The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Pyruvate kinase deficiency in 29 Turkish patients with two novel intronic variants.

Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty-nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695-1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non-spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling.

Systematic Review Examining the Association Between Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Prescription and Abdominal Aortic Aneurysm Growth and Events.

OBJECTIVE: Whether angiotensin II blockade is an effective medical treatment for abdominal aortic aneurysms (AAAs) has not been established. This systematic review and meta-analysis aimed to determine the association between angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) prescription and AAA growth and events. DATA SOURCES: MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library databases were searched from their inception to 4 January 2024, with no language restrictions. REVIEW METHODS: The five databases were searched for randomised controlled trials (RCTs) and observational studies reporting the association between ACEi or ARB prescription and AAA growth, repair, or rupture. The primary outcome was AAA growth, with secondary outcomes of AAA rupture, AAA repair, and AAA related events (rupture and repair combined). Risk of bias was assessed using the Risk of Bias 2 tool for RCTs and with a modified Newcastle-Ottawa scale for observational studies. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Random effects models were used for meta-analyses. RESULTS: Eleven studies (two RCTs, eight observational studies, and one meta-analysis of individual patient data from seven populations) involving 58 022 patients were included. ACEi prescription was not associated with a statistically significant reduction in AAA growth (standard mean difference 0.01 mm/year, 95% confidence interval [CI] -0.26 - 0.28; p = .93; I2 = 98%) or AAA repair (odds ratio [OR] 0.73, 95% CI 0.50 - 1.09; p = .65; I2 = 61%), but was associated with a statistically significantly lower risk of AAA rupture (OR 0.87, 95% CI 0.81 - 0.93; p < .001; I2 = 26%) and AAA related events (OR 0.82, 95% CI 0.72 - 0.95; p = .006; I2 = 80%). ARB prescription was not associated with significantly reduced AAA growth or a lower risk of AAA related events. The two RCTs had a low risk of bias, with one observational study having low, seven moderate, and one high risk of bias. All of the findings had a very low certainty of evidence based on the GRADE analysis. CONCLUSION: There was no association between ACEi or ARB prescription and AAA growth, but ACEi prescription was associated with a reduced risk of AAA rupture and AAA related events with very low certainty of evidence.

Computational and Experimental Investigations of Osmium-Rich Borides Hf2MOs5B2 (M = Mn, Fe, Co): From Spin Glass to Room-Temperature Magnetic Behaviors.

The metal borides, Hf2MOs5B2 (M = Mn, Fe, Co), which are the first Os-rich quaternary variants of the prolific Ti3Co5B2 structure type, were investigated computationally and experimentally. In their crystal structures, osmium builds a network of prisms, in which the other elements are located. The magnetic M elements are found in face-connected Os8 square prisms leading to M-chains with intra- and interchain distances of about 3.0 and 6.5 Å, respectively. Density functional theory (DFT) showed that magnetic ordering is hugely favored for M = Mn and Fe but only slightly favored for M = Co. Experimental investigations then confirmed and extended the DFT predictions as a metamagnetic behavior was found for the M = Mn and Fe phases, whereby the antiferromagnetic interactions (TN = 19 and 90 K) found at low magnetic fields change to ferromagnetic at higher fields. A very broad transition (TN = 45 K) is found for M = Co, suggesting spin-glass behavior for this phase. For M = Fe, a hard-magnet hysteresis at 5 K is found with a 40 kA/m coercivity, and even at room temperature, a significant hysteresis is found. This study paves the way for the discovery of Os-based magnets in this structure type and other intermetallics.

'It's where I belong': what does it mean to age in place from the perspective of people aged 80 and above? A longitudinal qualitative study (wave one).

