Two Brothers from Macedonia with Gitelman Syndrome.

Gitelman syndrome (GS) is a rare renal tubulopathy with an autosomal recessive mode of inheritance, caused by biallelic pathogenic variants in the SLC12A3 gene. The clinical features may overlap with other disorders, such as Bartter syndrome type 3, HNF1B nephropathy or even mitochondrial disease, but can be distinguished by molecular genetic analysis. Here we report on two preschool brothers, who presented with a several months' history of episodes of carpopedal spasms and muscle aches. The biochemical analyses revealed hypokalemia and hypomagnesemia without metabolic alkalosis. A 24-h urine sample demonstrated hypocalciuria. The molecular analyses showed that both patients were heterozygous for 3 (likely) pathogenic variants in SLC12A3: c.1805_1806del; p. (Tyr602Cysfs*31), c.2660+1G>A and c.2944 A>T; p. (Ile982Phe). Analysis of the parents showed that the mother was heterozygous for the c.2944 A>T p.(Ile982Phe) variant, and the father carried the other 2 variants (c.1805_1806del and c.2660+1G>A). Herein we present two children in a family from N. Macedonia with clinical manifestations and electrolyte imbalances suggestive of GS. The results of the tubulopathy next generation sequencing (NGS) panel confirmed the diagnosis. The boys are treated with a high salt diet and oral potassium and magnesium supplements.

Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

Understanding the impact of an intergenerational arts and health project: a study into the psychological well-being of participants, carers and artists.

OBJECTIVES: There is growing interest in arts practices in relation to public health, including their potential to support psychological well-being. This study sought to understand the impact of Hear and Now, an intergenerational arts and health project, upon indicators of psychological well-being among all groups involved: young people, older people with a diagnosis of dementia and their carers and partners and the project's artistic team. STUDY DESIGN: This was a descriptive exploratory qualitative study, using focus groups and observation as data collection methods. METHODS: Study participants were 65 people representing the four groups participating in the 2019 Hear and Now project: older adults living with a diagnosis of dementia, their carers and partners, young people and a team of professional artists and facilitators. Of these, 27 participated in one or more of seven focus groups. Participants were asked about their previous engagement with music and dance, thoughts about the intergenerational element of the project and other aspects of their experiences that related to indicators of well-being. In order to investigate the project's impact on participants' well-being, Seligman's PERMA model was adopted, which sets out five indicators of well-being: positive emotions, engagement, positive relationships, meaning and achievement/accomplishment. RESULTS: Experiences relating to all five areas of the PERMA model were evidenced by all groups in relation to their involvement in the project. Additional health benefits were also cited by some, as well as enhanced perceptions of other members of the project cohort. CONCLUSIONS: The findings support existing literature that intergenerational and arts activities can be beneficial for individuals' psychological health. Experiences relating to all five dimensions of the PERMA model of well-being (positive emotion, engagement, positive relationships, meaning, achievement/accomplishment) were cited by the four participant groups, which suggests examining the impact of such projects on all project collaborators is worthy of further study. Understanding the impact these projects can have on the various groups involved will enable artistic and healthcare communities to better collaborate and value each other's practices.

Delivering remote consultations: Talking the talk.

INTRODUCTION: There is an increasing affinity for remote health consultations (including telephone and virtual platforms), enabling new models of accessing services to evolve. Whilst many key skills are transferable from traditional to remote consultations, there is even greater emphasis on verbal communication skills during these interactions. PURPOSE: This masterclass considers the communication skills required for delivering remote health care consultations, in particular focussing on: 12 interactional features in an opening sequence of a remote call; active listening; how to offer advice using the Ask-Offer-Ask framework; and subtleties in phrasing and prosody when closing a call that may indicate a level of satisfaction (or otherwise). IMPLICATIONS: In planning for digitally-enabled services to become mainstream, the differences in communication between remote and face-to-face consultations must be recognised and embraced.

Appropriateness of computed tomography and magnetic resonance imaging scans in a rural regional hospital in South Africa: A 6-year follow-up study.

