Reducing the time to activation of the emergency call system in operating theatres: effect of installing vertical red line indicators.

BACKGROUND: The 7th National Audit Project of the Royal College of Anaesthetists (NAP7) recommended that an emergency call system be immediately accessible in all anaesthesia locations. It is essential that all theatre team members can rapidly call for help to reduce the risk of patient harm. However, the ability of staff to activate this system in a timely manner can be affected by cluttered or unfamiliar environments and cognitive overload. One proposed strategy to enable rapid identification and activation of emergency call systems is to install a red vertical painted stripe on the wall from the ceiling to the activation button. We investigated the effect of introducing this vertical red line on activation times in operating theatres in the UK and Australia. METHODS: Operating theatre team members, including anaesthetists, surgeons, anaesthetic nurses, surgical and theatre nurses, operating theatre practitioners, and technicians, were approached without prior warning and asked to simulate activation of an emergency call. Vertical red lines were installed, and data collection repeated in the same operating theatres 4-12 months later. RESULTS: After installation of vertical red lines, the proportion of activations taking >10 s decreased from 31.9% (30/94) to 13.6% (17/125, P=0.001), and >20 s decreased from 19.1% (18/94) to 4.8% (6/125, P<0.001). The longest duration pre-installation was 120 s, and post-installation 35 s. CONCLUSIONS: This simple, safe, and inexpensive design intervention should be considered as a design standard in all operating theatres to minimise delays in calling for help.

Peer support as a potential tool to promote pharmacists' wellbeing.

Discussion regarding burnout in health professionals, including community pharmacists, has grown substantially since the arrival of the COVID-19 pandemic. Rapid legislative and societal behavioural changes led to significant global disruption of physical and emotional wellbeing during the pandemic as pharmacists continued to provide care while under unprecedented levels of stress. Community pharmacists have had an essential role in maintaining face-to-face care as the number of COVID-19 diagnoses and deaths rose. Communications emerged from the World Health Organisation which implored long-term changes to healthcare workplaces, including increased access to psychosocial support for employees. Peer support is a unique initiative in that it is low-cost and accessible across many platforms. Its main purpose is to bring people together with shared experiences and can often include people in the same career field or workplace. The feasibility and efficacy of peer support programs have been studied in other professional groups such as nurses and physicians, and also in undergraduate medical students. The conclusions drawn from these studies suggest that involvement in peer support reduced the risk of burnout and increased workplace engagement. In contrast to many other healthcare professionals, community pharmacists often work in relative isolation. Research has shown that younger pharmacists, and those in the earlier stages of their careers, reported feeling stressed, undervalued and supported. They also mentioned a desire for access to a mentoring or coaching program. Following the success of peer support in other cohorts, research is needed to verify if this intervention will similarly benefit early career community pharmacists.

PRPH2-Related Retinal Dystrophies: Mutational Spectrum in 103 Families from a Spanish Cohort.

PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype-phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype-phenotype correlations.

Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study.

BACKGROUND: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated. RESULTS: In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; P=0.00043; femorals: 0.60 [0.47-0.78]; P=9.96×10-5; coronaries: 0.53 [0.39-0.74]; P=0.00013; and increased PESA score: 0.58 [0.48-0.71]; P=3.16×10-8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; P=4.70×10-9 versus 0.90 [0.57-1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. CONCLUSIONS: This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION: URL: https://www.clinicaltrials.gov: NCT01410318.

Medication-related problems identified by community pharmacists: a descriptive case study of two Australian populations.

