Post-Translational Modifications Control Phase Transitions of Tau.

The self-assembly of Tau(297-391) into filaments, which mirror the structures observed in Alzheimer's disease (AD) brains, raises questions about the role of AD-specific post-translational modifications (PTMs) in the formation of paired helical filaments (PHFs). To investigate this, we developed a synthetic approach to produce Tau(291-391) featuring N-acetyllysine, phosphoserine, phosphotyrosine, and N-glycosylation at positions commonly modified in post-mortem AD brains, thus facilitating the study of their roles in Tau pathology. Using transmission electron microscopy (TEM), cryo-electron microscopy (cryo-EM), and a range of optical microscopy techniques, we discovered that these modifications generally hinder the in vitro assembly of Tau into PHFs. Interestingly, while acetylation's effect on Tau assembly displayed variability, either promoting or inhibiting phase transitions in the context of cofactor free aggregation, heparin-induced aggregation, and RNA-mediated liquid-liquid phase separation (LLPS), phosphorylation uniformly mitigated these processes. Our observations suggest that PTMs, particularly those situated outside the fibril's rigid core are pivotal in the nucleation of PHFs. Moreover, in scenarios involving heparin-induced aggregation leading to the formation of heterogeneous aggregates, most AD-specific PTMs, except for K311, appeared to decelerate the aggregation process. The impact of acetylation on RNA-induced LLPS was notably site-dependent, exhibiting both facilitative and inhibitory effects, whereas phosphorylation consistently reduced LLPS across all proteoforms examined. These insights underscore the complex interplay between site-specific PTMs and environmental factors in modulating Tau aggregation kinetics, enhancing our understanding of the molecular underpinnings of Tau pathology in AD and highlighting the critical role of PTMs located outside the ordered filament core in driving the self-assembly of Tau into PHF structures.

TMEM106B Fibrils from FTLD Patients and Healthy Controls.

Recent studies involving four research teams have revealed that amyloid fibrils in FTLD-TDP patients and cognitively healthy individuals primarily consist of TMEM106B, a protein previously identified as a risk factor for FTLD-TDP. Through cryogenic electron microscopy, the studies identified various protofilament structures of TMEM106B fibrils from individuals with several neurodegenerative diseases. These findings raise new questions and opportunities for future research, as they suggest that TMEM106B plays a central role in FTLD pathology. These discoveries also prompt the need for the development of specific antibodies for fibrillar TMEM106B and necessitate further investigation of the potential mechanistic link between TMEM106B and other filamentous aggregates. The power of cryo-EM techniques is underscored in these unexpected findings and may be a vital tool for gaining further molecular insights into neurodegenerative diseases characterized by amyloid deposits.

Gender Bias in Clinical Trial Enrollment: Female Authorship Matters.

BACKGROUND: Despite initiatives to promote equal enrollment of human subjects in clinical trials, females continue to be underrepresented. The goal of this work is to determine if female enrollment in human clinical trials published in 3 high-impact journals from 2015 to 2019 is correlated with gender of first and/or senior authors. METHODS: Clinical trials published in the Journal of the American Medical Association (JAMA), The Lancet, and the New England Journal of Medicine (NEJM) from January 1, 2015, to December 31, 2019, were reviewed. Trials were excluded for ongoing enrollment, sex-specific disease research, or author name without gender assignment. One-sample χ2 pairwise comparisons and two-tailed proportion tests on the proportion of females between gender author pairings were done overall and for each subset analysis. RESULTS: In total, 1,427 articles enrolled a total of 2,104,509 females and 2,616,981 males (44.6% vs. 55.4%, P ≤ 0.0001) in clinical trials. Overall, more females were enrolled if both first and senior authors were female (51.7% vs. 48.3%, P ≤ 0.0001). Proportion of females enrolled decreased with the following first and senior author pairings: female-male (48.9%), male-female (48.6%), and male-male (40.5%, P ≤ 0.0001 compared to female-female authorship). Greater female enrollment in clinical trials with female-female compared to male-male authorship persisted in subset analyses by funding source, phase, randomization for study participants, drug and/or device trial, and geographic location. Female enrollment was higher in 3 surgical specialties: neurosurgery (all authors: 52%, P ≤ 0.01), ophthalmology (all authors: 53.6%, P ≤ 0.0001), and surgery (all authors: 54.4%, P ≤ 0.0001). The majority of surgical specialties did not publish trials with female-female authorship but when stratifying by author gender pairing, surgical oncology had the highest female enrollment with female-female authorship (98.4%, P ≤ 0.0001). CONCLUSIONS: Female authorship of clinical trial publications, specifically having both first and senior authors as female, was correlated with higher female enrollment in clinical trials when compared to male authorship and endured with multiple subset analyses.

