Greater intermanual transfer in the elderly suggests age-related bilateral motor cortex activation is compensatory

ABSTRACT. Hemispheric lateralization of movement control diminishes with age; whether this is compensatory or maladaptive is debated. The authors hypothesized that if compensatory, bilateral activation would lead to greater intermanual transfer in older subjects learning tasks that activate the cortex unilaterally in young adults. They studied 10 young and 14 older subjects, learning a unimanual visuomotor task comprising a feedforward phase, where there is unilateral cortical activation in young adults, and a feedback phase, which activates the cortex bilaterally in both age groups. Increased intermanual transfer was demonstrated in older subjects during feedforward learning, with no difference between groups during feedback learning. This finding is consistent with bilateral cortical activation being compensatory to maintain performance despite declining computational efficiency in neural networks

Association of the chronotype score with circulating trimethylamine n‐oxide (Tmao) concentrations

Individual differences in the chronotype, an attitude that best expresses the individual circadian preference in behavioral and biological rhythms, have been associated with cardiometabolic risk and gut dysbiosis. Up to now, there are no studies evaluating the association between chronotypes and circulating TMAO concentrations, a predictor of cardiometabolic risk and a useful marker of gut dysbiosis. In this study population (147 females and 100 males), subjects with the morning chronotype had the lowest BMI and waist circumference (p < 0.001), and a better metabolic profile compared to the other chronotypes. In addition, the morning chronotype had the highest adherence to the Mediterranean diet (p < 0.001) and the lowest circulating TMAO concentrations (p < 0.001). After adjusting for BMI and adherence to the Mediterranean diet, the correlation between circulating TMAO concentrations and chronotype score was still kept (r = −0.627, p < 0.001). Using a linear regression analysis, higher chronotype scores were mostly associated with lower circulating TMAO concentrations (β = −0.479, t = −12.08, and p < 0.001). Using a restricted cubic spline analysis, we found that a chronotype score ≥59 (p < 0.001, R2 = −0.824) demonstrated a more significant inverse linear relationship with circulating TMAO concentrations compared with knots <59 (neither chronotype) and <41 (evening chronotype). The current study reported the first evidence that higher circulating TMAO concentrations were associated with the evening chronotype that, in turn, is usually linked to an unhealthy lifestyle mostly characterized by low adherence to the MD

Early Economic Evaluation of Diagnostic Technologies: Experiences of the NIHR Diagnostic Evidence Co-operatives

Diagnostic tests are expensive and time-consuming to develop. Early economic evaluation using decision modeling can reduce commercial risk by providing early evidence on cost-effectiveness. The National Institute for Health Research Diagnostic Evidence Co-operatives (DECs) was established to catalyze evidence generation for diagnostic tests by collaborating with commercial developers; DEC researchers have consequently made extensive use of early modeling. The aim of this article is to summarize the experiences of the DECs using early modeling for diagnostics. We draw on 8 case studies to illustrate the methods, highlight methodological strengths and weaknesses particular to diagnostics, and provide advice. The case studies covered diagnosis, screening, and treatment stratification. Treatment effectiveness was a crucial determinant of cost-effectiveness in all cases, but robust evidence to inform this parameter was sparse. This risked limiting the usability of the results, although characterization of this uncertainty in turn highlighted the value of further evidence generation. Researchers evaluating early models must be aware of the importance of treatment effect evidence when reviewing the cost-effectiveness of diagnostics. Researchers planning to develop an early model of a test should also 1) consult widely with clinicians to ensure the model reflects real-world patient care; 2) develop comprehensive models that can be updated as the technology develops, rather than taking a “quick and dirty” approach that may risk producing misleading results; and 3) use flexible methods of reviewing evidence and evaluating model results, to fit the needs of multiple decision makers. Decision models can provide vital information for developers at an early stage, although limited evidence mean researchers should proceed with caution

Diagnosing ventilator-associated pneumonia (VAP) in UK NHS ICUs:the perceived value and role of a novel optical technology

BACKGROUND: Diagnosing ventilator-associated pneumonia (VAP) in an intensive care unit (ICU) is a complex process. Our aim was to collect, evaluate and represent the information relating to current clinical practice for the diagnosis of VAP in UK NHS ICUs, and to explore the potential value and role of a novel diagnostic for VAP, which uses optical molecular alveoscopy to visualise the alveolar space. METHODS: Qualitative study performing semi-structured interviews with clinical experts. Interviews were recorded, transcribed, and thematically analysed. A flow diagram of the VAP patient pathway was elicited and validated with the expert interviewees. Fourteen clinicians were interviewed from a range of UK NHS hospitals: 12 ICU consultants, 1 professor of respiratory medicine and 1 professor of critical care. RESULTS: Five themes were identified, relating to [1] current practice for the diagnosis of VAP, [2] current clinical need in VAP diagnostics, [3] the potential value and role of the technology, [4] the barriers to adoption and [5] the evidence requirements for the technology, to help facilitate a successful adoption. These themes indicated that diagnosis of VAP is extremely difficult, as is the decision to stop antibiotic treatment. The analysis revealed that there is a clinical need for a diagnostic that provides an accurate and timely diagnosis of the causative pathogen, without the long delays associated with return of culture results, and which is not dangerous to the patient. It was determined that the technology would satisfy important aspects of this clinical need for diagnosing VAP (and pneumonia, more generally), but would require further evidence on safety and efficacy in the patient population to facilitate adoption. CONCLUSIONS: Care pathway analysis performed in this study was deemed accurate and representative of current practice for diagnosing VAP in a UK ICU as determined by relevant clinical experts, and explored the value and role of a novel diagnostic, which uses optical technology, and could streamline the diagnostic pathway for VAP and other pneumonias. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41512-022-00117-x

