Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma.

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

Provision of dietary education in UK-based cardiac rehabilitation: a cross-sectional survey conducted in conjunction with the British Association for Cardiovascular Prevention and Rehabilitation.

Dietary education is a core component of cardiac rehabilitation (CR). It is unknown how or what dietary education is delivered across the UK. We aimed to characterise practitioners who deliver dietary education in UK CR and determine the format and content of the education sessions. A fifty-four-item survey was approved by the British Association for Cardiovascular Prevention and Rehabilitation (BACPR) committee and circulated between July and October 2021 via two emails to the BACPR mailing list and on social media. Practitioners providing dietary education within CR programmes were eligible to respond. Survey questions encompassed: practitioner job title and qualifications, resources, and the format, content and individual tailoring of diet education. Forty-nine different centres responded. Nurses (65·1 %) and dietitians (55·3 %) frequently provided dietary education. Practitioners had no nutrition-related qualifications in 46·9 % of services. Most services used credible resources to support their education, and 24·5 % used BACPR core competencies. CR programmes were mostly community based (40·8 %), lasting 8 weeks (range: 2-25) and included two (range: 1-7) diet sessions. Dietary history was assessed at the start (79·6 %) and followed up (83·7 %) by most centres; barriers to completing assessment were insufficient time, staffing or other priorities. Services mainly focused on the Mediterranean diet while topics such as malnutrition and protein intake were lower priority topics. Service improvement should focus on increasing qualifications of practitioners, standardisation of dietary assessment and improvement in protein and malnutrition screening and assessment.

Real time monitoring of COVID-19 intervention effectiveness through contact tracing data.

Communities worldwide have used vaccines and facemasks to mitigate the COVID-19 pandemic. When an individual opts to vaccinate or wear a mask, they may lower their own risk of becoming infected as well as the risk that they pose to others while infected. The first benefit-reducing susceptibility-has been established across multiple studies, while the second-reducing infectivity-is less well understood. Using a new statistical method, we estimate the efficacy of vaccines and facemasks at reducing both types of risks from contact tracing data collected in an urban setting. We find that vaccination reduced the risk of onward transmission by 40.7% [95% CI 25.8-53.2%] during the Delta wave and 31.0% [95% CI 19.4-40.9%] during the Omicron wave and that mask wearing reduced the risk of infection by 64.2% [95% CI 5.8-77.3%] during the Omicron wave. By harnessing commonly-collected contact tracing data, the approach can broadly provide timely and actionable estimates of intervention efficacy against a rapidly evolving pathogen.

Correction to: COVID-19: self-reported reductions in physical activity and increases in sedentary behaviour during the first national lockdown in the United Kingdom.

[This corrects the article DOI: 10.1007/s11332-022-01012-0.].

Serum transthyretin and aminotransferases are associated with lean mass in people with coronary heart disease: Further insights from the CARE-CR study.

Background: Low muscle mass disproportionately affects people with coronary heart disease compared to healthy controls but is under-researched and insufficiently treated. Inflammation, poor nutrition, and neural decline might contribute to low muscle mass. This study aimed to assess circulatory biomarkers related to these mechanisms [albumin, transthyretin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and C-terminal agrin fragment] and their relationship with muscle mass in people with coronary heart disease. Our findings could be beneficial to indicate mechanisms of sarcopenia, detect sarcopenia, and evaluate treatment. Methods: Serum blood samples from people with coronary heart disease were analysed for biomarker concentrations using enzyme-linked immunosorbent assays. Skeletal muscle mass was estimated using dual X-ray absorptiometry derived appendicular lean mass and reported as skeletal muscle index (SMI; kg m-2), and as a proportion of total body mass [appendicular skeletal mass (ASM%)]. Low muscle mass was defined as a SMI <7.0 and <6.0 kg m-2, or ASM% <25.72 and <19.43% for men and women, respectively. Associations between biomarkers and lean mass were adjusted for age and inflammation. Results: Sixty-four people were assessed; 14 (21.9%) had low muscle mass. People with low muscle mass had lower transthyretin (effect size 0.34, p = 0.007), ALT (effect size 0.34, p = 0.008), and AST (effect size 0.26, p = 0.037) concentrations, compared to those with normal muscle mass. SMI was associated with inflammation-corrected ALT (r = 0.261, p = 0.039) and with inflammation- and age-adjusted AST/ALT ratio (r = -0.257, p = 0.044). Albumin and C-terminal agrin fragment were not associated with muscle mass indices. Conclusion: Circulatory transthyretin, ALT and AST were associated with low muscle mass in people with coronary heart disease. Low concentrations of these biomarkers might indicate that low muscle mass is partially explained by poor nutrition and high inflammation in this cohort. Targeted treatments to address these factors could be considered for people with coronary heart disease.