The Feasibility and User-Experience of a Digital Health Intervention Designed to Prevent Weight Gain in New Kidney Transplant Recipients-The ExeRTiOn2 Trial.

Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruitment of 40% of the target sample size. Mixed-methods data provided important insights for future trial design. A definitive RCT is warranted and welcomed by KTRs. Clinical Trial Registration: www.clinicalTrials.gov, identifier: NCT03996551.

A qualitative evaluation of participants experiences of living with back pain, lumbar fusion surgery, and post-operative rehabilitation.

BACKGROUND: The use of lumbar fusion surgery is increasing in developed economies. High levels of patient dissatisfaction are reported post-operatively. To address this need, we developed a theoretically informed rehabilitation programme for use following lumbar fusion surgery (the REFS programme). We conducted a mixed methods randomised controlled feasibility study (REFS v 'usual care'). The numerical and feasibility outcomes are reported separately. The current qualitative study was 'nested' within the main feasibility study to explore participants' experiences before and after lumbar fusion surgery including the impact of rehabilitation content. This facilitated a deeper understanding of potential mechanisms of action, for theoretical and programme refinement. METHODS: A purposive sample (n = 10 'usual care', n = 10 REFS) was identified from the main feasibility study cohort. Individual semi-structured interviews were conducted post-operatively (median 8 months, range 5-11). Interview data were transcribed verbatim, coded, and analysed thematically. RESULTS: Three themes were constructed: the breadth and severity of impact associated with a chronic lumbar disorder was summarised in theme 1, 'Ever-decreasing circles; living with a chronic lumbar disorder'. Theme 2, 'What have I done? Reflections on recovery from lumbar fusion surgery', illustrated participants post-operative helplessness, which was associated with worsening mental health, problematic use of opioids, fear related to the instillation of metalware, and the important mitigating effect of informal social support. Theme 3 'Rehabilitation experiences' identified critical rehabilitation programme content including exercise, a shared rehabilitation experience, the opportunity for vicarious learning, and professional expertise. CONCLUSIONS: To enhance patient benefit future REFS programme iterations should consider reinforcement of the identified valued programme content. Additional content should be considered to mitigate post-operative fear, which frequently aligned with the instillation of metalware into the spine. Participant's perceptions regarding the necessity of lumbar fusion surgery has potential implications for the surgical consent process. TRIAL REGISTRATION: Study registration; ISRCTN60891364 , date registered 10/7/2014.

Cultural influences on physical activity and exercise beliefs in patients with chronic kidney disease: 'The Culture-CKD Study'-a qualitative study.

OBJECTIVES: This study used a mixed-method approach to explore cultural and ethnic influences on the perception of, and decision to engage with or not to engage with, physical activity and exercise therapy in patients with chronic kidney disease (CKD). DESIGN: Qualitative research was conducted through the use of semistructured interviews and focus groups. Self-reported physical activity levels were measured using the General Practice Physical Activity Questionnaire (GPPAQ), and self-efficacy for exercise with Bandura's Self-Efficacy for Exercise Scale. SETTING: This study was conducted in a non-clinical setting of a single National Health Service Hospital Trust between April 2018 and July 2019. PARTICIPANTS: Participants >18 years of age with a diagnosis of CKD, from black African, black Caribbean, South Asian or white ethnicity were eligible for the study. 84 patients with a diagnosis of CKD (stages 2-5), aged 25-79 (mean age 57) were recruited. Semistructured interviews (n=20) and six single-sex, ethnic-specific focus group discussions were undertaken (n=36). OUTCOMES: Primary outcome was to explore the perceptions, attitudes and values about exercise and physical activity in different ethnic groups through qualitative interviews, analysed using an inductive thematic analysis approach. Questionnaires were analysed using Pearson correlation to determine if there was a significant relationship between the self-efficacy and GPPAQ levels. RESULTS: Qualitative analysis provided four primary themes: I am who I am, Change of identity, Influences to physical activity and exercise and Support and education. Quantitative analysis using Pearson correlation revealed a significant correlation between GPPAQ levels of activity and self-efficacy to regulate exercise behaviour (r=-0.40, p=0.001). CONCLUSION: Understanding the cultural, attitudes and beliefs of individuals with CKD from a variety of ethnic backgrounds is complex. Understanding of patients' experiences, thoughts and beliefs may be of relevance to clinicians when designing CKD exercise services. TRIAL REGISTRATION NUMBER: NCT03709212; Pre-results.