BACKGROUND: Most people want to remain at home as they age. Ageing in place - remaining at home and connected to the community - is a national and international policy priority; however, to better understand how policy might be implemented, a more nuanced understanding is required about older adults' lived experiences of ageing in place, especially the experiences of those aged 80 and above. OBJECTIVE: To describe and explore the social processes which enable ageing in place from the perspective of community-dwelling older people (80+). METHODS: Forty-six respondents (80-100+ years) participated in the first wave of a longitudinal qualitative study set in North East England. Semi-structured interviews were conducted in participants' homes between June 2022 and January 2023. Interviews were analysed using reflexive thematic analysis. RESULTS: Participants positioned their homes as a place of freedom and as the antithesis of a 'care home'. Remaining in place was important for all participants; a key priority for them was to remain physically active to enable this. However, many participants faced significant hurdles to remaining in place. These were primarily related to health and mobility issues. Some participants were able to overcome such barriers by drawing on financial resources and available social networks. CONCLUSION: The home is central to understanding older peoples' (80+) experiences of ageing. In a socio-political context which promotes ageing in place, the social factors shaping experiences of ageing in place must be considered. This involves attending to the challenges of later life, particularly health and especially mobility and physical function. Currently, those with resources (social and economic) are better equipped to respond to such challenges, thus potentially exacerbating widening inequalities in ageing. By foregrounding the perspectives of those ageing in place alongside social factors shaping their experiences, our study has important implications for policy and health and social care. We show that a more equitable allocation of resources is vital to fulfil the ageing in place policy agenda. Furthermore, we highlight a need to recognise commitments to ageing in place displayed by people aged 80 and above, especially when remaining in place becomes difficult to achieve.

Constituting link working through choice and care: An ethnographic account of front-line social prescribing.

Link worker social prescribing has become a prominent part of NHS England's personalisation agenda. However, approaches to social prescribing vary, with multiple discourses emerging about the potential of social prescribing and different interpretations of personalisation. The transformational promise of social prescribing is the subject of ongoing debate, whilst the factors that shape the nature of front-line link working practices remain unclear. Based on 11 months of in-depth ethnographic research with link workers delivering social prescribing, we show how link workers' practices were shaped by the context of the intervention and how individual link workers navigated varied understandings of social prescribing. Following the work of Mol, we show how link workers drew differentially on the interacting logics of choice and care and trace a multiplicity in front-line link working practices within a single intervention. However, over time, it appeared that a logic of choice was becoming increasingly dominant, making it harder to deliver practices that aligned with a logic of care. We conclude that interpreting personalisation through a logic of choice could potentially undermine link working practices that privilege care whilst obscuring the need for wider investment in health care systems and the social determinants of health.

Social prescribing during the COVID-19 pandemic: a qualitative study of service providers' and clients' experiences.

BACKGROUND: COVID-19 public health restrictions, such as social distancing and self-isolation, have been particularly challenging for vulnerable people with health conditions and/or complex social needs. Link worker social prescribing is widespread in the UK and elsewhere and is regarded as having the potential to provide support to vulnerable people during the pandemic. This qualitative study explores accounts of how an existing social prescribing service adapted to meet clients' needs in the first wave of the pandemic, and of how clients experienced these changes. METHODS: Data were collected in a deprived urban area of North East England via remote interviews with clients (n = 44), link workers (n = 5) and service provider managerial staff (n = 8) from May-September 2020. Thematic data analysis was conducted. RESULTS: The research found that service providers quickly adapted to remote intervention delivery aiming to serve existing clients and other vulnerable groups. Service providers experienced improved access to some existing clients via telephone in the first months of remote delivery and in some cases were able to engage clients who had previously not attended appointments at GP surgeries. However, link workers also experienced challenges in building rapport with clients, engaging clients with the aims of the intervention and providing a service to digitally excluded people. Limited link worker capacity meant clients experienced variable contact with link workers with only some experiencing consistent support that was highly valued for helping to manage their conditions and mental wellbeing. Limited access to linked services also adversely affected clients. Clients living in less affluent circumstances and/or with worse health were more likely to experience negative impacts on their long-term condition. Some found their health and progress with social prescribing was 'on hold' or 'going backwards', which sometimes negatively affected their health. CONCLUSIONS: Social prescribing offered valued support to some during the pandemic, but remote support sometimes had limited impact for clients and findings highlight the vulnerability of social prescribing's success when linked services are disrupted. Findings also show the need for more to be done in the upscaling of social prescribing to provide support to digitally excluded populations.

