Background: Homelessness is associated with enormous health inequalities, including shorter life expectancy, higher morbidity and greater usage of acute hospital services. Viewed through the lens of social determinants, homelessness is a key driver of poor health, but homelessness itself results from accumulated adverse social and economic conditions. Indeed, in people who are homeless, the social determinants of homelessness and health inequities are often intertwined, and long term homelessness further exacerbates poor health. Aggregated health service data can mask this, and case histories thus provide important insights. Methods: This paper presents three case histories of homeless patients seen at an inner city public hospital in Perth, Western Australia. The case histories draw on several data sources: hospital data, information collected from rough sleepers and clinical observations. Estimates of the cost to the health system of the observed hospital usage by the three patients are included. Findings: The case histories illustrate the interplay of social determinants of health in homelessness that help explain the high level of hospital usage by rough sleepers. The cumulative healthcare costs for the three individuals over a 33 months period were substantial. Hospital attendance plummeted even in the short term when housing needs were addressed. Conclusions: Treating homelessness as a combined health and social issue is critical to improving the abysmal health outcomes of people experiencing homelessness. In addition, the enormous economic costs of hospital care for people who are homeless can be reduced when housing and other social determinants are taken into account.

Introduction Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear. Methods This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18–49: HR 3.57, CI 2.54–5.02), frailty (CFS 8 vs 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1–3: OR 7.00, CI 5.27–9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusions Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.

Original research article INTRODUCTIONSignificant advances in copy-number detection have broadened the mutation spectrum for many clinical genetic disorders. 1,2 Intragenic deletion mutations are of considerable frequency in many disease genes, such as PAX6, CDKL5, and STXPB1. Recurrent rearrangements between segmentally duplicated sequences are also associated with a number of syndromic disorders. 3 For these known disorders, targeted gene testing by multiplex ligation-dependent amplification or exon-focused arrays has been useful. With the increasing uptake of exome sequencing into the clinical diagnostic approach, the need for testing previously uncharacterized genes for pathogenic copynumber variation (CNV) is a significant consideration, not only to detect aberrations in genes that may cause disease when haplo-insufficient but also in genes associated with recessive disorders for which the mutation has been identified in only one of the alleles by exome sequencing. 4 Whereas exome sequencing is still gaining popularity as a powerful clinical tool, whole-genome chromosomal microarray analysis (CMA) has become an indispensable screening method that is now routinely used as a first-tier test for children with intellectual disability, developmental delay, or congenital anomalies. 5 In less than 10 years, the CMA designs have evolved from low-resolution arrays containing large bacterial artificial chromosome clones or <100,000 oligonucleotide probes to high-resolution versions with more than 1 million probes. 6 As a result, several groups have identified single-gene pathogenic aberrations that boost the analytical sensitivity of CMA. 7 However, although some of these more recent arrays have higher density at disease genes, they do not all cover every exon in those genes and are therefore not capable of detecting some pathogenic intragenic mutations. Separately, data from exon-focused arrays have shown that up to 40% of intragenic mutations can involve just one or two exons within a gene, and therefore it is essential to cover all exons within targeted genes. 1 Copy-number detection in clinical genetic testing eventually will occur entirely through examination of next-generation data, whereas array comparative genomic hybridization (aCGH) and other assays will serve as complementary and confirmatory methods. 8 To complement whole-exome sequencing (WES) or whole-genome sequencing data in a meaningful way, an array with coverage of virtually all exons is essential. Until the time that WES/whole-genome sequencing can be used routinely and reliably for copy-number detection, a whole-exome array can be used as the ultimate whole-genome CMA platform. Purpose: Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its ut...