COVID-19: self-reported reductions in physical activity and increases in sedentary behaviour during the first national lockdown in the United Kingdom.

Purpose: The United Kingdom (UK) government imposed its first national lockdown in response to COVID-19 on the 23rd of March 2020. Physical activity and sedentary behaviour levels are likely to have changed during this period. Methods: An online survey was completed by n = 266 adults living within the UK. Differences in day-to-day and recreational physical activity (at moderate and vigorous intensities), travel via foot/cycle, and sedentary behaviour were compared before and during the initial COVID-19 lockdown. Results: The median level of total weekly physical activity significantly reduced (- 15%, p < 0.001) and daily sedentary time significantly increased (+ 33%, p < 0.001). The former was caused by a significant reduction in weekly day-to-day physical activity at moderate intensities (p < 0.001), recreational activities at vigorous (p = 0.016) and moderate (p = 0.030) intensities, and travel by foot/cycle (p = 0.031). Sub-group analyses revealed that some populations became disproportionally more physically inactive and/or sedentary than others, such as those that were: living in a city (versus village), single (versus a relationship), an athlete (versus non-athlete), or earning an average household income < £25,000 (versus > £25,000). Conclusions: Now that the UK is transitioning to a state of normal living, strategies that can help individuals gradually return to physical activities, in accordance with the 2020 WHO guidelines, are of paramount importance to reducing risks to health associated with physical inactivity and sedentary behaviour.

Adoption of digital tools in the context of the COVID-19 pandemic in the Region of the Americas - the Go.Data experience.

The COVID-19 pandemic has accelerated the growth of digital health tools. Although a number of different tools exist to support field data collection in the context of outbreak response, they have not been sufficient. This prompted the World Health Organization (WHO) to collaborate with the Global Outbreak Alert and Response Network (GOARN) and GOARN partners to develop a comprehensive system, Go.Data. Go.Data, a digital tool for outbreak response has simplified how countries operationalize and monitor case and contact data. Since the start of the pandemic, WHO and GOARN partners have provided support to Go.Data projects in 65 countries and territories, yet the demand by countries to have documented success cases of Go.Data implementations continues to grow. This viewpoint documents the successful Go.Data implementation frameworks in two countries, Argentina and Guatemala and an academic institution, the University of Texas at Austin.

The effectiveness of the Healthworks Staying Steady community-based falls prevention exercise programme to improve physical function in older adults: a 6-year service evaluation.

BACKGROUND: Falls prevention exercise programmes are evidence-based and recommended for improving physical function in older adults. However, few service evaluations exist to assess the effectiveness of community-delivered interventions in practice. METHODS: We conducted a six-year, retrospective evaluation of the community-delivered Staying Steady programme (Healthworks, United Kingdom). Staying Steady is a 27-week, tailored strength and balance programme delivered in a group setting (1-h, once/week) and at home (30-40 min, 2-3 times/week). Participants were referred by healthcare professionals, or self-referred, due to a history or risk of falling. Routinely collected outcome measures (30-s chair stand, Timed Up and Go, four-stage balance test, and patient reported outcomes; including 'fear of falling' and 'ability to manage health') were analysed. Factors associated with programme completion were reported. The intervention effect on physical function was analysed in subgroups: participants used arms to chair-stand or a walking-aid at both ('aided'), neither ('unaided'), or one assessment timepoint ('aided at baseline only' or 'aided at follow-up only'). RESULTS: There were 1,426 referrals; 835 (67.3%) participants enrolled on to the Staying Steady programme, 406 (32.7%) declined, 185 (13.0%) were inappropriately referred and excluded from analysis. After enrolling, 451 (54.0%) participants completed, and 384 (46.0%) dropped out. Chair stand performance improved in participants who were unaided (n = 264; median 2.0 [1.0, 4.0] repetitions; P < 0.001), or aided at baseline, follow-up or both (n = 170, P < 0.05). Timed Up and Go performance improved in the unaided (n = 387; median -3.1 [-5.4, -1.4] s, P < 0.001), and aided at baseline only (n = 32; median -4.9 [-10.8, -3.4] s, P < 0.001) groups. Four-stage balance performance improved (n = 295; median 1.0 [0.0, 1.0] points, P < 0.001). After programme completion, participants self-reported an improved ability to manage their health and daily activities, improved confidence, and a reduced fear of falling. Presence of chronic obstructive pulmonary disease, fear of falling, prescribed nutritional support, disability and social deprivation influenced non-completion of Staying Steady. CONCLUSIONS: Completing Staying Steady improved physical function in older adults. Methods to encourage retention of participants from groups associated with low uptake and adherence should be investigated.