BACKGROUND: Requests for computed tomography (CT) and magnetic resonance imaging (MRI) scans by doctors with different levels of experience have cost and risk implications globally. Evidence-based appropriateness criteria guide doctors to the suitable use of radiology imaging. There are few studies regarding appropriateness of CT requests in the South African (SA) context. Previous research in the Garden Route district of Western Cape Province, SA, evaluated the appropriateness of scans. OBJECTIVES: To review the appropriateness of CT and MRI scans done in a 6-year follow-up study at one facility. METHODS: This was a retrospective descriptive study. All CT and MRI scans performed during October 2018 at George Hospital were classified according to American College of Radiology guidelines as: usually appropriate (UA), might be appropriate (MBA), or not appropriate (NA). Stratified analysis allowed simple statistics and some comparison with the previous study. RESULTS: A total of 515 CT and MRI scans were included, of which 81.4% were UA, 7.4% MBA and 11.2% NA. Most scans were requested by medical officers (n=255), followed by consultants (n=126) and junior doctors (n=70). Medical officers made the majority of inappropriate requests. Second-year interns requested the lowest number of inappropriate scans, with registrars not requesting any inappropriate scans. Most of the inappropriate scans were requested after hours. Thirty-seven of the 123 (30.1%) after-hours scans were inappropriately requested compared with 21 of 392 (5.4%) scans during normal working hours, which were inappropriate. CONCLUSIONS: Although the majority of scans were being ordered appropriately, pre-authorisation by experienced physicians and incorporation of guidelines would make requests more complete and possibly more appropriate, especially after hours.

Tuberculosis infection control in a South African rural regional hospital emergency centre: Prioritisation for patients and healthcare workers.

South Africa (SA) is in the midst of a tuberculosis (TB) epidemic and has one of the highest TB incidence rates globally. Despite increasing global commitment to eliminate TB, SA appears to be falling behind in this regard. This article examines key challenges to effective TB infection control from a rural regional hospital perspective. It uses the Eden District in Western Cape Province as an example to share lessons learnt. This quality-improvement project identifies four priorities for improving TB infection control in George Hospital and the Eden District: (i) prioritising TB infection control in local policy; (ii) improving the quality of TB screening in the emergency centre; (iii) increasing the number of TB patients followed up; and (iv) implementing TB infection control training for all staff. This project demonstrates the role of an emergency centre in TB screening, highlighting that this should not only be a priority for primary care, but also for secondary and tertiary care. Simple interventions, such as training of local healthcare workers in TB infection control and good-quality TB screening, can initiate a behavioural change. It also stresses the importance of good communication and co-ordination of care across primary and secondary care, ensuring that patients are not lost to follow-up. Local policy needs to reflect these straightforward interventions, empowering local healthcare workers and managers to increase responsibility and accountability for TB infection control.TB is preventable, and infection control needs to become a priority throughout SA primary, secondary and tertiary care. This project highlights that simple interventions, such as engaging local healthcare workers in a co-ordinated multisystem and multidisciplinary approach, could help to reduce the number of missing TB cases and bring SA's TB epidemic under control.

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.

Antimicrobial stewardship in a rural regional hospital - growing a positive culture.

Antimicrobial stewardship programmes have been introduced worldwide in response to the rise in antimicrobial resistance. The World Health Organization has mandated each Member State to produce a plan to address this problem. We report on the organic development of an antibiotic stewardship programme in a rural regional hospital in a resource-limited setting in South Africa. This has resulted in organisational change with increased awareness, participation, monitoring and education in antibiotic stewardship throughout the hospital.

Considering sex differences clarifies the effects of depression on facial emotion processing during fMRI.

BACKGROUND: Sex differences in emotion processing may play a role in women's increased risk for Major Depressive Disorder (MDD). However, studies of sex differences in brain mechanisms involved in emotion processing in MDD (or interactions of sex and diagnosis) are sparse. METHODS: We conducted an event-related fMRI study examining the interactive and distinct effects of sex and MDD on neural activity during a facial emotion perception task. To minimize effects of current affective state and cumulative disease burden, we studied participants with remitted MDD (rMDD) who were early in the course of the illness. In total, 88 individuals aged 18-23 participated, including 48 with rMDD (32 female) and 40 healthy controls (HC; 25 female). RESULTS: fMRI revealed an interaction between sex and diagnosis for sad and neutral facial expressions in the superior frontal gyrus and left middle temporal gyrus. Results also revealed an interaction of sex with diagnosis in the amygdala. LIMITATIONS: Data was from two sites, which might increase variability, but it also increases power to examine sex by diagnosis interactions. CONCLUSIONS: This study demonstrates the importance of taking sex differences into account when examining potential trait (or scar) mechanisms that could be useful in identifying individuals at-risk for MDD as well as for evaluating potential therapeutic innovations.

Linear rheology as a potential monitoring tool for sputum in patients with Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: The rheological properties of sputum may influence lung function and become modified in disease. OBJECTIVE: This study aimed to correlate the viscoelastic properties of sputum with clinical data on the severity of disease in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sputum samples from COPD patients were investigated using rheology, simple mathematical modelling and Scanning Electron Microscopy (SEM). The samples were all collected from patients within two days of their admission to Prince Philip Hospital due to an exacerbation of their COPD. Oscillatory and creep rheological techniques were used to measure changes in viscoelastic properties at different frequencies over time. RESULTS: COPD sputum was observed to behave as a viscoelastic solid at all frequencies studied. Comparing the rheology of exacerbated COPD sputum with healthy sputum (not diagnosed with a respiratory disease) revealed significant differences in response to oscillatory shear and creep-recovery experiments, which highlights the potential clinical benefits of better understanding sputum viscoelasticity. A common power law model G(t)=G0(tτ0)-m was successfully fitted to experimental rheology data over the range of frequencies studied. CONCLUSIONS: A comparison between clinical data and the power law index m obtained from rheology, suggested that an important possible future application of this parameter is as a potential biomarker for COPD severity.

Commissioning for health improvement following the 2012 health and social care reforms in England: what has changed?

BACKGROUND: The wide-ranging program of reforms brought about by the Health and Social Care Act (2012) in England fundamentally changed the operation of the public health system, moving responsibility for the commissioning and delivery of services from the National Health Service to locally elected councils and a new national public health agency. This paper explores the ways in which the reforms have altered public health commissioning. METHODS: We conducted multi-methods research over 33 months, incorporating national surveys of Directors of Public Health and local council elected members at two time-points, and in-depth case studies in five purposively selected geographical areas. RESULTS: Public health commissioning responsibilities have changed and become more fragmented, being split amongst a range of different organisations, most of which were newly created in 2013. There is much change in the way public health commissioning is done, in who is doing it, and in what is commissioned, since the reforms. There is wider consultation on decisions in the local council setting than in the NHS, and elected members now have a strong influence on public health prioritisation. There is more (and different) scrutiny being applied to public health contracts, and most councils have embarked on wide-ranging changes to the health improvement services they commission. Public health money is being used in different ways as councils are adapting to increasing financial constraint. CONCLUSIONS: Our findings suggest that, while some of the intended opportunities to improve population health and create a more joined-up system with clearer leadership have been achieved, fragmentation, dispersed decision-making and uncertainties regarding funding remain significant challenges. There have been profound changes in commissioning processes, with consequences for what health improvement services are ultimately commissioned. Time (and further research) will tell if any of these changes lead to improved population health outcomes and reduced health inequalities, but many of the opportunities brought about by the reforms are threatened by the continued flux in the system.

Binding of two bacterial biofilms to dialkyl carbamoyl chloride (DACC)-coated dressings in vitro.

OBJECTIVE: To date only planktonic bacteria have been shown to bind irreversibly to dialkyl carbamoyl chloride (DACC)-coated Cutimed Sorbact dressings. Therefore, this study was designed to determine whether bacterial biofilm bound to the DACC-coated dressing in vitro. METHOD: Samples of DACC-coated dressings and uncoated control dressings (supplied by BSN medical Ltd, Hull) were placed in contact with plastic coverslips on which biofilms of either Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus (MRSA) had been cultivated for 24 hours. Dressing samples were examined by scanning electron microscopy to detect the presence of biofilm. RESULTS: Pseudomonas aeruginosa biofilm bound avidly to both DACC-coated and uncoated dressing samples. MRSA bound more extensively to DACC-coated dressings than to uncoated samples. CONCLUSION: Biofilms of two different test bacteria bound to dressings in vitro with the DACC-coating on the dressings enhancing the binding of MRSA biofilm. DECLARATION OF INTEREST: This study was supported by BSN medical Ltd (Hull). The company had no influence on the experimental design or the interpretation of the results.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Efficacy and long-term outcomes of palivizumab prophylaxis to prevent respiratory syncytial virus infection in infants with cystic fibrosis in Northern Ireland.

BACKGROUND: RSV causes considerable morbidity and mortality in children. In cystic fibrosis (CF) viral infections are associated with worsening respiratory symptoms and bacterial colonization. Palivizumab is effective in reducing RSV hospitalization in high risk patient groups. Evidence regarding its effectiveness and safety in CF is inconclusive. CF screening in N. Ireland enabled timely palivizumab prophylaxis, becoming routine in 2002. OBJECTIVES: To determine the effect of palivizumab on RSV-related hospitalization and compare lung function and bacterial colonization at age 6 years for those born pre- and post-introduction of palivizumab prophylaxis. METHODS: A retrospective audit was conducted for all patients diagnosed with CF during the period from 1997 to 2007 inclusive. RSV-related hospitalization, time to Pseudomonas aeruginosa (PA) 1st isolate, lung function and growth parameters were recorded. Comparisons were made for outcomes pre- and post-introduction of routine palivizumab administration in 2002. A cost evaluation was also performed. RESULTS: Ninety-two children were included; 47 pre- and 45 post-palivizumab introduction. The overall RSV-positive hospitalization rate was 13%. The relative risk of RSV infection in palivizumab non-recipients versus recipients was 4.78 (95%CI: 1.1-20.7), P = 0.027. Notably, PA 1st isolate was significantly earlier in the palivizumab recipient cohort versus non-recipient cohort (median 57 vs. 96 months, P < 0.025) with a relative risk of 2.5. Chronic PA infection at 6 years remained low in both groups, with similar lung function and growth parameters. Total costs were calculated at £96,127 ($151,880) for the non-recipient cohort versus £137,954 ($217,967) for the recipient cohort. CONCLUSION: Palivizumab was effective in reducing RSV-related hospitalization infection in CF patients. Surprisingly, we found a significantly earlier time to 1st isolate of PA in palivizumab recipients which we could not explain by altered or improved diagnostic tests.

