Analysis of drug resistance among difficult-to-treat tuberculosis patients in Ghana identifies several pre-XDR TB cases

BACKGROUND: Resistance to tuberculosis (TB) drugs has become a major threat to global control efforts. Early case detection and drug susceptibility profiling of the infecting bacteria are essential for appropriate case management. The objective of this study was to determine the drug susceptibility profiles of difficult-to-treat (DTT) TB patients in Ghana. METHODS: Sputum samples obtained from DTT-TB cases from health facilities across Ghana were processed for rapid diagnosis and detection of drug resistance using the Genotype MTBDRplus and Genotype MTBDRsl.v2 from Hain Life science. RESULTS: A total of 298 (90%) out of 331 sputum samples processed gave interpretable bands out of which 175 (58.7%) were resistant to at least one drug (ANY(r)); 16.8% (50/298) were isoniazid-mono-resistant (INH(r)), 16.8% (50/298) were rifampicin-mono-resistant (RIF(r)), and 25.2% (75/298) were MDR. 24 (13.7%) of the ANY(r) were additionally resistant to at least one second line drug: 7.4% (2 RIF(r), 1 INH(r), and 10 MDR samples) resistant to only FQs and 2.3% (2 RIF(r), 1 INH(r), and 1 MDR samples) resistant to AMG drugs kanamycin (KAN), amikacin (AMK), capreomycin (CAP), and viomycin (VIO). Additionally, there were 4.0% (5 RIF(r) and 2 MDR samples) resistant to both FQs and AMGs. 81 (65.6%) out of 125 INH-resistant samples including INH(r) and MDR had katG-mutations (MT) whereas 15 (12%) had inhApro-MT. The remaining 28 (22.4%) had both katG and inhA MT. All the 19 FQ-resistant samples were gyrA mutants whereas the 10 AMGs were rrs (3), eis (3) as well as rrs, and eis co-mutants (4). Except for the seven pre-XDR samples, no sample had eis MT. CONCLUSION: The detection of several pre-XDR TB cases in Ghana calls for intensified drug resistance surveillance and monitoring of TB patients to, respectively, ensure early diagnosis and treatment compliance

Patient and public involvement in health literacy interventions: a mapping review

Background: Health literacy is a critical mediating factor that impacts on the health of older adults. Patient and public involvement in health and social care research, policy and design of care delivery is one mechanism that can promote production of better health literacy. This mapping review looks for and describes practices, concepts and methods that have been reported involving patients, public and (non-researcher) professionals in the development and design of health literacy interventions for older people. Methods: Studies that aimed to improve health literacy were identified within a previously created compatible inventory of health behaviour studies for older people. Articles were screened for whether they addressed health literacy and featured involvement of stakeholders other than investigators and patients. Two reviewers independently read each study to identify any patient, public and professional involvement in the research process. We also noted some aspects of outcomes. Results: Twenty-two studies included patient, public and/or professional involvement in at least one research domain: design, management or evaluation. Involvement included volunteers, older people, professionals, patients, and community representatives. All studies were driven by an organisational or biomedical agenda. Conclusions: Patient, public and professional involvement wasrarely reported in studies on health literacy interventions for older people. This could help explain why some interventions fail to improve health literacy in older people. Key words – health literacy intervention research, older people, patient and public involvement, mapping revie

Who wants to be involved in health care decisions? Comparing preferences for individual and collective involvement in England and Sweden

Background: Patient and public involvement (PPI) is framed as positive for individuals, the health system, public health, as well as for communities and society as a whole. We investigated whether preferences for PPI differed between two countries with Beveridge type health systems-Sweden and England. We measured willingness to be involved in individual treatment decisions and in decisions about the organization and provision of local health and social care services. Methods: This was a comparative cross-sectional study of the general population's preferences. Together, the two samples included 3125 respondents; 1625 in England and 1500 in Sweden. Country differences were analysed in a multinomial regression model controlling for gender, age and educational attainment. Results: Overall, 68% of respondents wanted a passive patient role and 44% wanted to be involved in local decisions about organization and provision of services. In comparison with in Sweden, they were in England less likely to want a health professional such as a GP or consultant to make decisions about their treatment and also more likely to want to make their own decisions. They were also less likely to want to be involved in local service development decisions. An increased likelihood of wanting to be involved in organizational decision-making was associated with individuals wanting to make their own treatment decisions. Women were less likely to want health professionals to make decisions and more likely to want to be involved in organizational decisions. Conclusions: An effective health system that ensures public health must integrate an effective approach to PPI both in individual treatment decisions and shaping local health and social care priorities. To be effective, involvement activities must take in to account the variation in the desire for involvement and the implications that this has for equity. More work is needed to understand the relationship between the desire to be involved and actually being involved, but both appear related to judgements of the impact of involvement on health care decisions