SARS-CoV-2 viral load is associated with risk of transmission to household and community contacts.

BACKGROUND: Factors that lead to successful SARS-CoV-2 transmission are still not well described. We investigated the association between a case's viral load and the risk of transmission to contacts in the context of other exposure-related factors. METHODS: Data were generated through routine testing and contact tracing at a large university. Case viral loads were obtained from cycle threshold values associated with a positive polymerase chain reaction test result from October 1, 2020 to April 15, 2021. Cases were included if they had at least one contact who tested 3-14 days after the exposure. Case-contact pairs were formed by linking index cases with contacts. Chi-square tests were used to evaluate differences in proportions of contacts testing positive. Generalized estimating equation models with a log link were used to evaluate whether viral load and other exposure-related factors were associated with a contact testing positive. RESULTS: Median viral load among the 212 cases included in the study was 5.6 (1.8-10.4) log10 RNA copies per mL of saliva. Among 365 contacts, 70 (19%) tested positive following their exposure; 36 (51%) were exposed to a case that was asymptomatic or pre-symptomatic on the day of exposure. The proportion of contacts that tested positive increased monotonically with index case viral load (12%, 23% and 25% corresponding to < 5, 5-8 and > 8 log10 copies per mL, respectively; X2 = 7.18, df = 2, p = 0.03). Adjusting for cough, time between test and exposure, and physical contact, the risk of transmission to a close contact was significantly associated with viral load (RR = 1.27, 95% CI 1.22-1.32). CONCLUSIONS: Further research is needed to understand whether these relationships persist for newer variants. For those variants whose transmission advantage is mediated through a high viral load, public health measures could be scaled accordingly. Index cases with higher viral loads could be prioritized for contact tracing and recommendations to quarantine contacts could be made according to the likelihood of transmission based on risk factors such as viral load.

The effectiveness of COVID-19 testing and contact tracing in a US city.

Although testing, contact tracing, and case isolation programs can mitigate COVID-19 transmission and allow the relaxation of social distancing measures, few countries worldwide have succeeded in scaling such efforts to levels that suppress spread. The efficacy of test-trace-isolate likely depends on the speed and extent of follow-up and the prevalence of SARS-CoV-2 in the community. Here, we use a granular model of COVID-19 transmission to estimate the public health impacts of test-trace-isolate programs across a range of programmatic and epidemiological scenarios, based on testing and contact tracing data collected on a university campus and surrounding community in Austin, TX, between October 1, 2020, and January 1, 2021. The median time between specimen collection from a symptomatic case and quarantine of a traced contact was 2 days (interquartile range [IQR]: 2 to 3) on campus and 5 days (IQR: 3 to 8) in the community. Assuming a reproduction number of 1.2, we found that detection of 40% of all symptomatic cases followed by isolation is expected to avert 39% (IQR: 30% to 45%) of COVID-19 cases. Contact tracing is expected to increase the cases averted to 53% (IQR: 42% to 58%) or 40% (32% to 47%), assuming the 2- and 5-day delays estimated on campus and in the community, respectively. In a tracing-accelerated scenario, in which 75% of contacts are notified the day after specimen collection, cases averted increase to 68% (IQR: 55% to 72%). An accelerated contact tracing program leveraging rapid testing and electronic reporting of test results can significantly curtail local COVID-19 transmission.

Primary Lymphomas of the Breast: A Review.