Unilateral diaphragm paralysis with COVID-19 infection.

Neurological complications are well described in SARS-CoV-2, but for the first time we report a case of unilateral diaphragm paralysis occurring early in mechanical ventilation for respiratory failure due to such an infection. The patient subsequently required tracheostomy and ventilator support for 37 days, and had increased breathlessness and an elevated diaphragm at clinic review 9 months later. Dynamic chest radiography demonstrated persistent diaphragm paralysis with an accompanying postural change in lung volumes, and he subsequently underwent surgical plication. This case demonstrates that although persistent dyspnoea is a common feature following SARS-CoV-2 infection and is usually due to deconditioning or persistent parenchymal involvement, it can be due to other causes and needs to be investigated appropriately.

Usability and experience testing to refine an online intervention to prevent weight gain in new kidney transplant recipients.

OBJECTIVES: Weight gain in the first year following kidney transplantation increases the risk of adverse health outcomes. Currently, there is no recognized intervention available to prevent weight gain after kidney transplantation. An online kidney transplant-specific resource, entitled Exercise in Renal Transplant Online (ExeRTiOn), has been co-created by a multi-professional team, including patients, to assist with weight prevention. This study aimed to evaluate patient and health care professional usability and experience of the ExeRTiOn online resource. DESIGN: Qualitative study utilizing 'Think-Aloud' and semi-structured interviews. METHODS: Participants (n = 17) were purposively sampled to include new kidney transplant recipients (n = 11) and transplant health care professionals (n = 6). Kidney transplant recipient participants were from a spread of physical activity levels based on scores from the General Practice Physical Activity Questionnaire (GPPAQ). 'Think-Aloud' interviews assessed the usability of ExeRTiOn. Semi-structured interviews explored participants' experience of ExeRTiOn, weight gain, and physical activity. The data set were analysed thematically. Participant characteristics, including login data and self-reported body weight, were collected. RESULTS: Data analyses identified valued intervention content and usability aspects which were summarized by two themes. The first theme 'You need to know how to manage yourself' included subthemes: (1) the resource filled a guidance gap, (2) expert patient content resonated, and (3) the importance of goal setting and monitoring progress. The second theme 'room for improvement' included subthemes: (2) web support and (2) content and operational change suggestions. CONCLUSIONS: Results have allowed for identification of potential areas for resource refinement. This has facilitated iterative enhancement of ExeRTiOn in preparation for a randomized controlled feasibility trial.

Rehabilitation following lumbar fusion surgery (REFS) a randomised controlled feasibility study.

PURPOSE: Following lumbar fusion surgery (LFS), 40% of patients are unsure/dissatisfied with their outcome. A prospective, single-centre, randomised, controlled trial was conducted to evaluate the feasibility (including clinical and economic impact) of a theoretically informed rehabilitation programme following LFS (REFS). METHODS: REFS was informed by an explicit theoretical framework and consisted of 10 consecutive weekly group rehabilitation sessions (education, low-tech cardiovascular, limb and spine strengthening exercises, and peer support). Participants were randomised to REFS or 'usual care.' Primary feasibility outcomes included recruitment and engagement. Secondary outcomes, collected preoperatively and 3, 6, and 12  months postoperatively, comprised the Oswestry disability index, European Quality of Life 5 dimensions score, pain self-efficacy questionnaire, hospital anxiety and depression scale and the aggregated functional performance time. Economic impact was evaluated with the Client Services Receipt Inventory. RESULTS: Fifty-two of 58 eligible participants were recruited, and engagement with REFS was > 95%. REFS participants achieved a clinically meaningful reduction in unadjusted mean short-term disability (- 13.27 ± 13.46), which was not observed in the 'usual care' group (- 2.42 ± 12.33). This was maintained in the longer term (- 14.72% ± 13.34 vs - 7.57 ± 13.91). Multilevel regression analyses, adjusted for body mass index, baseline depression, and smoking status reported a statistically significant short-term improvement in disability (p = 0.014) and pain self-efficacy (p = 0.007). REFS costs £275 per participant. CONCLUSIONS: Results suggest that REFS is feasible and potentially affordable for delivery in the National Health Service. It is associated with a clinically meaningful impact. A multicentre randomised controlled study to further elucidate these results is warranted. These slides can be retrieved under Electronic Supplementary Material.