Experiences of living with mental health problems during the COVID-19 pandemic in the UK: a coproduced, participatory qualitative interview study

Purpose Research is beginning to quantify the impact of COVID-19 on people with pre-existing mental health conditions. Our paper addresses a lack of in-depth qualitative research exploring their experiences and perceptions of how life has changed at this time. Methods We used qualitative interviews (N = 49) to explore experiences of the pandemic for people with pre-existing mental health conditions. In a participatory, coproduced approach, researchers with lived experiences of mental health conditions conducted interviews and analysed data as part of a multi-disciplinary research team. Results Existing mental health difficulties were exacerbated for many people. People experienced specific psychological impacts of the pandemic, struggles with social connectedness, and inadequate access to mental health services, while some found new ways to cope and connect to the community. New remote ways to access mental health care, including digital solutions, provided continuity of care for some but presented substantial barriers for others. People from black and ethnic minority (BAME) communities experienced heightened anxiety, stigma and racism associated with the pandemic, further impacting their mental health. Conclusion There is a need for evidence-based solutions to achieve accessible and effective mental health care in response to the pandemic, especially remote approaches to care. Further research should explore the long-term impacts of COVID-19 on people with pre-existing mental health conditions. Particular attention should be paid to understanding inequalities of impact on mental health, especially for people from BAME communities

Designing high-quality implementation research: development, application, feasibility and preliminary evaluation of the implementation science research development (ImpRes) tool and guide

Background:  Designing implementation research can be a complex and daunting task, especially for applied health researchers who have not received specialist training in implementation science. We developed the Implementation Science Research Development (ImpRes) tool and supplementary guide to address this challenge and provide researchers with a systematic approach to designing implementation research. Methods:  A multi-method and multi-stage approach was employed. An international, multidisciplinary expert panel engaged in an iterative brainstorming and consensus-building process to generate core domains of the ImpRes tool, representing core implementation science principles and concepts that researchers should consider when designing implementation research. Simultaneously, an iterative process of reviewing the literature and expert input informed the development and content of the tool. Once consensus had been reached, specialist expert input was sought on involving and engaging patients/service users; and economic evaluation. ImpRes was then applied to 15 implementation and improvement science projects across the National Institute of Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South London, a research organisation in London, UK. Researchers who applied the ImpRes tool completed an 11-item questionnaire evaluating its structure, content and usefulness. Results:  Consensus was reached on ten implementation science domains to be considered when designing implementation research. These include implementation theories, frameworks and models, determinants of implementation, implementation strategies, implementation outcomes and unintended consequences. Researchers who used the ImpRes tool found it useful for identifying project areas where implementation science is lacking (median 5/5, IQR 4–5) and for improving the quality of implementation research (median 4/5, IQR 4–5) and agreed that it contained the key components that should be considered when designing implementation research (median 4/5, IQR 4–4). Qualitative feedback from researchers who applied the ImpRes tool indicated that a supplementary guide was needed to facilitate use of the tool. Conclusions:  We have developed a feasible and acceptable tool, and supplementary guide, to facilitate consideration and incorporation of core principles and concepts of implementation science in applied health implementation research. Future research is needed to establish whether application of the tool and guide has an effect on the quality of implementation research

Diet-Independent Remodeling of Cellular Membranes Precedes Seasonally Changing Body Temperature in a Hibernator

Polyunsaturated fatty acids (PUFA) have a multitude of health effects. Their incorporation into membrane phospholipids (PL) is generally believed to depend directly on dietary influx. PL influence transmembrane protein activity and thus can compensate temperature effects; e.g. PL n-6 PUFA are thought to stabilize heart function at low body temperature (Tb), whereas long chain (>C18) n-3 PUFA may boost oxidative capacity. We found substantial remodeling of membranes in free-living alpine marmots which was largely independent of direct dietary supply. Organ PL n-6 PUFA and n-6 to n-3 ratios were highest at onset and end of hibernation after rapid increases during a brief transitional period prior to hibernation. In contrast, longer chain PL n-3 PUFA content was low at end of summer but maximal at end of hibernation. After termination of hibernation in spring, these changes in PL composition were rapidly reversed. Our results demonstrate selective trafficking of PUFA within the body, probably governed by a circannual endogenous rhythm, as hibernating marmots were in winter burrows isolated for seven months from food and external cues signaling the approaching spring. High concentrations of PL n-6 PUFA throughout hibernation are in line with their hypothesized function of boosting SERCA 2a activity at low Tb. Furthermore, we found increasing rate of rewarming from torpor during winter indicating increasing oxidative capacity that could be explained by the accumulation of long-chain PL n-3 PUFA. It may serve to minimize the time necessary for rewarming despite the increasing temperature range to be covered, because rewarming is a period of highest metabolic rate and hence production of reactive oxygen species. Considering the importance of PUFA for health our results may have important biomedical implications, as seasonal changes of Tb and associated remodeling of membranes are not restricted to hibernators but presumably common among endothermic organisms

