LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic ß cells.

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning ß cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and ß cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human ß cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in ß cells to maintain appropriate insulin release.

Oral anticoagulant prescribing among patients with cancer and atrial fibrillation in England, 2009-2019.

BACKGROUND: Anticoagulation of patients with atrial fibrillation (AF) and cancer is challenging because of their high risk for stroke and bleeding. Little is known of the variations of oral anticoagulant (OAC) prescribing in patients with AF with and without cancer. METHODS: Patients with first-time AF during 2009-2019 from the Clinical Practice Research Datalink were included. Cancer diagnosis was defined as a history of breast, prostate, colorectal, lung, or hematological cancer. Competing-risk analysis was used to assess the risk of OAC prescribing in patients with AF and cancer adjusted for clinical and sociodemographic factors. RESULTS: Of 177,065 patients with AF, 11.7% had cancer. Compared to patients without cancer, patients with cancer were less likely to receive OAC: prostate cancer (subhazard ratio [SHR], 0.95; 95% CI, 0.91-0.99), breast cancer (SHR, 0.93; 95% CI, 0.89-0.98), colorectal cancer (SHR, 0.93; 95% CI, 0.88-0.99), hematological cancer (SHR, 0.70; 95% CI, 0.65-0.75), and lung cancer (SHR, 0.44; 95% CI, 0.38-0.50). The cumulative incidence function (CIF) of OAC prescribing was lowest for patients with lung cancer and hematological cancer compared with patients without cancer. The difference between the CIF of OAC prescribing in patients with and without cancer becomes narrower in the most deprived areas. Elderly patients (aged ≥85 years) overall had the lowest CIF of OAC prescribing regardless of cancer status. CONCLUSIONS: In patients with AF, underprescribing of OAC is independently associated with certain cancer types. Patients with hematological and lung cancer are the least likely to receive anticoagulation therapy compared with patients without cancer. Underprescribing of OAC in cancer is linked to old age. Further studies of patients with AF and cancer are warranted to assess the net clinical benefit of anticoagulation in certain cancer types.

Common Cancer Types and Risk of Stroke and Bleeding in Patients With Nonvalvular Atrial Fibrillation: A Population-Based Study in England.

BACKGROUND: The association between cancer and stroke or bleeding outcomes in atrial fibrillation is unclear. We sought to examine how certain types of cancer influence the balance between stroke and bleeding risk in patients with nonvalvular atrial fibrillation (NVAF). METHODS AND RESULTS: We estimated stroke and bleeding risk among adult patients with NVAF and certain types of cancer (breast, prostate, colorectal, lung, and hematological cancer) from 2009 to 2019 based on data from the UK Clinical Practice Research Datalink GOLD and Aurum databases. The control group included patients with NVAF only. Of 177 065 patients with NVAF, 11379 (6.4%) had cancer (1691 breast, 3955 prostate, 1666 colorectal, 2491 hematological, and 1576 lung). Compared with patients without cancer, stroke risk was higher in patients with breast cancer (adjusted hazard ratio [aHR], 1.20 [95% CI, 1.07-1.35) and with prostate cancer (aHR, 1.11 [95% CI, 1.01-1.12) if diagnosed within 6 months before NVAF. The risk of bleeding was increased in subjects with hematological cancer (aHR, 1.55 [95% CI, 1.40-1.71]), lung cancer (aHR, 1.49 [95% CI, 1.25, 1.77]), prostate cancer (aHR, 1.38 [95% CI, 1.28-1.49]), and colorectal cancer (aHR, 1.36 [95% CI, 1.21-1.53]), but not for subjects with breast cancer. The more recent the cancer diagnosis before NVAF diagnosis (within 6 months), the higher the risk of bleeding. CONCLUSIONS: Breast and prostate cancer are associated with increased stroke risk, whereas in some cancer types, the risk of bleeding seemed to exceed stroke risk. In these patients, prescribing of oral anticoagulant should be carefully evaluated to balance bleeding and stroke risk.

Aspergillus in COVID-19 intensive care unit; what is lurking above your head?

Introduction: Through routine respiratory samples surveillance among COVID-19 patients in the intensive care, three patients with aspergillus were identified in a newly opened general intensive care unit during the second wave of the pandemic. Methodology: As no previous cases of aspergillus had occurred since the unit had opened. An urgent multidisciplinary outbreak meeting was held. The possible sources of aspergillus infection were explored. The multidisciplinary approach enabled stakeholders from different skills to discuss possible sources and management strategies. Environmental precipitants like air handling units were considered and the overall clinical practice was reviewed. Settle plates were placed around the unit to identify the source. Reports of recent water leaks were also investigated. Results: Growth of aspergillus on a settle plate was identified the potential source above a nurse's station. This was the site of a historic water leak from the ceiling above, that resolved promptly and was not investigated further. Subsequent investigation above the ceiling tiles found pooling of water and mould due to a slow water leak from a pipe. Conclusion: Water leaks in patient areas should be promptly notified to infection prevention. Detailed investigation to ascertain the actual cause of the leak and ensure any remedial work could be carried out swiftly. Outbreak meetings that include diverse people with various expertises (clinical and non-clinical) can enable prompt identification and resolution of contaminated areas to minimise risk to patients and staff. During challenging pandemic periods hospitals must not lose focus on other clusters and outbreaks occurring simultaneously.

The Biochemical Assessment of Mitochondrial Respiratory Chain Disorders.

Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in both blood and urine and the measurement of lactate, pyruvate and amino acid levels, as well as urine organic acids. Recently, hormone-like cytokines, such as fibroblast growth factor-21 (FGF-21), have also been used as a means of assessing evidence of MRC dysfunction, although work is still required to confirm their diagnostic utility and reliability. The assessment of evidence of oxidative stress may also be an important parameter to consider in the diagnosis of MRC function in view of its association with mitochondrial dysfunction. At present, due to the lack of reliable biomarkers available for assessing evidence of MRC dysfunction, the spectrophotometric determination of MRC enzyme activities in skeletal muscle or tissue from the disease-presenting organ is considered the 'Gold Standard' biochemical method to provide evidence of MRC dysfunction. The purpose of this review is to outline a number of biochemical methods that may provide diagnostic evidence of MRC dysfunction in patients.

Progesterone and Preterm Birth: Using Empirical Research to Explore Structural Racism Within Midwifery-Led Care.

BACKGROUND: Progesterone has been the standard of practice for the prevention of preterm birth for decades. The drug received expedited Food and Drug Administration approval, prior to the robust demonstration of scientific efficacy. METHODS: Prospective research from the American Association of Birth Centers Perinatal Data Registry, 2007-2020. Two-tailed t tests, logistic regression, and propensity score matching were used. RESULTS: Midwifery-led care was underutilized by groups most at risk for preterm birth and was shown to be effective at maintaining low preterm birth rates. The model did not demonstrate reliable access to progesterone. People of color are most at risk of preterm birth, yet were least likely to receiving progesterone treatment. Progesterone was not demonstrated to be effective at decreasing preterm birth when comparing the childbearing people with a history of preterm birth who used the medication and those who did not within this sample. CONCLUSIONS: This study adds to the body of research that demonstrates midwifery-led care and low preterm birth rates. The ineffectiveness of progesterone in the prevention of preterm birth among people at risk was demonstrated.

Mindfulness-based intervention in patients with persistent pain in chest (MIPIC) of non-cardiac cause: a feasibility randomised control study.