Lymphomas of the breast are rare neoplasms that arise from breast lymphoid tissue and are characterised by neoplastic B or T cells. Breast lymphomas arising from B cells include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, extra-nodal marginal zone lymphoma and Burkitt lymphoma. Anaplastic large cell lymphoma (ALCL) is of a T cell origin and both anaplastic lymphoma kinase (ALK)-positive and ALK-negative presentations have been noted in the breast. In addition, there is a more recently identified presentation of ALK-negative ALCL that arises around textured breast implants and is usually confined to a periprosthetic fibrous capsule. Here, we discuss the clinical presentations, histological and immunohistochemical features and treatment options for each type of primary breast lymphoma. We hope that this review will highlight the importance of the timely and accurate diagnosis of breast lymphoma in order to tailor the most appropriate treatment. We also wish to raise awareness of the breast implant-associated lymphomas, with the goal of stimulating work that will aid our understanding of their epidemiology and pathogenesis.

Screening Programs for SARS-CoV-2 Infections on a University Campus - Austin, Texas, September 30-November 30, 2020.

Colleges and universities in the United States have relied on various measures during the COVID-19 pandemic to prevent transmission of SARS-CoV-2, the virus that causes COVID-19, including implementing testing programs (1-3). These programs have permitted a safer return to campus for students by identifying infected persons and temporarily isolating them from the campus population (2,3). The University of Texas at Austin (UT Austin) implemented COVID-19 prevention measures in Fall 2020* including the following testing programs: clinic-based diagnostic testing, voluntary community screening, and targeted screening (testing of specific student populations in situations of increased transmission risk). During September 30-November 30, 2020, UT Austin students participated in tests for SARS-CoV-2, which resulted in the detection of 401 unique student cases of COVID-19 from among 32,401 tests conducted.† Among students who participated in one targeted screening program for students attending campus events, 18 (37.5%) of 48 infected students were asymptomatic at the time of their positive test result compared with 45 (23%) of 195 students identified through community testing and nine (5.8%) of 158 students identified through clinic-based testing. Targeted screening also identified a different population of students than did clinic-based and community testing programs. Infected students tested through targeted screening were more likely to be non-Hispanic White persons (chi square = 20.42; p<0.03), less likely to engage in public health measures, and more likely to have had interactions in settings where the risk for SARS-CoV-2 transmission is higher, such as restaurants, gyms, and residence halls. In addition to clinic-based SARS-CoV-2 testing at colleges and universities, complementary testing programs such as community and targeted screening might enhance efforts to identify and control SARS-CoV-2 transmission, especially among asymptomatic persons and disproportionately affected populations that might not otherwise be reached.

The influence of resistance training on neuromuscular function in middle-aged and older adults: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Deterioration of neuromuscular function is a major mechanism of age-related strength loss. Resistance training (RT) improves muscle strength and mass. However, the effects of RT on neuromuscular adaptations in middle-aged and older adults are unclear. METHODS: Randomised controlled RT interventions (≥2 weeks) involving adults aged ≥50 years were identified. Primary outcome measures were voluntary activation (VA), electromyographic (EMG) activity during maximal voluntary contraction (MVC), and antagonist coactivation. Data were pooled using a weighted random-effect model. Sub-analyses were conducted by muscle or muscle group and health status of participants. Sensitivity analysis was based on study quality. P < 0.05 indicated statistical significance. RESULTS: Twenty-seven studies were included. An effect was found for VA (standardised mean difference [SMD] 0.54, 0.01 to 1.07, P = 0.04), This result remained significant following sensitivity analysis involving only studies that were low risk of bias. Subgroup analyses showed an effect for plantar flexor VA (SMD 1.13, 0.20 to 2.06, P = 0.02) and VA in healthy participants (SMD 1.04, 0.32 to 1.76, P = 0.004). There was no effect for EMG activity or antagonist coactivation of any muscle group (P > 0.05). DISCUSSION: Resistance training did not alter EMG activity or antagonist coactivation in older adults. Sensitivity analysis resulted in the effect for VA remaining significant, indicating that this finding was not dependent on study quality. Studies predominantly involved healthy older adults (78%), limiting the generalisability of these findings to clinical cohorts. Future research should determine the effects of RT on neuromuscular function in people with sarcopenia and age-related syndromes.

Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery.

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.

The effect of acute exercise on environmentally induced symptoms of dry eye.