Working for patient safety: a qualitative study of women’s help-seeking during acute perinatal events

Background Women and their relatives can play an important role in early detection and help seeking for acute perinatal events. Recent UK reports indicate that patient-professional partnership in ‘working for safety’ can be difficult to achieve in practice, sometimes with catastrophic consequences. This research explored the experiences of women and relatives who had experienced early warning signs about their condition and sought help in escalating care. Methods Secondary analysis of case study data which included qualitative interviews with 22 women purposively sampled on account of experiencing a step up in care and 4 of their relatives from two NHS Trusts in England during 2010. Analysis focused on the type of safety work participants engaged in, and the opportunities and challenges reported by women and family members when negotiating safety at home and in hospital. Results Women and relatives took on a dual responsibility for self-diagnosis, self-care and seeking triage, whilst trying to avoid overburdening stretched services. Being informed, however, did not necessarily enable engagement from staff and services. The women’s narratives highlighted the work that they engaged in to build a case for clinical attention, the negotiations that took place with health care professionals and the strategies women and partners drew on (such as objective signs and symptoms, use of verbal insistence and repetition) to secure clinical help. For some women, the events left them with a lasting feeling that their concerns had been disregarded. Some described a sense of betrayal and loss of trust in an institution they believed had failed to care for them. Conclusion The notion of ‘safety partnerships’ which suggests a sense of equality and reciprocity was not borne out by our data, especially with regards to the experiences of teenage women. To enable women and families to secure a rapid response in clinical emergencies, strategies need to move beyond the provision of patient information about warning signs. Effective partnerships for safety may be supported by system level change such as improved triage, continuity of care, self-referral pathways and staff training to address asymmetries of power that persist within the health system

Structure and dynamics of the yeast SWR1:nucleosome complex

INTRODUCTION Canonical nucleosomes contain two copies of each of four histone proteins: H2A, H2B, H3, and H4. However, variants of these histones can be inserted by adenosine triphosphate (ATP)–dependent chromatin-remodeling machines. The yeast SWR1 chromatin-remodeling complex, a member of the INO80 remodeler family, catalyzes the exchange of H2A-H2B dimers for dimers containing Htz1 (H2A.Z in human) in an ATP-dependent manner. However, the mechanism by which SWR1 exchanges histones is poorly understood. Despite having a DNA translocase subunit similar to that in the INO80 complex that slides nucleosomes, no net translocation of nucleosomes has been reported for SWR1. Consequently, the function of the ATPase activity, which is required for histone exchange in SWR1, has remained enigmatic. RATIONALE To obtain sufficient quantities for structural analysis, we generated the complete 14-subunit yeast SWR1 complex in insect cells. Binding of nucleosomes to SWR1 is stabilized in the presence of an ATP analog (ADP•BeF3), which we used to prepare a complex with a canonical yeast H2A-containing nucleosome. Structural analysis was undertaken by cryo–electron microscopy (cryo-EM). We also used single-molecule FRET (smFRET) techniques to probe the dynamics of nucleosomes bound to SWR1. Fluorescent probes were positioned on the H2A histones and the end of the DNA to monitor changes in nucleosome dynamics upon binding of SWR1 and ATP (or ATP analogs). RESULTS We determined the cryo-EM structure of the SWR1-nucleosome complex at 3.6-Å resolution. The architecture of the complex shows how the SWR1 complex is assembled around a heterohexameric core of the RuvBL1 and RuvBL2 subunits. The Swr1 motor subunit binds at superhelical location 2 (SHL2), a position it shares in common with other remodelers but not with its most closely related complex, INO80, which binds at SHL6-SHL7. Binding of ATP or ADP•BeF3 to the SWR1-nucleosome complex induces substantial unwrapping of the DNA wrap. Conformational changes in the motor domains of the Swr1 subunit drive a single–base pair translocation of the DNA wrap from the DNA entry site. The single–base pair DNA translocation accompanies conformational changes in the histone core that begin to destabilize the histone dimer interface. Using smFRET methods, we further probed these conformational changes to show how an increase in the dynamics of the SWR1-bound nucleosomes is dependent on binding of ATP but not hydrolysis. CONCLUSION The cryo-EM structure of the SWR1 complex bound to a nucleosome reveals details of the intricate interactions between components of the SWR1 complex and its nucleosome substrate. Interactions between the Swr1 motor domains and the DNA wrap at SHL2 distort the DNA, causing a bulge with concomitant translocation of the DNA by one base pair, coupled to conformational changes of the histone core that likely destabilize the dimer interface. Furthermore, partial unwrapping of the DNA from the histone core takes place upon binding of nucleosomes to the SWR1 complex. Single-molecule data monitor this unwrapping and show how the dynamics are altered by ATP binding prior to hydrolysis