OBJECTIVE: The study evaluated the feasibility of mindfulness-based cognitive therapy (MBCT) in patients with non-cardiac chest pain by assessing their willingness to participate and adhere to the programme, and for these data to help further refine the content of MBCT for chest pain. PATIENTS AND METHODS: This prospective 2:1 randomised controlled trial compared the intervention of adapted MBCT as an addition to usual care with just usual care in controls. Among 573 patients who attended the rapid access chest pain clinic over the previous 12 months and were not diagnosed with a cardiac cause but had persistent chest pain were invited. The intervention was a 2-hour, weekly, online guided 8-week MBCT course. Compliance with attendance and the home practice was recorded. Enrolled patients completed the Seattle angina questionnaire (SAQ), Hospital Anxiety and Depression Scale, Cardiac Anxiety Questionnaire, Five-Facet Mindfulness Questionnaire, and Euro Quality of Life-5 Dimensions-5 Level at baseline assessment and after 8-week period. RESULTS: Persistent chest pain was reported by 114 patients. Of these, 33 (29%) patients with a mean age of 54.2 (±12.2) years and 68% women, consented to the study. Baseline questionnaires revealed mild physical limitation (mean SAQ, 76.8±25), high levels of anxiety (76%) and depression (53%), modest cardiac anxiety (CAQ,1.78±0.61) and mindfulness score (FFMQ, 45.5±7.3). Six patients subsequently withdrew due to bereavement, caring responsibilities and ill health. Of the remaining 27 participants, 18 in the intervention arm attended an average of 5 sessions with 61% attending ≥6 sessions. Although not statistically powered, the study revealed a significant reduction in general anxiety, improved mindfulness and a trend towards improvement in SAQ scores in the intervention arm. CONCLUSION: One-third of patients with persistent non-cardiac chest pain were willing to participate in mindfulness-based therapy. An improvement in anxiety and mindfulness was detected in this feasibility study. A larger trial is required to demonstrate improvement in chest pain symptoms.

Experiences of Compassion in Adults With a Diagnosis of Borderline Personality Disorder: An Interpretative Phenomenological Analysis.

The study explored experiences of compassion in adults with a diagnosis of Borderline Personality Disorder (BPD) to further the development of the construct of compassion in relation to BPD. Interpretative Phenomenological Analysis was used to develop themes from the narratives of six adults with a diagnosis of BPD. Five themes emerged: Emotional Connection to Suffering, Empathic Understanding, Prioritisation of Needs, A Model of Genuine Compassion and Developing Acceptance and Worth. Participants described the role of compassion in their difficulties, including the adverse impact of experiences of incompassion upon their sense of self. The themes were integrated into a model that highlighted a process of recovery through therapeutic encounters with others in which genuine compassion was modelled. In addition, barriers to compassion and factors facilitating the development of compassion emerged from the analysis and have implications for clinical practice.

The Second Victim Phenomenon: How Are Midwives Affected?

Perinatal care providers are likely to encounter adverse events such as intrapartum emergencies, traumatic births, or maternal or fetal deaths. As a result of being directly or indirectly involved in an adverse event, health care providers can be considered second victims. The experience of the second victim phenomenon can lead to significant physical, psychological, and psychosocial sequelae that can negatively impact the provider's personal and professional life for either a short or long duration of time. When health care providers experience an adverse event, they may manifest symptoms of guilt, shame, blame, flashbacks, nightmares, insomnia, isolation, helplessness, and hopelessness, thereby becoming the second victim. Following an adverse event, health care providers who experience second victim phenomenon experience stages of recovery that influence subsequent professional and personal well-being. Persons who experience the second victim phenomenon can incorporate self-care behaviors to assist with recovery. Health care organizations have a responsibility to implement efficacious support programs that promote the provider's recovery and a return to safe and full function in the workplace.

Memory, attention and fluency deficits in COPD may be a specific form of cognitive impairment.

There is increasing evidence demonstrating an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. We present a narrative review of published studies on the subject and a cross-sectional study investigating domain-specific cognitive impairment in people with COPD compared to people with known Alzheimer's dementia, and controls without known COPD or cognitive impairment. The aim of the study was to compare prevalence and pattern of cognitive impairment between the three groups using the Addenbrooke's Cognitive Examination (ACE)-III tool. A total of 89 participants were recruited (44 with COPD, 17 with Alzheimer's and 28 controls). Patients with COPD had significantly lower total ACE-III scores than controls (p<0.001). When comparing the COPD group to the known Alzheimer's dementia group, overall ACE-III scores were significantly lower in the Alzheimer's dementia group than the COPD group (p=0.019). The domain-specific scores for attention (p<0.004), memory (p<0.004) and fluency (p<0.001) were significantly lower in the Alzheimer's dementia group than the COPD group. Our result suggest that the COPD group were significantly more likely to have cognitive impairment than the healthy control group. This was supported by the results of a narrative review of the published literature. Our results show that the pattern of impairment in the COPD group is different to the pattern of impairment shown in the known Alzheimer's dementia group, with significant differences in the cognitive domains affected. These results are in keeping with the findings of other previously published studies included in the narrative review.