BACKGROUND: Medication-related problems (MRPs) contribute significantly to preventable patient harm and global healthcare expenditure. Vulnerable populations, including Indigenous Australians (please note that the use of the term 'Indigenous' in this paper includes all Aboriginal and Torres Strait Islander people and acknowledges their rich traditions and heterogenous cultures.) and people living with severe and persistent mental illness (SPMI), may be at increased risk of MRPs. Pharmacist-led medication reviews can identify MRPs for targeted action. OBJECTIVE: To characterize MRPs identified and recommendations made by community pharmacists during medication reviews conducted with Indigenous Australians and people living with SPMI. METHODS: Participants were recruited through two Australian trials testing the feasibility and/or effectiveness of novel community pharmacist-led interventions, the Indigenous Medication Review Service (IMeRSe) feasibility study (June 2018-July 2019) and Bridging the Gap between Physical and Mental Illness in Community Pharmacy (PharMIbridge) randomized controlled trial (September 2020-December 2021). Trained community pharmacists conducted medication reviews responsive to the cultural and health needs of participants. MRPs, MRP severity and pharmacist recommendations were documented and classified using an established classification system (DOCUMENT). MRP severity was assessed by pharmacists and an independent assessor. Data were analysed descriptively, and paired t-tests were used to compare severity ratings. RESULTS: Pharmacists identified 795 MRPs with 411 participants across both trials (n = 255 IMeRSe, n = 156 PharMIbridge). Non-adherence to medication was the most common (n = 157, 25.1%) and second-most common (n = 25, 14.7%) MRP in IMeRSe and PharMIbridge, respectively. Undertreatment was the second-most common MRP in the sample of Indigenous Australians (n = 139, 22.2%), and reports of toxicity/adverse reactions were most common in people living with SPMI (n = 41, 24.1%). A change in pharmacotherapy was the most frequent recommendation made by pharmacists (40.2% and 55.0% in IMeRSe and PharMIbridge, respectively). Severity ratings varied, with the majority being 'Mild' or 'Moderate' in both groups. Significant differences were found in the severity rating assigned by trial pharmacists and the independent assessor. CONCLUSIONS: Community pharmacists identified a range of MRPs experienced by two at-risk populations, most commonly non-adherence and toxicity or adverse reactions, when conducting medication reviews and proposed diverse strategies to manage these, frequently recommending a change in pharmacotherapy. These findings highlight the opportunity for more targeted approaches to identifying and managing MRPs in primary care and tailored community pharmacist-led interventions may be of value in this space. TRAIL REGISTRATION: Australian and New Zealand Clinical Trial Registry records (IMeRSe ACTRN12618000188235 registered 06/02/2018 & PharMIbridge ACTRN12620000577910 registered 18/05/2020).

Understanding the hospital discharge planning process for medical patients with dementia.

Background: Poor hospital discharge processes can result in the readmission of patients and potentially increase the stress levels of carers. Therefore, this study sought to understand the factors related to the discharge planning process for patients with dementia.Methods: The researchers interviewed 32 carers of patients with dementia and 20 hospital staff who worked on medical wards in a United Kingdom (UK) hospital. The semi-structured interviews were analysed thematically using a systems theory (patient-carer-staff relationships, hospital equipment and policies).Results: The findings indicated that the following factors could either have a positive or negative impact on discharge planning: patient (e.g. cognitive capacity), carer (e.g. preconceived ideas about care homes), staff (e.g. communication skills), policy (e.g. procedures such as discharge meetings), equipment (e.g. type of service provider delivering the equipment) and the wider social context (e.g. availability of specialist dementia beds in care homes).Conclusion: It is important for hospital staff to adopt a systems perspective and to integrate the different elements of the hospital system when planning for patients' discharge.

The enduring enigma of sporadic chorea: A single center case series.

Chorea can have a wide variety of causes including neurodegenerative, pharmacological, structural, metabolic, infectious, immunologic and paraneoplastic processes. We reviewed the clinical records of patients with apparently sporadic choreic movements and no relevant family history, who presented to our neurology department (Hospital Fundación Jimenez Diaz) between 1991 and 2022. We detected 38 cases of apparent sporadic chorea (ASC); Our analysis revealed 5 cases of genetic chorea (including 3 cases with Huntington's disease) while 6 cases were autoimmune/hematological; 6 drug-related chorea, 5 metabolic-vascular, 5 due to miscellaneous conditions and 4 were of mixed etiology. No clear etiology was identified in 8 cases. The differential diagnosis of ASC is extensive and challenging. Highlights: Chorea can have a wide variety of genetic and sporadic causesWe reviewed the clinical records of patients with apparently sporadic chorea (ASC), who presented to our neurology department over the last 30 yearsWe detected 38 cases of apparent ASC; Our analysis revealed a wide array of different sporadic conditions and 5 cases of genetic choreaThe differential diagnosis of ASC is extensive and challenging.

Activating pharmacists to reduce the frequency of medication-related problems (ACTMed): a stepped wedge cluster randomised trial.

BACKGROUND: Medicines are the most frequent health care intervention type; their safe use provides significant benefits, but inappropriate use can cause harm. Systemic primary care approaches can manage serious medication-related problems in a timely manner. OBJECTIVES: ACTMed (ACTivating primary care for MEDicine safety) uses information technology and financial incentives to encourage pharmacists to work more closely with general practitioners to reduce the risk of harm, improve patients' experience of care, streamline workflows, and increase the efficiency of medical care. METHODS AND ANALYSIS: The stepped wedge cluster randomised trial in 42 Queensland primary care practices will assess the effectiveness of the ACTMed intervention. The primary outcome will be the proportion of people at risk of serious medication-related problems - patients with atrial fibrillation, heart failure, cardiovascular disease, type 2 diabetes, or asthma or chronic obstructive pulmonary disease - who experience such problems. We will also estimate the cost per averted serious medication-related problem and the cost per averted potentially preventable medication-related hospitalisation. ETHICS APPROVAL: The University of Queensland Human Research Ethics Committee approved the pilot (2021/HE002189) and trial phases of the ACTMed study (2022/HE002136). Access to Patron data was granted by the Patron Data Governance Committee (PAT052ACTMed). Access to linked hospitalisations and deaths data are subject to Public Health Act approval (pending). DISSEMINATION OF FINDINGS: A comprehensive dissemination plan will be co-developed by the researchers, the ACTMed steering committee and consumer advisory group, project partners, and trial site representatives. Aboriginal and Torres Strait Islander communities will be supported in leading community-level dissemination. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (pilot: ACTRN12622000595718; 21 April 2022; full trial: ACTRN12622000574741; 14 April 2022).