Can mid-regional pro-adrenomedullin (MR-proADM) increase the prognostic accuracy of NEWS in predicting deterioration in patients admitted to hospital with mild to moderately severe illness? A prospective single-centre observational study

Objective: To assess the value added to the National Early Warning Score (NEWS) by mid-regional pro-adrenomedullin (MR-proADM) blood level in predicting deterioration in mild to moderately ill people. Design: Prospective observational study. Setting: The Medical Admissions Suite of the Royal Victoria Infirmary, Newcastle. Participants: 300 adults with NEWS between 2 and 5 on admission. Exclusion criteria included receiving palliative care, or admitted for social reasons or self-harming. Patients were enrolled between September and December 2015, and followed up for 30 days after discharge. Outcome measure: The primary outcome measure was the proportion of patients who, within 72 hours, had an acuity increase, defined as any combination of an increase of at least 2 in the NEWS; transfer to a higher-dependency bed or monitored area; death; or for those discharged from hospital, readmission for medical reasons. Results: NEWS and MR-proADM together predicted acuity increase more accurately than NEWS alone, increasing the area under the curve (AUC) to 0.61 (95% CI 0.54 to 0.69) from 0.55 (95% CI 0.48 to 0.62). When the confounding effects of presence of chronic obstructive pulmonary disease or heart failure and interaction with MR-proADM were included, the prognostic accuracy further increased the AUC to 0.69 (95% CI 0.63 to 0.76). Conclusions: MR-proADM is potentially a clinically useful biomarker for deterioration in patients admitted to hospital with a mild to moderately severe acute illness, that is, with NEWS between 2 and 5. As a growing number of National Health Service hospitals are routinely recording the NEWS on their clinical information systems, further research should assess the practicality and use of developing a decision aid based on admission NEWS, MR-proADM level, and possibly other clinical data and other biomarkers that could further improve prognostic accuracy

Systematic review of studies investigating ventilator associated pneumonia diagnostics in intensive care

Abstract Background Ventilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP. Methods We conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies. Results We identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none. Conclusions Nearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used

At what times during infection is SARS-CoV-2 detectable and no longer detectable using RT-PCR-based tests? A systematic review of individual participant data

Background: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity. / Methods: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites. / Results: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from − 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset. / Conclusions: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated

Absence of SCAPER causes male infertility in humans and Drosophila by modulating microtubule dynamics during meiosis

Mutation in S-phase cyclin A-associated protein rin the endoplasmic reticulum (SCAPER) have been found across ethnicities and have been shown to cause variable penetrance of an array of pathological traits, including intellectual disability, retinitis pigmentosa and ciliopathies. Human clinical phenotyping, surgical testicular sperm extraction and testicular tissue staining. Generation and analysis of short spindle 3 (ssp3) (SCAPER orthologue) Drosophila CAS9-knockout lines. In vitro microtubule (MT) binding assayed by total internal reflection fluorescence microscopy. We show that patients homozygous for a SCAPER mutation lack SCAPER expression in spermatogonia (SPG) and are azoospermic due to early defects in spermatogenesis, leading to the complete absence of meiotic cells. Interestingly, Drosophila null mutants for the ubiquitously expressed ssp3 gene are viable and female fertile but male sterile. We further show that male sterility in ssp3 null mutants is due to failure in both chromosome segregation and cytokinesis. In cells undergoing male meiosis, the MTs emanating from the centrosomes do not appear to interact properly with the chromosomes, which remain dispersed within dividing spermatocytes (SPCs). In addition, mutant SPCs are unable to assemble a normal central spindle and undergo cytokinesis. Consistent with these results, an in vitro assay demonstrated that both SCAPER and Ssp3 directly bind MTs. Our results show that SCAPER null mutations block the entry into meiosis of SPG, causing azoospermia. Null mutations in ssp3 specifically disrupt MT dynamics during male meiosis, leading to sterility. Moreover, both SCAPER and Ssp3 bind MTs in vitro. These results raise the intriguing possibility of a common feature between human and Drosophila meiosis