Are the patterns of cytomegalovirus viral load seen after solid organ transplantation affected by circadian rhythm?

Background: Cytomegalovirus (CMV) is an important opportunistic pathogen after transplantation. Some virological variation in transplant recipients is explained by donor and recipient CMV serostatus, but not all. Circadian variability of herpesviruses has been described, so we investigated the effect of time of day of transplantation on posttransplant CMV viremia. Methods: We performed a retrospective analysis of 1517 patients receiving liver or kidney allografts at a single center from 2002 to 2018. All patients were given preemptive therapy with CMV viremia monitoring after transplantation. Circulatory arrest and reperfusion time of donor organ were categorized into 4 periods. Patients were divided into serostatus groups based on previous CMV infection in donor and recipient. CMV viremia parameters were compared between time categories for each group. Factor analysis of mixed data was used to interrogate this complex data set. Results: Live-donor transplant recipients were less likely to develop viremia than recipients of deceased-donor organs (48% vs 61%; P < .001). After controlling for this, there was no evidence of time of day of transplantation affecting CMV parameters in any serostatus group, by logistic regression or factor analysis of mixed data. Discussion: We found no evidence for a circadian effect of transplantation on CMV viremia, but these novel results warrant confirmation by other centers

A prospective study of MRI biomarkers in the brain and lower limb muscles for prediction of lower limb motor recovery following stroke

The aim of this prospective observational longitudinal study was to explore and decipher the predictive value of prospective MRI biomarkers in the brain and lower limb muscles for 3-month lower limb motor recovery following stroke. In the brain, we measured the integrity of the corticospinal tract (fractional anisotropy/"FA"). In the muscles, we measured volume, fatty replacement (fat fraction analysis and proton spectroscopy) and oedema. Measurements were taken at two time points: (1) within 4 weeks of stroke (baseline measurement, clinical and imaging) and (2) 3 months following stroke (follow up measurement, clinical only). Clinical measurements consisted of assessments of functional ability and strength (Fugl-Meyer score, motor NIHSS, Functional Ambulation Category/"FAC", and muscle dynamometry). Twenty-three patients completed imaging and clinical assessments at baseline and follow-up; five patients had partial imaging assessment. The results provided some evidence that damage to the corticospinal tract would result in less motor recovery: recovery of the Fugl-Meyer score and dynamometric ankle plantarflexion, ankle dorsiflexion, and knee extension correlated positively and significantly with fractional anisotropy (0.406-0.457; p = 0.034-p = 0.016). However, fractional anisotropy demonstrated a negative correlation with recovery of the Functional Ambulation Category (-0.359, p = 0.046). For the muscle imaging, significant inverse correlation was observed between vastus lateralis fat fraction vs. NIHSS recovery (-0.401, p = 0.04), and a strong positive correlation was observed between ratio of intra- to extra-myocellular lipid concentrations and the recovery of knee flexion (0.709, p = 0.007). This study supports previous literature indicating a positive correlation between the integrity of the corticospinal tract and motor recovery post-stroke, expanding the limited available literature describing this relationship specifically for the lower limb. However, recovery of functional ambulation behaved differently to other clinical recovery markers by demonstrating an inverse relationship with corticospinal tract integrity. The study also introduces some muscle imaging biomarkers as potentially valuable in the prediction of 3-month lower limb motor recovery following stroke

Inferring bacterial transmission dynamics using deep sequencing genomic surveillance data

Within host variation is increasingly being cited as a tool to distinguish transmission pairs. However, the role of within-host diversity in transmission is understudied due to a lack of experimental and clinical datasets that capture within-host diversity in both donors and recipients. Here, we assess the utility of deep-sequenced genomic surveillance within a mouse transmission model where the gastrointestinal pathogen Citrobacter rodentium was controllably spread during co-housing of infected and naïve animals. We observed that within 38 host variants were maintained over multiple transmission steps until fixation or elimination and present a model for inferring the likelihood that a given pair of samples are linked by transmission, by comparing the allelic frequency at variant genomic loci. Because within-host single nucleotide variants (iSNVs) can repeatedly pass from donor to recipient along the transmission chain, sharing of iSNVs offers limited discriminatory power in identifying a transmission pair. Beyond the presence and absence of within-host variants, we show that differences arising in the relative abundance of iSNVs (allelic frequency) can infer transmission pairs more precisely. However, in applying this method it is important to carefully consider routes of transmission, bottleneck sizes and mutation rates. Additionally, genomic artefacts must be carefully curated to avoid spurious inferences of transmission. An important component of our approach is that the inference is based solely on sequence data, without incorporating epidemiological or demographic data for context. Therefore, it can be adapted and used to complement existing epidemiologic tools

Estimating the effectiveness and cost-effectiveness of establishing additional endovascular Thrombectomy stroke Centres in England::a discrete event simulation

Background We have previously modelled that the optimal number of comprehensive stroke centres (CSC) providing endovascular thrombectomy (EVT) in England would be 30 (net 6 new centres). We now estimate the relative effectiveness and cost-effectiveness of increasing the number of centres from 24 to 30. Methods We constructed a discrete event simulation (DES) to estimate the effectiveness and lifetime cost-effectiveness (from a payer perspective) using 1 year’s incidence of stroke in England. 2000 iterations of the simulation were performed comparing baseline 24 centres to 30. Results Of 80,800 patients admitted to hospital with acute stroke/year, 21,740 would be affected by the service reconfiguration. The median time to treatment for eligible early presenters (< 270 min since onset) would reduce from 195 (IQR 155–249) to 165 (IQR 105–224) minutes. Our model predicts reconfiguration would mean an additional 33 independent patients (modified Rankin scale [mRS] 0–1) and 30 fewer dependent/dead patients (mRS 3–6) per year. The net addition of 6 centres generates 190 QALYs (95%CI − 6 to 399) and results in net savings to the healthcare system of £1,864,000/year (95% CI -1,204,000 to £5,017,000). The estimated budget impact was a saving of £980,000 in year 1 and £7.07 million in years 2 to 5. Conclusion Changes in acute stroke service configuration will produce clinical and cost benefits when the time taken for patients to receive treatment is reduced. Benefits are highly likely to be cost saving over 5 years before any capital investment above £8 million is required

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Language and alexithymia: Evidence for the role of the inferior frontal gyrus in acquired alexithymia

The clinical relevance of alexithymia, a condition associated with difficulties identifying and describing one’s own emotion, is becoming ever more apparent. Increased rates of alexithymia are observed in multiple psychiatric conditions, and also in neurological conditions resulting from both organic and traumatic brain injury. The presence of alexithymia in these conditions predicts poorer regulation of one’s emotions, decreased treatment response, and increased burden on carers. While clinically important, the aetiology of alexithymia is still a matter of debate, with several authors arguing for multiple ‘routes’ to impaired understanding of one’s own emotions, which may or may not result in distinct subtypes of alexithymia. While previous studies support the role of impaired interoception (perceiving bodily states) in the development of alexithymia, the current study assessed whether acquired language impairment following traumatic brain injury, and damage to language regions, may also be associated with an increased risk of alexithymia. Within a sample of 129 participants with penetrating brain injury and 33 healthy controls, neuropsychological testing revealed that deficits in a non-emotional language task, object naming, were associated with alexithymia, specifically with difficulty identifying one’s own emotions. Both region-of-interest and whole-brain lesion analyses revealed that damage to language regions in the inferior frontal gyrus was associated with the presence of both this language impairment and alexithymia. These results are consistent with a framework for acquired alexithymia that incorporates both interoceptive and language processes, and support the idea that brain injury may result in alexithymia via impairment in any one of a number of more basic processes