Data-driven modeling of diabetes care teams using social network analysis.

OBJECTIVE: We assess working relationships and collaborations within and between diabetes health care provider teams using social network analysis and a multi-scale community detection. MATERIALS AND METHODS: Retrospective analysis of claims data from a large employer over 2 years was performed. The study cohort contained 827 patients diagnosed with diabetes. The cohort received care from 2567 and 2541 health care providers in the first and second year, respectively. Social network analysis was used to identify networks of health care providers involved in the care of patients with diabetes. A multi-scale community detection was applied to the network to identify groups of health care providers more densely connected. Social network analysis metrics identified influential providers for the overall network and for each community of providers. RESULTS: Centrality measures identified medical laboratories and mail-order pharmacies as the central providers for the 2 years. Seventy-six percent of the detected communities included primary care physicians, and 97% of the communities included specialists. Pharmacists were detected as central providers in 24% of the communities. DISCUSSION: Social network analysis measures identified the central providers in the network of diabetes health care providers. These providers could be considered as influencers in the network that could enhance the implication of promotion programs through their access to a large number of patients and providers. CONCLUSION: The proposed framework provides multi-scale metrics for assessing care team relationships. These metrics can be used by implementation experts to identify influential providers for care interventions and by health service researchers to determine impact of team relationships on patient outcomes.

Identifying Key Players in the Care Process of Patients with Diabetes Using Social Network Analysis and Administrative Data.

Determining networks of healthcare providers quantitatively can identify impactful care processes that improve health outcomes for a high-risk populations such as elderly people with multiple chronic conditions. By applying social network analysis to health claim data of a large university in the Midwest, we measured healthcare provider networks of patients with diabetes for two consecutive years. Networks were built based on the assumption that having common patients may indicate potential working relationships between providers. Measures of the social network analysis including degree and betweenness centrality were utilized to identify healthcare providers with an important role in the care process. Both degree and betweenness centrality measures identified a supply center and three laboratories as the central providers of the network for both years. This study can positively impact informed decision-making of policymakers and insurance companies to better design their insurance coverage plans based on the collaboration patterns of the healthcare providers.

Impact of an Onsite Clinic on Utilization of Preventive Services.

OBJECTIVE: To assess impact of an onsite clinic on healthcare utilization of preventive services for employees of a public university and their dependents. METHOD: Descriptive statistics, logistic regression and classification tree techniques were used to assess health claim data to identify changes in patterns of healthcare utilization and factors impacting usage of onsite clinic. RESULT: Utilization of preventive services significantly increased for women and men employees by 9% and 14% one year after implementation of the onsite clinic. Hourly-paid employees, employees without diabetes, employees with spouse opt out or no coverage were more likely to go to the onsite clinic. CONCLUSION: Adapted framework for assessing performance of onsite clinics based on usage of health informatics would help to identify health utilization patterns and interaction between onsite clinic and offsite health providers.

Validation of a Prediction Tool for Abusive Head Trauma.

