e45 years of age. Unbiased ascertainment of mutation carriers provides no evidence that this mutation alone causes non-syndromic hearing impairment in the UK. The findings lend weight to arguments for genetic testing for this mutation prior to aminoglycoside administration, as hearing in susceptible individuals is expected to be preserved well into adult life. Since global use of aminoglycosides is likely to increase, development of a rapid test is a priority. ARTICLE SUMMARY Article focus-Individuals who have the m.1555A>G mutation are exquisitely sensitive to rapid-onset hearing loss after receiving aminoglycosides at normal therapeutic levels. -We sought to determine whether a cohort of mature individuals with the m.1555A>G mutation have hearing loss by their mid-40s because the mutation has been reported to cause lateronset less severe hearing loss in people who have never been exposed to aminoglycosides. We wished to determine whether genetic screening prior to aminoglycoside administration is justified. Key messages-This study demonstrates the prevalence of m.1555A>G to be 1 in 385 (95% CI 1 in 714 to 1 in 263) in the 1958 British birth cohort, confirming that this mutation occurs frequently in Caucasian populations. -The hearing of individuals with the m.1555A>G mutation is no different to that of the general population at age 44e45 years, in contrast to previous reports which suggested that hearing decreases with age in people with m.1555A>G; any such effect is not large and likely to be subject to previous ascertainment bias. -...

Background staff burnout and turnover lead to care home residents receiving poorer quality care. Burnout is thought to cause turnover, but this has never been investigated. We know little about which care home staffs are burnt out. Aims to explore burnout’s relationship with staff turnover and prevalence and predictors of burnout. Method we calculated the relationship between Maslach Burnout Inventory scores and future staff turnover (12-month number of staff leaving/number employed). We explored staff, resident and care home predictors of burnout, measured as emotional exhaustion (EE), depersonalisation (DP) and personal accomplishment (PA). Results two-thousand sixty-two care staff in 97 care home units participated. Median yearly staff turnover was 22.7%, interquartile range (IQR) 14.0–37.7%. Care staff recorded low median burnout (median EE: 14, IQR: 7–22; DP: 1, IQR: 0–5; PA 42, IQR: 36–45). We found no association between staff burnout and turnover rate. Younger staff age was associated with higher burnout (EE coefficient − 0.09; 95% confidence interval (CI): −0.13, −0.05; DP −0.02; 95% CI: −0.04, −0.01; PA 0.05; 95% CI: 0.02, 0.08). Speaking English as a second language predicted higher EE (1.59; 95% CI: 0.32, 2.85), males had higher DP (0.02; 95% CI: 0.01, 0.04) and staff working only night shifts lower PA (−2.08; 95% CI: −4.05, −1.30). Conclusions we found no association between care homes staff burnout level and staff turnover rates. It is a myth that burnout levels are high. Interventions for burnout could focus on at-risk groups. Future studies could consider turnover at an individual level.