Ease of use of tobramycin inhalation powder compared with nebulized tobramycin and colistimethate sodium: a crossover study in cystic fibrosis patients with pulmonary Pseudomonas aeruginosa infection.

BACKGROUND: This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). METHODS: A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ⩾6 years with forced expiratory volume in 1 second (FEV1) ⩾25% to ⩽90% predicted. Patients were assigned to one of the three treatment arms in Cycle 1; all patients received TIP in Cycle 2. Each cycle consisted of 28 days on and 28 days off the treatment. RESULTS: A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP ( n = 14); COLI/TIP ( n = 28); TIP/TIP ( n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP ( p = 0.0112) and COLI/TIP ( p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT® questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity. CONCLUSION: The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile.

Rehabilitation Following Lumbar Fusion Surgery: A Systematic Review and Meta-Analysis.

STUDY DESIGN: A systematic review with meta-analysis. OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis of current evidence evaluating the effectiveness of rehabilitation following lumbar fusion surgery (LFS). SUMMARY OF BACKGROUND DATA: LFS for the management of lower back pain, with(out) neurogenic leg pain, is increasing as the population ages. Clinical outcomes commonly lag behind surgical outcomes and 40% of patients experience significant back-related disability 12 months after LFS. Identifying rehabilitation strategies to improve function and quality of life following LFS is important. METHODS: A systematic review of databases were searched, including MEDLINE, CINAHL, and grey literature. Studies identified were screened for inclusion by title and abstract. Full text of eligible/potentially eligible studies was evaluated against predetermined eligibility criteria. Included studies were subjected to critical appraisal and risk of bias evaluation. The GRADE approach to quality of evidence was utilized. A meta-analysis comparing usual care with "complex rehabilitation," comprising exercise and cognitive behavioral therapy, for outcomes relating to pain, disability, fear of movement, and mental health was conducted at short and longer term (<3 and >12 months postsurgery) time points. RESULTS: Three studies were identified for the systematic review and 2 included in the meta-analysis (n = 237, female = 62%, mean age = 55). Low-quality evidence suggests that "complex rehabilitation" provides short-term improvement in disability [effect size, -0.85, 95% confidence interval (95% CI), -1.41 to -0.29] and fear avoidance behavior (-1.07, 95% CI -1.33, -0.80), compared with usual care. Low-quality evidence exists favoring "complex rehabilitation" over usual care for longer term disability (-0.84, 95% CI -1.11 to -0.58) and fear avoidance behavior (-1.40, 95% CI -1.69 to -1.12). CONCLUSIONS: A small number of low-quality studies suggest that "complex rehabilitation" reduces short and long-term disability and fear avoidance behavior following LFS. More, high-quality research is required to confirm the effectiveness of "complex rehabilitation" programs.

The chlorine isotope fingerprint of the lunar magma ocean.

The Moon contains chlorine that is isotopically unlike that of any other body yet studied in the Solar System, an observation that has been interpreted to support traditional models of the formation of a nominally hydrogen-free ("dry") Moon. We have analyzed abundances and isotopic compositions of Cl and H in lunar mare basalts, and find little evidence that anhydrous lava outgassing was important in generating chlorine isotope anomalies, because (37)Cl/(35)Cl ratios are not related to Cl abundance, H abundance, or D/H ratios in a manner consistent with the lava-outgassing hypothesis. Instead, (37)Cl/(35)Cl correlates positively with Cl abundance in apatite, as well as with whole-rock Th abundances and La/Lu ratios, suggesting that the high (37)Cl/(35)Cl in lunar basalts is inherited from urKREEP, the last dregs of the lunar magma ocean. These new data suggest that the high chlorine isotope ratios of lunar basalts result not from the degassing of their lavas but from degassing of the lunar magma ocean early in the Moon's history. Chlorine isotope variability is therefore an indicator of planetary magma ocean degassing, an important stage in the formation of terrestrial planets.

Evaluating rehabilitation following lumbar fusion surgery (REFS): study protocol for a randomised controlled trial.