Integration, influence and change in public health: findings from a survey of Directors of Public Health in England.

BACKGROUND: Following the Health and Social Care Act in England, public health teams were formally transferred from the NHS to local authorities in April 2013. METHODS: Online survey of Directors of Public Health (DsPH) in local authorities in England (n = 152) to investigate their experience within local government 1 year on. Tests of association were used to explore relationships between the perceived integration and influence of public health, and changes in how the public health budget was being spent. RESULTS: The organization of and managerial arrangements for public health within councils varied. Most DsPH felt that good relationships had been established within the council, and the move had made them more able to influence priorities for health improvement, even though most felt their influence was limited. Changes in commissioning using the public health budget were already widespread and included the de-commissioning of services. CONCLUSIONS: There was a widespread feeling amongst DsPH that they had greater influence since the reforms, and that this went across the local authority and beyond. Public health's influence was most apparent when the transfer of staff to local government had gone well, when collaborative working relationships had developed, and when local partnership groups were seen as being effective.

Safety and efficacy of a new device for inducing ejaculation in men with spinal cord injuries.

STUDY DESIGN: Prospective case series. OBJECTIVES: Male infertility is a common sequela of spinal cord injury (SCI). Fatherhood is a goal in this group of young patients; however, most are anejaculatory. Penile vibratory stimulation is recommended as the first line of treatment for this condition. Our study evaluated the safety and efficacy of a new device designed to induce ejaculation in these patients. SETTING: The Miami Project to Cure Paralysis, Miami, FL, USA. METHODS: The Viberect-X3 (Reflexonic, Frederick, MD, USA) was applied to 30 consecutive anejaculatory men with SCI whose level of injury was T10 and rostral. RESULTS: The ejaculatory success was 77% (23/30). No adverse events occurred, and there were no malfunctions of the device. CONCLUSION: In this first report on the efficacy of the Viberect-X3 for treatment of anejaculation in men with SCI, we conclude that the device is safe and effective for inducing ejaculation in men with SCI. Recommendation of the Viberect-X3 versus other devices intended for this purpose should not be made until randomized controlled trials are performed.

Inhibition of biofilms of Pseudomonas aeruginosa by Medihoney in vitro.

OBJECTIVE: Pseudomonas aeruginosa has been linked to chronic wound infections, where its ability to form biofilms and to tolerate antimicrobial agents helps to facilitate its persistence. This study aimed to investigate the susceptibility of biofilms of Pseudomonas aeruginosa to Medihoney in vitro. METHOD: Biofilms were cultivated in microtitre plates with and without a range of concentrations of Medihoney, and effects on biofilm were monitored by optical density (at 650nm), biomass (by staining with crystal violet), metabolic activity (using an esterase assay) and viability (by determining total cell counts). Structural effects on established biofilms were examined by scanning electron microscopy and epifluorescence following staining by LIVE/DEAD® BacLight, which also showed effects on vitality. RESULTS: The lowest concentration of Medihoney found to prevent biofilm formation was 17%(w/v), whereas on average 35.5%(w/v) of Medihoney was required to inhibit established biofilms. Susceptibility did not vary with length of biofilm establishment between 24 and 72 hours. Extensive structural changes in established biofilms were seen in the sample with less than or equal to 30%(w/v) Medihoney using scanning electron microscopy and loss of viability was found in test samples with less than or equal to 20%(w/v) Medihoney concentration using fluorescent staining, together with loss of biofilm structure. CONCLUSION: Using a range of methods to evaluate biofilm integrity, this study demonstrates that Medihoney inhibits Pseudomonas aeruginosa biofilms in vitro at concentrations that are attainable in clinical use. Whether Medihoney has the potential to disrupt Pseudomonas aeruginosa biofilms in cutaneous wounds must now be tested in patients. DECLARATION OF INTEREST: This study was sponsored by Derma Sciences Inc, NJ. An unrestricted grant was provided and the sponsors were not involved in the design of the experiments or the preparation of this manuscript.