'He called me out of the blue': An ethnographic exploration of contrasting temporalities in a social prescribing intervention.

Social prescribing, a way of connecting patients to local services, is central to the NHS Personalised Care agenda. This paper employs ethnographic data, generated with 19 participants between November 2018 and July 2020, to explore the socio-temporal relations shaping their experiences of a local social prescribing intervention. Our focus is on the ways in which the intervention synchronised with the multitude of shifting, complex and often contradictory 'timespaces' of our participants. Our focus on the temporal rhythms of everyday practice allows us to trace a tension between the linearity and long horizon of the intervention and the oft contrasting timeframes of participants, sometimes leading to a mismatch that limited the intervention's impact. Further, we observed an interventional 'drift' from continuity towards unsupported signposting and 'out-of-the-blue' contacts which favour the temporality of the intervention. We demonstrate a need for intervention planning to be flexible to multiple, often conflicting, temporalities. We argue that health interventions must account for the temporal relations lived by the people they seek to support.

Genetics of cluster headache.

BACKGROUND: Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility. METHODS: We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection. RESULTS: The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME. CONCLUSIONS: The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.

Pesticides and Related Toxicants in the Atmosphere.

Pesticides and other toxicants released into the environment can contaminate air, water, soil, and biota. This review focuses on sources, exposures, fate, analysis, and trends. The potential for exposures due to atmospheric transport and deposition of pesticides and related contaminants may pose risks to humans and wildlife. Emissions of chemicals to air are related to physicochemical properties (e.g., vapor pressure and chemical stability). Experimental design and computer-based modeling, as related to emissions and dispersion of pesticides along transects downwind from release sources, will be discussed using the example of pesticide volatilization and drift in California agriculture that results in the transport and deposition downwind to the Sierra Nevada mountains, where much work has been done to refine exposure data for use in risk assessment and management. Predictably, those chemicals found frequently in air are those used most extensively, have multiple emission sources, and resist degradation. Yet to be determined are definitive connections with adverse impacts to humans and wildlife, although the accumulating evidence suggests that endocrine disrupting chemicals, ChE inhibitors, and others warrant further attention. Steps that are being taken to limit emissions, such as in pest control and fuel combustion, offer promising opportunities for improving the quality of air and of the overall environment. Chemical degradation rates and products from trace organics in the air merit more attention, as do the potential for activation by photooxidation and bioaccumulation in food chains. The potential effect of climate change, on atmospheric processes affecting contaminant behavior, is an area ripe for further study.

A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations.

PURPOSE: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. METHODS: A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. RESULTS: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre-Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. CONCLUSION: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

Clinical and genetic aspects of KBG syndrome.

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

"Successful" ageing in later older age: A sociology of class and ageing in place.

Supporting people to 'age in place' - to live independently at home and remain connected to the community - is an international policy priority. But the process of ageing in place is mediated in a socio-cultural context where neoliberal tropes of successful ageing reproduce a pervasive model about 'ageing well' by elevating ideals of individualised choice and self-governance. Based on two waves of qualitative interviews and interim observations, we employ a Bourdieusian logic to explore the ramifications of this context on the experiences of 46 people in later older age (80+) ageing in place in North East England. All participants enacted everyday improvisatory practices to render their homes habitable. But our participants - most of whom were located in middle-class social positions - supplemented such improvisions with a strategic disposition to plan for and actively shape their ageing-in-place futures. Our participants conveyed a distinct sense of agency over their ageing futures. Underpinning their orientations to practice was an awareness of the value attached to individually 'ageing well' and a distancing from the agedness associated with the fourth age. Our analysis demonstrates the role of capital, accrued throughout the life course, in bringing such future trajectories into effect. The central argument of this paper therefore is that the embodiment of (neoliberal) ideals of successful ageing in place requires the deployment of classed capital. In sum, contrary to the individualising narratives ubiquitous in policy pertaining to ageing well, we show the importance of classed structural moorings in this process.

The domestication of remote monitoring: The materialisation of care?