Alcohol use disorder (AUD) is a leading cause of morbidity and mortality. 1-2 Alcohol consumption is related to approximately 4% of the global burden of disease. 1 It has been estimated that, in clinical settings and compared to the general population, the relative risk of mortality is 3.38 for male patients and 4.57 for female patients with AUD. 2 Patients who reduce their alcohol consumption may halve this increased risk of mortality compared to patients with AUD who do not. 3 However, currently the approved pharmacotherapies that may help patients with AUD to achieve abstinence and/or reduce alcohol consumption to lower drinking levels are limited in number and efficacy. 4-5 Therefore, there is an urgent need to develop more effective treatments in this area. Preclinical and human studies suggest that baclofen, a GABA B receptor agonist, might be a novel treatment for patients with moderate to severe AUD. 6 Notably, a few years after initial randomized clinical trials (RCTs) were conducted, the potential use of this medication for AUD dramatically increased in its popularity due to a French case report describing the use of very high doses of baclofen to treat alcohol craving and drinking. 7 This intriguing yet purely anecdotical case report led to significant scientific and mass media attention and to the use of baclofen (off-label) in the treatment of AUD, such that the French drugs regulatory agency became involved in evaluating the use of baclofen in AUD. However, clinical studies conducted in Europe, USA, Australia, Israel and that evaluated baclofen efficacy in AUD have yielded conflicting results with some but not all RCTs showing an effect of baclofen. 6 The three recent meta-analyses do not draw definitive conclusions on the efficacy of baclofen in the treatment of AUD. 8-10 In fact, one meta-analysis 8 found no significant superiority of baclofen over placebo on the outcomes of each study whereas the other two found that baclofen treatment significantly increased the rate of abstinent patients 9-10 and time to first lapse 9 compared to placebo. Furthermore, one meta-analysis found larger effect sizes of baclofen among heavy drinkers and studies using lower doses. 9 The other study found no significant efficacy of baclofen in reducing the severity of craving for alcohol, anxiety, and depression. 10 In addition, these two meta-analyses reported no significant efficacy of baclofen on other important outcomes such as rate of abstinence days 9-10 or rate of heavy drinking days. 10 Chiefly, all three meta-analyses found overall a small effect size and substantial heterogeneity among studies. 8-10 Following the publication of these metaanalyses, 8-10 a further RCT has been completed and data analysis is currently under way (JC Garbutt, unpublished; ClinicalTrials.gov: NCT01980706). Despite the lack of consistent evidence of efficacy, baclofen is frequently used off-label to treat AUD, especially in some European countries and Australia. However, there is significant variability in the use of baclofen for cl...

Purpose Homelessness is a colossal issue, precipitated by a wide array of social determinants, and mirrored in substantial health disparities and a revolving hospital door. Connecting people to safe and secure housing needs to be part of the health system response. The paper aims to discuss these issues. Design/methodology/approach This mixed-methods paper presents emerging findings from the collaboration between an inner city hospital, a specialist homeless medicine GP service and Western Australia’s inaugural Housing First collective impact project (50 Lives 50 Homes) in Perth. This paper draws on data from hospitals, homelessness community services and general practice. Findings This collaboration has facilitated hospital identification and referral of vulnerable rough sleepers to the Housing First project, and connected those housed to a GP and after hours nursing support. For a cohort (n=44) housed now for at least 12 months, significant reductions in hospital use and associated costs were observed. Research limitations/implications While the observed reductions in hospital use in the year following housing are based on a small cohort, this data and the case studies presented demonstrate the power of care coordinated across hospital and community in this complex cohort. Practical implications This model of collaboration between a hospital and a Housing First project can not only improve discharge outcomes and re-admission in the shorter term, but can also contribute to ending homelessness which is itself, a social determinant of poor health. Originality/value Coordinated care between hospitals and programmes to house people who are homeless can significantly reduce hospital use and healthcare costs, and provides hospitals with the opportunity to contribute to more systemic solutions to ending homelessness.

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Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30–80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an “off-label” prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

Purpose: Mendelian disorders are most commonly caused by mutations identifiable by DNA sequencing. Exonic deletions and duplications can go undetected by sequencing, and their frequency in most Mendelian disorders is unknown. methods:We designed an array comparative genomic hybridization (CGH) test with probes in exonic regions of 589 genes. Targeted testing was performed for 219 genes in 3,018 patients. We demonstrate for the first time the utility of exon-level array CGH in a large clinical cohort by testing for 136 autosomal dominant, 53 autosomal recessive, and 30 X-linked disorders.Results: Overall, 98 deletions and two duplications were identified in 53 genes, corresponding to a detection rate of 3.3%. Approximately 40% of positive findings were deletions of only one or two exons. A high frequency of deletions was observed for several autosomal dominant disorders, with a detection rate of 2.9%. For autosomal recessive disorders, array CGH was usually performed after a single mutation was identified by sequencing. Among 138 individuals tested for recessive disorders, 10.1% had intragenic deletions. For X-linked disorders, 3.5% of 313 patients carried a deletion or duplication.conclusion: Our results demonstrate that exon-level array CGH provides a robust option for intragenic copy number analysis and should routinely supplement sequence analysis for Mendelian disorders. 2012:14(6):594-603 Genet Med