The purpose of this study was to investigate the effects of acute exercise on environmentally induced symptoms of dry eye. Twelve participants without dry eye disease volunteered to complete three experimental visits in a randomized order; (1) control condition seated for 1 h at a relative humidity (RH) of 40% (CONT), (2) dry condition seated for 1 h at a RH of 20% (DRY), and (3) exercise condition seated for 40 min followed by 20 min of cycling exercise at a RH of 20% (EXER). Tear volume, tear matrix metalloproteinase 9 (MMP-9), perception of dry eye symptoms (frequency and severity), core temperature, and ocular surface temperature (OST) were measured at the end of each exposure. The perception of dry eye frequency and MMP-9 concentration were significantly higher in DRY compared to CONT (P < 0.012), with no differences in EXER compared to CONT. The results suggest that an acute bout of exercise may attenuate symptoms of environmentally induced dry eye, and warrant further research.

A Lexicon for the Sick Room: Virginia Woolf's Narrative Medicine.

In her 1926 essay On Being Ill, Virginia Woolf explores the "poverty of the language" in matters of illness and uncovers a lexical rift between patients and caregivers-one that continues to trouble contemporary medical culture. Even as her essay exposes and deplores the sick room's scant lexicon, Woolf herself worked to address these shortcomings throughout her career, steadily crafting a wider and more capacious vocabulary for illness. Such a language, she felt, could heighten the patient's ability to articulate the sensory nuances of illness and, in so doing, foster empathy for the ill. In arguing for the patient's expressive autonomy and advancing new models of humane caregiving, Woolf's writings and nascent lexicography anticipate the rise of narrative medicine in the twenty-first century.

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin.

The persistence of drug resistant cell populations following chemotherapeutic treatment is a significant challenge in the clinical management of cancer. Resistant subpopulations arise via both cell intrinsic and extrinsic mechanisms. Extrinsic factors in the microenvironment, including neighboring cells, glycosaminoglycans, and fibrous proteins impact therapy response. Elevated levels of extracellular fibrous proteins are associated with tumor progression and cause the surrounding tissue to stiffen through changes in structure and composition of the extracellular matrix (ECM). We sought to determine how this progressively stiffening microenvironment affects the sensitivity of breast cancer cells to chemotherapeutic treatment. MDA-MB-231 triple negative breast carcinoma cells cultured in a 3D alginate-based hydrogel system displayed a stiffness-dependent response to the chemotherapeutic doxorubicin. MCF7 breast carcinoma cells cultured in the same conditions did not exhibit this stiffness-dependent resistance to the drug. This differential therapeutic response was coordinated with nuclear translocation of YAP, a marker of mesenchymal differentiation. The stiffness-dependent response was lost when cells were transferred from 3D to monolayer cultures, suggesting that endpoint ECM conditions largely govern the response to doxorubicin. To further examine this response, we utilized a platform capable of dynamic ECM stiffness modulation to allow for a change in matrix stiffness over time. We found that MDA-MB-231 cells have a stiffness-dependent resistance to doxorubicin and that duration of exposure to ECM stiffness is sufficient to modulate this response. These results indicate the need for additional tools to integrate mechanical stiffness with therapeutic response and inform decisions for more effective use of chemotherapeutics in the clinic.

Reducing copper use in the environment: the use of larixol and larixyl acetate to treat downy mildew caused by Plasmopara viticola in viticulture.

BACKGROUND: Plant extracts might provide sustainable alternatives to copper fungicides, which are still widely used despite their unfavourable ecotoxicological profile. Larch bark extract and its constituents, larixyl acetate and larixol, have been shown to be effective against grapevine downy mildew (Plasmopara viticola) under semi-controlled conditions. The aim of this study was to reduce the gap between innovation and the registration of a marketable product, namely to develop scalable extraction processes and to evaluate and optimise the performance of larch extracts under different conditions. RESULTS: Toxicologically and technically acceptable solvents like ethanol were used to extract the active compounds larixyl acetate and larixol from bark in sufficient amounts and their combined concentration could be increased by up to 39% by purification steps. The combined concentration of larixyl acetate and larixol from larch turpentine could be increased by up to 66%. The Minimal Inhibitory Concentration (MIC100 ) against P. viticola in vitro (6-23 µg mL-1 ) and the Effective Concentration (EC50 ) in planta under semi-controlled conditions (0.2-0.4 mg mL-1 ) were promising compared with other plant extracts. In vineyards, efficacies of larch extracts reached up to 68% in a stand-alone strategy and 84% in low-copper strategies. CONCLUSION: Larch extracts represent valid candidates for copper reduction in organic vineyards, and their development into a sustainable plant protection product might be feasible. © 2017 Society of Chemical Industry.