3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7

Background Online consultations (OCs) allow patients to contact their care providers on the web. Worldwide, OCs have been rolled out in primary care rapidly owing to policy initiatives and COVID-19. There is a lack of evidence regarding how OC design and implementation influence care quality. Objective We aimed to synthesize research on the impacts of OCs on primary care quality, and how these are influenced by system design and implementation. Methods We searched databases from January 2010 to February 2022. We included quantitative and qualitative studies of real-world OC use in primary care. Quantitative data were transformed into qualitative themes. We used thematic synthesis informed by the Institute of Medicine domains of health care quality, and framework analysis informed by the nonadoption, abandonment, scale-up, spread, and sustainability framework. Strength of evidence was judged using the GRADE-CERQual approach. Results We synthesized 63 studies from 9 countries covering 31 OC systems, 14 (22%) of which used artificial intelligence; 41% (26/63) of studies were published from 2020 onward, and 17% (11/63) were published after the COVID-19 pandemic. There was no quantitative evidence for negative impacts of OCs on patient safety, and qualitative studies suggested varied perceptions of their safety. Some participants believed OCs improved safety, particularly when patients could describe their queries using free text. Staff workload decreased when sufficient resources were allocated to implement OCs and patients used them for simple problems or could describe their queries using free text. Staff workload increased when OCs were not integrated with other software or organizational workflows and patients used them for complex queries. OC systems that required patients to describe their queries using multiple-choice questionnaires increased workload for patients and staff. Health costs decreased when patients used OCs for simple queries and increased when patients used them for complex queries. Patients using OCs were more likely to be female, younger, and native speakers, with higher socioeconomic status. OCs increased primary care access for patients with mental health conditions, verbal communication difficulties, and barriers to attending in-person appointments. Access also increased by providing a timely response to patients’ queries. Patient satisfaction increased when using OCs owing to better primary care access, although it decreased when using multiple-choice questionnaire formats. Conclusions This is the first theoretically informed synthesis of research on OCs in primary care and includes studies conducted during the COVID-19 pandemic. It contributes new knowledge that, in addition to having positive impacts on care quality such as increased access, OCs also have negative impacts such as increased workload. Negative impacts can be mitigated through appropriate OC system design (eg, free text format), incorporation of advanced technologies (eg, artificial intelligence), and integration into technical infrastructure (eg, software) and organizational workflows (eg, timely responses). Trial Registration PROSPERO CRD42020191802; https://tinyurl.com/2p84ezjy

3-M syndrome is an autosomal recessive disorder characterised by pre- and post-natal growth restriction, facial dysmorphism, normal intelligence and radiological features (slender long bones and tall vertebral bodies). It is known to be caused by mutations in the genes encoding cullin 7, obscurin-like 1 and coiled-coil domain containing 8. The mechanisms through which mutations in these genes impair growth are unclear. The aim of this study was to identify novel pathways involved in the growth impairment in 3-M syndrome. RNA was extracted from fibroblast cell lines derived from four 3-M syndrome patients and three control subjects, hybridised to Affymetrix HU 133 plus 2.0 arrays with quantitative real-time PCR used to confirm changes found on microarray. IGF-II protein levels in conditioned cell culture media were measured by ELISA. Of the top 10 downregulated probesets, three represented IGF2 while H19 was identified as the 23rd most upregulated probeset. QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001). Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01). 3-M syndrome is associated with a gene expression profile of reduced IGF2 expression and increased H19 expression similar to that found in Silver–Russell syndrome. Loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M syndrome.

BackgroundIn people with COVID-19, hypoxia at the time of admission is known to be related to mortality. Monitoring of oxygen saturations (SpO2) is therefore an increasingly common part of community-based care, with the aim of improving the identification of adults who are deteriorating. We set out to investigate whether rigid SpO2 triggers, or absolute change in SpO2, is more indicative of deterioration in COVID-19.MethodsA prospective, uncontrolled, open-label study in a large UK general practice was conducted between May and November 2020. Participants recorded twice daily oximetry and symptom diary for 14 days after test-confirmed COVID-19. Primary outcomes were the proportion of people whose SpO2 dropped to ≤ 94% and ≤ 92%, the average maximum reduction in SpO2, and admission to hospital. We also investigated the relationship between MRC Dyspnoea scale, modified Roth score, and SpO2 through correlation analyses.Results52 participants were recruited, following which 41 participants completed the study. The average age was 45.9 years with 63.4% identifying as female. The mean maximum reduction in SpO2 was 2.8%. The average time to maximum reduction in SpO2 was 6.4 days. Nine participants (22.0%) had a reduction in SpO2 to ≤94%. Three of these had a reduction in SpO2 to ≤92%, for which all three were admitted to hospital. Modified Roth score and SpO2 were weakly positively correlated (.31). MRC dyspnoea scale score and SpO2 were moderately negatively correlated (-.53).ConclusionsA reduction in SpO2 to ≤92% was found to be highly predictive for admission to hospital. Modified Roth score or MRC dyspnoea scale scores should not be used as proxy measures for oximetry. This study contributes to the ongoing narrative around community-based oximetry and provides insight and recommendations for those currently engaging in or planning to roll out similar schemes.Strengths and limitations of this studyThis study is pragmatically designed to answer an important clinical question in primary care.This study focused on previously published values of SpO2 for triggering escalation of care and therefore provides answers based on current clinical practice.11 of the 52 patients who were recruited into the study did not return their oximeter or oximetry diary at the end of the study period.We did not validate the accuracy or reliability of the oximetry / symptom diaries, as these were self-completed by the participants themselves.Other than admission to hospital and mortality within the study period, no other clinical outcomes have been recorded.Funding statementThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.Competing interestsJane Wilcock has no competing interests to declare.Ciaran Grafton-Clarke has no competing interests to declare.Tessa Coulson has no competing interests to declare.

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