BACKGROUND AND OBJECTIVES: Abusive head trauma (AHT) may be missed in the clinical setting. Clinical prediction tools are used to reduce variability in practice and inform decision-making. From a systematic review and individual patient data analysis we derived the Predicting Abusive Head Trauma (PredAHT) tool, using multilevel logistic regression to predict likelihood of AHT. This study aims to externally validate the PredAHT tool. METHODS: Consecutive children aged <36 months admitted with an intracranial injury, confirmed as abusive or nonabusive, to 2 sites used in the original model were ascertained. Details of 6 influential features were recorded (retinal hemorrhage, rib and long -bone fractures, apnea, seizures, and head or neck bruising). We estimated the likelihood of an unrecorded feature being present with multiple imputation; analysis included sensitivity, specificity, and area under the curve, with 95% confidence intervals (CIs). RESULTS: Data included 133 non-AHT cases and 65 AHT cases, 97% of children were <24 months old. Consistent with original predictions, when ≥3 features were present in a child <36 months old with intracranial injury, the estimated probability of AHT was >81.5% (95% CI, 63.3-91.8). The sensitivity of the tool was 72.3% (95% CI, 60.4-81.7), the specificity was 85.7% (95% CI, 78.8-90.7), area under the curve 0.88 (95% CI, 0.823-0.926). CONCLUSIONS: When tested on novel data, the PredAHT tool performed well. This tool has the potential to contribute to decision-making in these challenging cases. An implementation study is needed to explore its performance and utility within the child protection process.

Conserved expression of truncated telethonin in a patient with limb-girdle muscular dystrophy 2G.

Limb-girdle muscular dystrophy 2G is caused by mutations in the TCAP gene that encodes for telethonin. Here we describe a 49 year-old male patient of Indian descent presenting a classical LGMD phenotype. He had normal motor milestones but became noticeably slower in his early teens and was wheelchair bound by age 44. The muscle biopsy showed myopathic features and absence of labeling with an antibody to the C-terminal portion of telethonin. Sequence analysis of the TCAP gene revealed a novel homozygous mutation in exon 2, predicted to generate a truncated protein of 81 amino acids. Interestingly, an antibody for the full-length protein showed labeling on sections and a single band of ~10 kDa on Western blot. The truncated protein co-localized with filamin C at the Z-line. Our findings indicate that mutant telethonin can be incorporated into the sarcomere and that other LGMD2G patients with retention of telethonin expression may exist.

A new monoclonal antibody DAG-6F4 against human alpha-dystroglycan reveals reduced core protein in some, but not all, dystroglycanopathy patients.

We generated a novel monoclonal antibody, DAG-6F4, against alpha-dystroglycan which immunolabels the sarcolemma in human muscle biopsies. Its seven amino-acid epitope, PNQRPEL, was identified using phage-displayed peptides and is located immediately after the highly-glycosylated mucin domain of alpha-dystroglycan. On Western blots of recombinant alpha-dystroglycan, epitope accessibility was reduced, but not entirely prevented, by glycosylation. DAG-6F4 immunolabelling was markedly reduced in muscle biopsies from Duchenne muscular dystrophy patients consistent with disruption of the dystroglycan complex. In a range of dystroglycanopathy patients with reduced/altered glycosylation, staining by DAG-6F4 was often less reduced than staining by IIH6 (antibody against the glycan epitope added by LARGE and commonly used to identify glycosylated alpha-dystroglycan). Whereas IIH6 was reduced in all patients, DAG-6F4 was hardly changed in a LARGE patient, less reduced than IIH6 in limb-girdle muscular dystrophy type 2I, but as reduced as IIH6 in some congenital muscular dystrophy patients. Although absence of the LARGE-dependent laminin-binding site appears not to affect alpha-dystroglycan stability at the sarcolemma, the results suggest that further reduction in aDG glycosylation may reduce its stability. These studies suggest that DAG-6F4 may be a useful addition to the antibody repertoire for evaluating the dystroglycan complex in neuromuscular disorders.

Emotion and self-cutting: narratives of service users referred to a personality disorder service.

Theory and existing research suggest that emotion regulation capabilities develop during the formative years. Emotion dysregulation is associated with psychological distress and may contribute towards difficulties such as personality disorder and self-harm. This study aimed to explore the contexts in which individuals' narratives of emotional experience and self-harm developed. Eight participants who cut themselves and were seen by a personality disorder service were recruited. Semi-structured interviews were carried out, and interview transcripts were analysed using a narrative approach. Five temporal themes were generated: 'Seen and not heard', 'A big release … to get rid of all the pain and hurt', 'A vicious circle', 'A different world' and 'Trying to turn my life around'. The findings highlight how early experiences may have led participants to perceive emotions as unacceptable and subsequently suppress emotion in adulthood. Suppression of emotions appeared to be related to appraisals of emotions and to secondary emotional distress. Furthermore, cutting was linked to suppression of emotions as well as negative self-beliefs formed during childhood and reinforced through subsequent experiences. The study emphasizes the need for therapeutic approaches to focus on emotions when working with individuals who self-cut. Furthermore, the findings indicate the need for compassionate and validating health services that may help service users develop more optimistic future narratives.