Recent years have seen an influx of technologies aimed at enabling older people to remain at home. Remote monitoring is one such technology. By tracking the body as it moves through time and space, remote monitoring enables a care connection which transcends the physical boundaries of the home. Based on 43 interviews conducted with 21 older people trialling remote monitoring, this study critically explores how older people integrate (or not) remote monitoring into the material and symbolic fabric of their homes. Drawing on the concept of domestication alongside materialities of care, we explore the active ways in which participants make sense of, and incorporate, remote monitoring into the intimacy of their homes. We find that domesticating remote monitoring, an apparently mundane and ordinary object, is a complex and conflicting process which has consequences for the ageing body. Through its domestication, remote monitoring occupies an ambiguous symbolic and material position at the intersection of public and private. While the rationale behind remote monitoring is to minimise physical risk, we find that its proximity to intimacy and its capacity to 'monitor' everyday practice poses symbolic and social risks to people's sense of home and their identities. Our findings highlight how ageing bodies are mediated and reconfigured through these technologies and how ageing bodies are potentially viewed as in decline and/or risky. Remote monitoring was viewed as a 'safety net'; however, acknowledging that safety was a concern, simultaneously positioned participants as 'at risk', a category associated with decline and dependency. Once incorporated into the home, the technology represented an 'active ageing' gaze which, through its imagined capacity to judge, risked disrupting the flow of everyday routines; it elicited a heightened awareness of otherwise taken-for-granted practices. Despite this, for some participants, remote monitoring was appropriated to enact care for others, a way to alleviate the emotional labour of family members, and thus refute normative assumptions underpinning remote monitoring about older people as passive recipients of care. Remote monitoring is not passively incorporated into the domestic setting. On the contrary, older people actively assign symbolic meaning to it.

Implementation and impact of a social prescribing intervention: an ethnographic exploration.

BACKGROUND: Social prescribing involves referral of patients from primary care to link workers, who work with them to access appropriate local voluntary and community sector services. AIM: To explore how a social prescribing intervention was delivered by link workers and the experiences of those referred to the intervention. DESIGN AND SETTING: The study used ethnographic methods to conduct a process evaluation of a social prescribing intervention delivered to support those living with long-term conditions in an economically deprived urban area of the North of England. METHOD: Participant observation, shadowing, interviews, and focus groups were used to examine the experiences and practices of 20 link workers and 19 clients over a period of 19 months. RESULTS: Social prescribing provided significant help for some people living with long-term health conditions. However, link workers experienced challenges in embedding social prescribing in an established primary care and voluntary sector landscape. The organisations providing social prescribing drew on broader social discourses emphasising personal responsibility for health, which encouraged a drift towards an approach that emphasised empowerment for lifestyle change more than intensive support. Pressures to complete assessments, required for funding, also encouraged a drift to this lighter-touch approach. A focus on individual responsibility was helpful for some clients but had limited capacity to improve the circumstances or health of those living in the most disadvantaged circumstances. CONCLUSION: Careful consideration of how social prescribing is implemented within primary care is required if it is to provide the support needed by those living in disadvantaged circumstances.

GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Impact of a social prescribing intervention in North East England on adults with type 2 diabetes: the SPRING_NE multimethod study.