Comprehensive Genotyping and Phenotyping Analysis of GUCY2D-Associated Rod- and Cone-Dominated Dystrophies.

PURPOSE: To describe the genetic and clinical spectrum of GUCY2D-associated retinopathies and to accurately establish their prevalence in a large cohort of patients. DESIGN: Retrospective case series. METHODS: Institutional study of 47 patients from 27 unrelated families with retinal dystrophies carrying disease-causing GUCY2D variants from the Fundación Jiménez Díaz hospital dataset of 8000 patients. Patients underwent ophthalmological examination and molecular testing by Sanger or exome sequencing approaches. Statistical and principal component analyses were performed to determine genotype-phenotype correlations. RESULTS: Four clinically different associated phenotypes were identified: 66.7% of families with cone/cone-rod dystrophy, 22.2% with Leber congenital amaurosis, 7.4% with early-onset retinitis pigmentosa, and 3.7% with congenital night blindness. Twenty-three disease-causing GUCY2D variants were identified, including 6 novel variants. Biallelic variants accounted for 28% of patients, whereas most carried dominant alleles associated with cone/cone-rod dystrophy. The disease onset had statistically significant differences according to the functional variant effect. Patients carrying GUCY2D variants were projected into 3 subgroups by allelic combination, disease onset, and presence of nystagmus or night blindness. In contrast to patients with the most severe phenotype of Leber congenital amaurosis, 7 patients with biallelic GUCY2D had a later and milder rod form with night blindness in infancy as the first symptom. CONCLUSIONS: This study represents the largest GUCY2D cohort in which 4 distinctly different phenotypes were identified, including rare intermediate presentations of rod-dominated retinopathies. We established that GUCY2D is linked to about 1% of approximately 3000 molecularly characterized families of our cohort. All of these findings are critical for defining cohorts for inclusion in future clinical trials.

A narrative review of staff views about dementia care in hospital through the lens of a systems framework.

Background: Significant numbers of people with dementia are admitted into acute settings. They are likely to face poor health outcomes during hospitalisation. There is the need to fully understand the care provided to people with dementia through novel methods such as a systems approach (i.e. human interactions, policy, environment and equipment). Aim: The aim of this literature review is to explore hospital practitioners' views on dementia care and to analyse findings using a systems approach. Methods: We conducted a narrative review of primary studies that examined dementia care in acute settings. We analysed a total of 33 papers using Thomas and Harden's thematic synthesis guidelines. Results: Thirty-three papers met the inclusion criteria for the review. The findings were as follows: (1) staff-patient relationships (e.g. coping with difficult behaviour), (2) staff-family relationships (e.g. the benefits of involving families in patient care), (3) staff-staff relationships (e.g. building a robust multidisciplinary team), (4) staff-patient care decisions (e.g. decisions directly related to the patient), (5) the environment (e.g. difficulty in adjusting to the hospital environment), (6) policies (e.g. hospital bureaucratic processes) and (7) equipment (e.g. pain assessment tools). Conclusion: The paper revealed multidimensional challenges in the provision of dementia care within hospitals. We conclude that training programmes, hospital policies and processes aimed at improving outcomes for patients with dementia should adopt a systems approach which focuses on the relational, environmental, procedural and instrumental aspects of the hospital system.

Team Immediate Meet tool to help intensive care staff: Staff perception of an updated version and preliminary feedback following implementation.

Intensive Care Unit staff deal with potentially traumatic cases throughout their careers. We designed and implemented a 'Team Immediate Meet' (TIM) tool, a communication aid designed to facilitate a two-minute 'hot debrief' after a critical event, provide the team with information about the normal reaction to such an event and signpost staff to strategies to help support their colleagues (and themselves). We describe our TIM tool awareness campaign, quality improvement project and subsequent feedback from staff who reported that the tool would be useful for navigating the aftermath of potentially traumatic events and could be transferable to other ICUs.