Is contact with adult mental health services helpful for individuals with a diagnosable BPD? A study of service users views in the UK.

BACKGROUND: Previous research in the UK has suggested that individuals with a diagnosable borderline personality disorder (BPD) have often found contact with adult mental health services unhelpful. In 2003, UK government guidance outlined how services might address this issue. Since this guidance, there has been little research that seeks to understand services users' experiences of services and provide information about how services might improve. AIMS: To explore the experiences of individuals with a diagnosis of BPD in accessing adult mental health services and to better understand which aspects of contact with services can be helpful or unhelpful. METHODS: Nine service users with a diagnosable BPD were recruited through voluntary sector services in England. Semi-structured interviews were used and interview data was analysed using an inductive thematic analysis. RESULTS: Three themes were generated including "The diagnostic process influences how service users feel about BPD", "Non-caring care" and "It's all about the relationship". CONCLUSION: The participants' accounts identify a number of practical points which services could implement to improve the experiences of service users.

Cultivating positive emotions: a useful adjunct when working with people who self-harm?

UNLABELLED: This narrative review draws upon a broad range of literature, including theory and empirical research, to argue that positive emotions are a useful adjunct to therapy when working with individuals who self-harm. The review highlights how self-harm is often employed as a method of emotion regulation and may be both negatively and positively reinforced. It is suggested that individuals who self-harm have potential difficulty in experiencing positive and negative emotions. The compatibility of an emotion focused approach to therapy for individuals who self-harm is therefore deemed an appropriate one. However, current therapeutic models predominantly focus on unpleasant or negative emotions and largely tend to neglect positive emotions, such as happiness. Broaden and build theory indicates that positive emotions can reduce the effects of negative emotions and aid recovery from intolerable negative emotions that may underpin self-harming behaviours. Therefore, the incorporation of positive emotions into therapy is likely to be helpful. In addition, if cultivated over time, positive emotions can build resilience that may enable individuals to cope better with events that precipitate self-injurious behaviours. The review emphasizes how positive emotions represent a valuable addition to therapeutic work but also highlights that the negatively valenced and painful emotions often experienced by those who self-injure must still be addressed. KEY PRACTITIONER MESSAGE: When working with individuals who self-harm it may be beneficial for practitioners to consider clients' experiences of positive emotions, and how to cultivate these, in addition to targeting the negative emotions which tend to underpin self-harming behaviours.

Origin of trisomy: no evidence to support the ovarian mosaicism theory.

OBJECTIVE: Trisomy is the most common type of chromosome abnormality, affecting 4% of clinically recognised pregnancies, of which, trisomies 16, 21 and 22 are the most prevalent. It has been suggested that a large proportion of maternally derived trisomic pregnancies, specifically trisomy 21, are the result of low-level ovarian mosaicism. In this study, we aimed to reproduce these previously published results on trisomy 21 and investigate the other common maternally derived trisomies (i.e. trisomies 16 and 22) by determining chromosome copy number in fetal ovarian and control skin cells. METHODS: Ovarian and control skin tissue was collected from eight karyotypically normal female fetuses of between 10 and 14 weeks gestation, which were terminated for social reasons. Tissues were dissociated and fluorescence in situ hybridisation was performed with break-apart probes: CBFß (16q22), RUNX1 (21q22) and EWSR1 (22q12). RESULTS: A small number of trisomic cells, 13 out of 51,146 cells examined (0.025%), were identified in both ovarian and control skin samples. Only three of these trisomic cells were present in the fetal ovarian tissue. CONCLUSION: This study found no evidence of fetal ovarian mosaicism for trisomies 16, 21 and 22.