Background: Link worker social prescribing enables health-care professionals to address patients' non-medical needs by linking patients into various services. Evidence for its effectiveness and how it is experienced by link workers and clients is lacking. Objectives: To evaluate the impact and costs of a link worker social prescribing intervention on health and health-care costs and utilisation and to observe link worker delivery and patient engagement. Data sources: Quality Outcomes Framework and Secondary Services Use data. Design: Multimethods comprising (1) quasi-experimental evaluation of effects of social prescribing on health and health-care use, (2) cost-effectiveness analysis, (3) ethnographic methods to explore intervention delivery and receipt, and (4) a supplementary interview study examining intervention impact during the first UK COVID-19 lockdown (April-July 2020). Study population and setting: Community-dwelling adults aged 40-74 years with type 2 diabetes and link workers in a socioeconomically deprived locality of North East England, UK. Intervention: Link worker social prescribing to improve health and well-being-related outcomes among people with long-term conditions. Participants: (1) Health outcomes study, approximately n = 8400 patients; EuroQol-5 Dimensions, five-level version (EQ-5D-5L), study, n = 694 (baseline) and n = 474 (follow-up); (2) ethnography, n = 20 link workers and n = 19 clients; and COVID-19 interviews, n = 14 staff and n = 44 clients. Main outcome measures: The main outcome measures were glycated haemoglobin level (HbA1c; primary outcome), body mass index, blood pressure, cholesterol level, smoking status, health-care costs and utilisation, and EQ-5D-5L score. Results: Intention-to-treat analysis of approximately 8400 patients in 13 intervention and 11 control general practices demonstrated a statistically significant, although not clinically significant, difference in HbA1c level (-1.11 mmol/mol) and a non-statistically significant 1.5-percentage-point reduction in the probability of having high blood pressure, but no statistically significant effects on other outcomes. Health-care cost estimates ranged from £18.22 (individuals with one extra comorbidity) to -£50.35 (individuals with no extra comorbidity). A statistically non-significant shift from unplanned (non-elective and accident and emergency admissions) to planned care (elective and outpatient care) was observed. Subgroup analysis showed more benefit for individuals living in more deprived areas, for the ethnically white and those with fewer comorbidities. The mean cost of the intervention itself was £1345 per participant; the incremental mean health gain was 0.004 quality-adjusted life-years (95% confidence interval -0.022 to 0.029 quality-adjusted life-years); and the incremental cost-effectiveness ratio was £327,250 per quality-adjusted life-year gained. Ethnographic data showed that successfully embedded, holistic social prescribing providing supported linking to navigate social determinants of health was challenging to deliver, but could offer opportunities for improving health and well-being. However, the intervention was heterogeneous and was shaped in unanticipated ways by the delivery context. Pressures to generate referrals and meet targets detracted from face-to-face contact and capacity to address setbacks among those with complex health and social problems. Limitations: The limitations of the study include (1) a reduced sample size because of non-participation of seven general practices; (2) incompleteness and unreliability of some of the Quality and Outcomes Framework data; (3) unavailability of accurate data on intervention intensity and patient comorbidity; (4) reliance on an exploratory analysis with significant sensitivity analysis; and (5) limited perspectives from voluntary, community and social enterprise. Conclusions: This social prescribing model resulted in a small improvement in glycaemic control. Outcome effects varied across different groups and the experience of social prescribing differed depending on client circumstances. Future work: To examine how the NHS Primary Care Network social prescribing is being operationalised; its impact on health outcomes, service use and costs; and its tailoring to different contexts. Trial registration: This trial is registered as ISRCTN13880272. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme, Community Groups and Health Promotion (grant no. 16/122/33) and will be published in full in Public Health Research; Vol. 11, No. 2. See the NIHR Journals Library website for further project information.

Social prescribing happens when health-care staff refer patients to a link worker. Link workers support and help patients to access community services to improve their health and well-being. Social prescribing is popular within the NHS, but there is little evidence that it works. We looked at a social prescribing model being delivered in a disadvantaged area in north-east England.

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin.

PURPOSE: The interpretation of genetic information has always been challenging, but next-generation sequencing produces data on such a vast scale that many more variants of uncertain pathogenicity will be found. We exemplify this issue with reference to human rhodopsin, in which pathogenic mutations can lead to autosomal dominant retinitis pigmentosa. METHODS: Rhodopsin variants, with unknown pathogenicity, were found in patients by next-generation and Sanger sequencing and a multidisciplinary approach was used to determine their functional significance. RESULTS: Four variants in rhodopsin were identified: F45L, P53R, R69H, and M39R, with the latter two substitutions being novel. We investigated the cellular transport and photopigment function of all four human substitutions and found that the F45L and R69H variants behave like wild-type and are highly unlikely to be pathogenic. By contrast, P53R (a de novo change) and M39R were retained in the endoplasmic reticulum with significantly reduced functionality and are clearly pathogenic. CONCLUSION: Potential pathogenicity of variants requires careful assessment using clinical, genetic, and functional data. We suggest that a multidisciplinary pathway of assessment, using several functional assays, will be required if next-generation sequencing is to be used effectively, reliably, and safely in the clinical environment.