Clinical and genetic analysis further delineates the phenotypic spectrum of ALDH1A3-related anophthalmia and microphthalmia.

Biallelic pathogenic variants in ALDH1A3 are responsible for approximately 11% of recessively inherited cases of severe developmental eye anomalies. Some individuals can display variable neurodevelopmental features, but the relationship to the ALDH1A3 variants remains unclear. Here, we describe seven unrelated families with biallelic pathogenic ALDH1A3 variants: four compound heterozygous and three homozygous. All affected individuals had bilateral anophthalmia/microphthalmia (A/M), three with additional intellectual or developmental delay, one with autism and seizures and three with facial dysmorphic features. This study confirms that individuals with biallelic pathogenic ALDH1A3 variants consistently manifest A/M, but additionally display neurodevelopmental features with significant intra- and interfamilial variability. Furthermore, we describe the first case with cataract and highlight the importance of screening ALDH1A3 variants in nonconsanguineous families with A/M.

Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation.

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.

Prioritization of New Candidate Genes for Rare Genetic Diseases by a Disease-Aware Evaluation of Heterogeneous Molecular Networks.

Screening for pathogenic variants in the diagnosis of rare genetic diseases can now be performed on all genes thanks to the application of whole exome and genome sequencing (WES, WGS). Yet the repertoire of gene-disease associations is not complete. Several computer-based algorithms and databases integrate distinct gene-gene functional networks to accelerate the discovery of gene-disease associations. We hypothesize that the ability of every type of information to extract relevant insights is disease-dependent. We compiled 33 functional networks classified into 13 knowledge categories (KCs) and observed large variability in their ability to recover genes associated with 91 genetic diseases, as measured using efficiency and exclusivity. We developed GLOWgenes, a network-based algorithm that applies random walk with restart to evaluate KCs' ability to recover genes from a given list associated with a phenotype and modulates the prediction of new candidates accordingly. Comparison with other integration strategies and tools shows that our disease-aware approach can boost the discovery of new gene-disease associations, especially for the less obvious ones. KC contribution also varies if obtained using recently discovered genes. Applied to 15 unsolved WES, GLOWgenes proposed three new genes to be involved in the phenotypes of patients with syndromic inherited retinal dystrophies.

Biallelic intragenic tandem duplication of CPLANE1 in Joubert syndrome: A case report.

Joubert syndrome (JS) is a clinically and genetically heterogeneous genetic disorder. To date, 40 JS-causing genes have been reported and CPLANE1 is one of the most frequently mutated, with biallelic pathogenic missense and truncating variants explaining up to 14% of JS cases. We present a case of JS diagnosed after the identification of a novel biallelic intragenic duplication of exons 20-46 of CPLANE1. The quadruplication was identified by short-read sequencing and copy number variant analysis and confirmed in tandem by long PCR with the breakpoints defined by a nanopore-based long-read sequencing approach. Based on the genetic findings and the clinical presentation of the patient, a brain MRI was ordered, evidencing the molar tooth sign, which confirmed the diagnosis of JS in the patient. This is, to the best of our knowledge, the first report of an intragenic duplication in this gene as the potential molecular mechanism of JS.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Application of multicolour reflectance imaging for the characterisation of inherited retinal disorders.

AIM: To describe the role of multicolour reflectance images (MCI) in the phenotypic diagnosis of inherited retinal disorders (IRDs). METHODS: A retrospective review of consecutive patients affected by IRDs examined with MCI techniques from January to December 2019 at a tertiary care referral centre. All patients had MCI, fundus autofluorescence and optical coherence tomography taken at the same time point. The ability of each modality to highlight clinical features was assessed. Lesions' size was also measured and compared among imaging modalities. RESULTS: Thirty eyes of 15 patients were included in the study, 6 males and 9 females, with a mean age of 44 years (range: 19-57.5). The most frequent clinical diagnosis were: pattern dystrophies, and late-onset retinal degeneration. Next-generation or Sanger sequencing analysis was carried out in all patients. Blue and green reflectance were relevant in highlighting peripheral mottling in fundus albipunctatus, pseudoreticular drusen in late-onset retinal degeneration, parafoveal hyperreflective area in bull's eye maculopathy and crystals in Bietti's crystalline dystrophy. Likewise, it is to mention the ability of infrared reflectance to detect hyperreflective patches in posterior pole in neurofibromatosis type 1 and retinal changes in pattern dystrophies and cone dystrophies. CONCLUSION: Multicolour imaging technique enables the detection of clinical features that could be overlooked by other imaging modalities, allowing accurate phenotypic characterisation of IRDs and guiding genetic diagnose, and may become a meaningful monitoring tool for future treatments.