BACKGROUND: The rate of lumbar fusion surgery (LFS) is increasing. Clinical recovery often lags technical outcome. Approximately 40% of patients undergoing LFS rate themselves as symptomatically unchanged or worse following surgery. There is little research describing rehabilitation following LFS with no clear consensus as to what constitutes the optimum strategy. It is important to develop appropriate rehabilitation strategies to help patients manage pain and recover lost function following LFS. METHODS/DESIGN: The study design is a randomised controlled feasibility trial exploring the feasibility of providing a complex multi-method rehabilitation intervention 3 months following LFS. The rehabilitation protocol that we have developed involves small participant groups of therapist led structured education utilising principles of cognitive behavioral therapy (CBT), progressive, individualised exercise and peer support. Participants will be randomly allocated to either usual care (UC) or the rehabilitation group (RG). We will recruit 50 subjects, planning to undergo LFS, over 30 months. Following LFS all participants will experience normal care for the first 3 months. Subsequent to a satisfactory 3 month surgical review they will commence their allocated post-operative treatment (RG or UC). Data collection will occur at baseline (pre-operatively), 3, 6 and 12 months post-operatively. Primary outcomes will include an assessment of feasibility factors (including recruitment and compliance). Secondary outcomes will evaluate the acceptability and characteristics of a limited cluster of quantitative measures including the Oswestry Disability Index (ODI) and an aggregated assessment of physical function (walking 50 yards, ascend/descend a flight of stairs). A nested qualitative study will evaluate participants' experiences. DISCUSSION: This study will evaluate the feasibility of providing complex, structured rehabilitation in small groups 3 months following technically successful LFS. We will identify strengths and weakness of the proposed protocol and the usefulness and characteristics of the planned outcome measures. This will help shape the development of rehabilitation strategies and inform future work aimed at evaluating clinical efficacy. TRIAL REGISTRATION: ISRCTN60891364, 10/07/2014.

Biotechnology: delivering on the promise.

The research and development of innovative new therapies are expensive and risky processes, and companies require substantial resources if they are to translate basic science into modern biomedical products. When resources are limited, as in the current economic climate, biotechnology start-up companies are often among the first casualties in the fight for assets. Policy-makers can play an important role in bolstering these important innovators.

Microbial diversity of boron-rich volcanic hot springs of St. Lucia, Lesser Antilles.

The volcanic Sulphur Springs, St. Lucia, present an extreme environment due to high temperatures, low pH values, and high concentrations of sulfate and boron. St. Lucia offers some unique geochemical characteristics that may shape the microbial communities within the Sulphur Springs area. We chose six pools representing a range of geochemical characteristics for detailed microbial community analyses. Chemical concentrations varied greatly between sites. Microbial diversity was analyzed using 16S rRNA gene clone library analyses. With the exception of one pool with relatively low concentrations of dissolved ions, microbial diversity was very low, with Aquificales sequences dominating bacterial communities at most pools. The archaeal component of all pools was almost exclusively Acidianus spp. and did not vary between sites with different chemical characteristics. In the pool with the highest boron and sulfate concentrations, only archaeal sequences were detected. Compared with other sulfur springs such as those at Yellowstone, the microbial diversity at St. Lucia is very different, but it is similar to that at the nearby Lesser Antilles island of Montserrat. While high elemental concentrations seem to be related to differences in bacterial diversity here, similarities with other Lesser Antilles sites suggest that there may be a biogeographical component as well.

Continuing professional development for Australian rural psychiatrists by videoconference.

OBJECTIVE: The Rural Special Interest Group (RSIG) of the Royal Australian and New Zealand College of Psychiatrists provided a program of educational meetings for psychiatrists and trainees in rural locations to decrease professional isolation and facilitate opportunities to obtain credit for continuing professional development (CPD) purposes in ongoing professional registration. A pilot peer review group by videoconference was also implemented in Western Australia, to provide peer review for psychiatrists working in isolation. METHOD: Six national interactive videoconferenced education seminars were provided. The membership was polled prior to the program for topic preferences and requested speakers, who were subsequently approached to present the seminars. A West Australian peer review group was formed, involving psychiatrists from five different rural locations and one psychiatrist from the metropolitan area. RESULTS: National seminars were attended by 106 individuals (67% consultant psychiatrists, 17% trainees and 16% allied health professionals). Evaluation demonstrates favourable views of the content and quality of the presentations and impact on practice patterns. CONCLUSIONS: Attendance at seminars via videoconferencing provided rural psychiatrists with opportunities to obtain CPD credit without the need to travel, providing a cost-effective alternative for accessing education. Involvement enabled interaction among peers throughout Australia, alleviating professional isolation and generating networking opportunities. The West Australian peer review group demonstrated sustainability with a commitment to continuation and positive impact on practice.