Do proxies reflect patients' health concerns about urinary incontinence and gait problems?

BACKGROUND: While falls and urinary incontinence are prevalent among older patients, who sometimes rely on proxies to provide their health information, the validity of proxy reports of concern about falls and urinary incontinence remains unknown. METHODS: Telephone interviews with 43 consecutive patients with falls or fear of falling and/or bothersome urinary incontinence and their proxies chosen by patients as most knowledgeable about their health. The questionnaire included items derived from the Medical Outcomes Study Short Form 12 (SF-12), a scale assessing concerns about urinary incontinence (UI), and a measure of fear of falling, the Falls Efficacy Scale (FES). Scores were estimated using items asking the proxy perspective (6 items from the SF-12, 10 items from a UI scale, and all 10 FES items). Proxy and patient scores were compared using intraclass correlation coefficients (ICC, one-way model). Variables associated with absolute agreement between patients and proxies were explored. RESULTS: Patients had a mean age of 81 years (range 75–93) and 67% were female while proxies had a mean age of 70 (range 42–87) and 49% were female. ICCs were 0.63 for the SF-12, 0.52 for the UI scale, and 0.29 for the FES. Proxies tended to understate patients' general health and incontinence concern, but overstate patients' concern about falling. Proxies who lived with patients and those who more often see patients more closely reflected patient FES scores compared to those who lived apart or those who saw patients less often. Internal consistency reliability of proxy responses was 0.62 for the SF-12, 0.86 for the I-QOL, and 0.93 for the FES. In addition, construct validity of the proxy FES scale was supported by greater proxy-perceived fear of falling for patients who received medical care after a fall during the past 12 months (p < .05). CONCLUSION: Caution should be exercised when using proxies as a source of information about older patients' health perceptions. Questions asking about proxies' views yield suboptimal agreement with patient responses. However, proxy scales of UI and fall concern are internally consistent and may provide valid independent information

Motivational Interviewing Post-Stroke: An Analysis of Stroke Survivors' Concerns and Adjustment

Our earlier research demonstrated that participation in four sessions of motivational interviewing (MI) early post-stroke has a positive impact on stroke survivors' mood. However, the theoretical underpinnings of MI in supporting adjustment (rather than its traditional use in supporting behavior change) require clarification. This article describes a content analysis of MI transcripts for 10 participants in our previous study, to identify the focus of discussions (patient "concerns") and potential effective components of our MI approach. Patients' post-stroke concerns were shown in 16 categories, including frustration, family impact, and getting well. There was a pattern of change discourse across sessions: "Sustain talk" (reasons for not changing) reduced from Session 1 onward, "change talk" (intent to change) increased then reduced, and "change expressed" (changes achieved) increased from Sessions 1 to 4. MI facilitates healthy adjustment post-stroke in some patients, in turn affecting mood, but clarification of how this effect is achieved requires further exploration

Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates

Pain relief in labour: a qualitative study to determine how to support women to make decisions about pain relief in labour

Background Engagement in decision making is a key priority of modern healthcare. Women are encouraged to make decisions about pain relief in labour in the ante-natal period based upon their expectations of what labour pain will be like. Many women find this planning difficult. The aim of this qualitative study was to explore how women can be better supported in preparing for, and making, decisions during pregnancy and labour regarding pain management. Methods Semi-structured interviews were conducted with 13 primiparous and 10 multiparous women at 36 weeks of pregnancy and again within six weeks postnatally. Data collection and analysis occurred concurrently to identify key themes. Results Three main themes emerged from the data. Firstly, during pregnancy women expressed a degree of uncertainty about the level of pain they would experience in labour and the effect of different methods of pain relief. Secondly, women reflected on how decisions had been made regarding pain management in labour and the degree to which they had felt comfortable making these decisions. Finally, women discussed their perceived levels of control, both desired and experienced, over both their bodies and the decisions they were making. Conclusion This study suggests that the current approach of antenatal preparation in the NHS, of asking women to make decisions antenatally for pain relief in labour, needs reviewing. It would be more beneficial to concentrate efforts on better informing women and on engaging them in discussions around their values, expectations and preferences and how these affect each specific choice rather than expecting them to make to make firm decisions in advance of such an unpredictable event as labour

Experimental Evolution of a Plant Pathogen into a Legume Symbiont

Following acquisition of a rhizobial symbiotic plasmid, adaptive mutations in the virulence pathway allowed pathogenic Ralstonia solanacearum to evolve into a legume symbiont under plant selection

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead