The global distribution of plants used by humans.

Plants sustain human life. Understanding geographic patterns of the diversity of species used by people is thus essential for the sustainable management of plant resources. Here, we investigate the global distribution of 35,687 utilized plant species spanning 10 use categories (e.g., food, medicine, material). Our findings indicate general concordance between utilized and total plant diversity, supporting the potential for simultaneously conserving species diversity and its contributions to people. Although Indigenous lands across Mesoamerica, the Horn of Africa, and Southern Asia harbor a disproportionate diversity of utilized plants, the incidence of protected areas is negatively correlated with utilized species richness. Finding mechanisms to preserve areas containing concentrations of utilized plants and traditional knowledge must become a priority for the implementation of the Kunming-Montreal Global Biodiversity Framework.

Nocardioform placentitis in a sample population of mares foaling in southeastern Pennsylvania and northeastern Maryland in 2020.

Nocardioform placentitis (NP) has been associated with mid to late pregnancy loss in mares. To date, disease outbreaks have been described only in central Kentucky, although sporadic, isolated cases have been reported globally. This study describes a series of cases of NP that occurred in a sample population of 299 mares foaling in southeastern Pennsylvania and northeastern Maryland in 2020. These cases coincided with an outbreak of NP that occurred in Kentucky that same year. On farms that reported information on both normal and abnormal foalings, nocardioform organisms/DNA were isolated from 6.3% of placental samples based on aerobic culture and/or PCR. In cases with characteristic gross lesions of the chorion, 41% of cases were positive on aerobic culture and/or PCR. NP was confirmed in 16 mares that had not resided in Kentucky for breeding or any part of gestation. Characteristics of mares confirmed positive for NP, including age, gestation length, and problems during gestation are described. Standardbred mares bred by artificial insemination were less likely to be affected than Thoroughbred mares bred by natural cover. Affected mares had prolonged Stage III labor compared with normal mares. These findings suggest that regional increases in NP may occur outside of Kentucky, potentially in parallel with Kentucky outbreaks.

The Interface of Therapeutics and Genomics in Cardiovascular Medicine.

Pharmacogenomics has a burgeoning role in cardiovascular medicine, from warfarin dosing to antiplatelet choice, with recent developments in sequencing bringing the promise of personalised medicine ever closer to the bedside. Further scientific evidence, real-world clinical trials, and economic modelling are needed to fully realise this potential. Additionally, tools such as polygenic risk scores, and results from Mendelian randomisation analyses, are only in the early stages of clinical translation and merit further investigation. Genetically targeted rational drug design has a strong evidence base and, due to the nature of genetic data, academia, direct-to-consumer companies, healthcare systems, and industry may meet in an unprecedented manner. Data sharing navigation may prove problematic. The present manuscript addresses these issues and concludes a need for further guidance to be provided to prescribers by professional bodies to aid in the consideration of such complexities and guide translation of scientific knowledge to personalised clinical action, thereby striving to improve patient care. Additionally, technologic infrastructure equipped to handle such large complex data must be adapted to pharmacogenomics and made user friendly for prescribers and patients alike.

Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

BACKGROUND: The number of patients living with co-existing diseases is growing. This study aimed to assess the extent of multimorbidity, medication use, and drug- and gene-based interactions in patients following a non-ST elevation acute coronary syndrome (NSTE-ACS). METHODS: In 1456 patients discharged from hospital for a NSTE-ACS, comorbidities and multimorbidity (≥ 2 chronic conditions) were assessed. Of these, 698 had complete drug use recorded at discharge, and 652 (the 'interaction' cohort) had drug use and actionable genotypes available for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, SLCO1B1, TPMT, UGT1A1, and VKORC1. The following drug interactions were investigated: pharmacokinetic drug-drug (DDIs) involving CYPs (CYPs above, plus CYP1A2, CYP2C8, CYP3A4), SLCO1B1, and P-glycoprotein; drug-gene (DGIs); drug-drug-gene (DDGIs); and drug-gene-gene (DGGIs). Interactions predicted to be 'substantial' were defined as follows: DDIs due to strong inhibitors/inducers, DGIs due to variant homozygous/compound heterozygous genotypes, and DDGIs/DGGIs where the constituent DDI/DGI(s) both influenced the victim drug in the same direction. RESULTS: In the whole cohort, 727 (49.9%) patients had multimorbidity. Non-linear relationships between age and increasing comorbidities and decreasing coronary intervention were observed. There were 98.1% and 39.8% patients on ≥ 5 and ≥ 10 drugs, respectively (from n = 698); women received more non-cardiovascular drugs than men (median (IQR) 3 (1-5) vs 2 (1-4), p = 0.014). Overall, 98.7% patients had at least one actionable genotype. Within the interaction cohort, 882 interactions were identified in 503 patients (77.1%), of which 346 in 252 patients (38.7%) were substantial: 59.2%, 11.6%, 26.3%, and 2.9% substantial interactions were DDIs, DGIs, DDGIs, and DGGIs, respectively. CYP2C19 (49.5% of all interactions) and SLCO1B1 (18.4%) were involved in the largest number of interactions. Multimorbidity (p = 0.019) and number of drugs (p = 9.8 × 10-10) were both associated with patients having ≥ 1 substantial interaction. Multimorbidity (HR 1.76, 95% CI 1.10-2.82, p = 0.019), number of drugs (HR 1.10, 95% CI 1.04-1.16, p = 1.2 × 10-3), and age (HR 1.05, 95% CI 1.03-1.07, p = 8.9 × 10-7), but not drug interactions, were associated with increased subsequent major adverse cardiovascular events. CONCLUSIONS: Multimorbidity, polypharmacy, and drug interactions are common after a NSTE-ACS. Replication of results is required; however, the high prevalence of DDGIs suggests integrating co-medications with genetic data will improve medicines optimisation.

Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Estimating seasonal variation in Australian pertussis notifications from 1991 to 2016: evidence of spring to summer peaks.

Unlike for many other respiratory infections, the seasonality of pertussis is not well understood. While evidence of seasonal fluctuations in pertussis incidence has been noted in some countries, there have been conflicting findings including in the context of Australia. We investigated this issue by analysing the seasonality of pertussis notifications in Australia using monthly data from January 1991 to December 2016. Data were made available for all states and territories in Australia except for the Australian Capital Territory and were stratified into age groups. Using a time-series decomposition approach, we formulated a generalised additive model where seasonality is expressed using cosinor terms to estimate the amplitude and peak timing of pertussis notifications in Australia. We also compared these characteristics across different jurisdictions and age groups. We found evidence that pertussis notifications exhibit seasonality, with peaks observed during the spring and summer months (November-January) in Australia and across different states and territories. During peak months, notifications are expected to increase by about 15% compared with the yearly average. Peak notifications for children <5 years occurred 1-2 months later than the general population, which provides support to the theory that older household members remain an important source of pertussis infection for younger children. In addition, our results provide a more comprehensive spatial picture of seasonality in Australia, a feature lacking in previous studies. Finally, our findings suggest that seasonal forcing may be useful to consider in future population transmission models of pertussis.

Computationally efficient methods for fitting mixed models to electronic health records data.

Motivated by two case studies using primary care records from the Clinical Practice Research Datalink, we describe statistical methods that facilitate the analysis of tall data, with very large numbers of observations. Our focus is on investigating the association between patient characteristics and an outcome of interest, while allowing for variation among general practices. We explore ways to fit mixed-effects models to tall data, including predictors of interest and confounding factors as covariates, and including random intercepts to allow for heterogeneity in outcome among practices. We introduce (1) weighted regression and (2) meta-analysis of estimated regression coefficients from each practice. Both methods reduce the size of the dataset, thus decreasing the time required for statistical analysis. We compare the methods to an existing subsampling approach. All methods give similar point estimates, and weighted regression and meta-analysis give similar standard errors for point estimates to analysis of the entire dataset, but the subsampling method gives larger standard errors. Where all data are discrete, weighted regression is equivalent to fitting the mixed model to the entire dataset. In the presence of a continuous covariate, meta-analysis is useful. Both methods are easy to implement in standard statistical software.

Label-invariant models for the analysis of meta-epidemiological data.

Rich meta-epidemiological data sets have been collected to explore associations between intervention effect estimates and study-level characteristics. Welton et al proposed models for the analysis of meta-epidemiological data, but these models are restrictive because they force heterogeneity among studies with a particular characteristic to be at least as large as that among studies without the characteristic. In this paper we present alternative models that are invariant to the labels defining the 2 categories of studies. To exemplify the methods, we use a collection of meta-analyses in which the Cochrane Risk of Bias tool has been implemented. We first investigate the influence of small trial sample sizes (less than 100 participants), before investigating the influence of multiple methodological flaws (inadequate or unclear sequence generation, allocation concealment, and blinding). We fit both the Welton et al model and our proposed label-invariant model and compare the results. Estimates of mean bias associated with the trial characteristics and of between-trial variances are not very sensitive to the choice of model. Results from fitting a univariable model show that heterogeneity variance is, on average, 88% greater among trials with less than 100 participants. On the basis of a multivariable model, heterogeneity variance is, on average, 25% greater among trials with inadequate/unclear sequence generation, 51% greater among trials with inadequate/unclear blinding, and 23% lower among trials with inadequate/unclear allocation concealment, although the 95% intervals for these ratios are very wide. Our proposed label-invariant models for meta-epidemiological data analysis facilitate investigations of between-study heterogeneity attributable to certain study characteristics.

Xenografting of isolated equine (Equus caballus) testis cells results in de novo morphogenesis of seminiferous tubules but not spermatogenesis.

The study of spermatogenesis in the horse is challenging because of the absence of an in vitro system that is capable of reproducing efficient spermatogenesis and because of the difficulties and costs associated with performing well-controlled studies in vivo. In an attempt to develop novel methods for the study of equine spermatogenesis, we tested whether cells from enzymatically digested pre-pubertal equine testicular tissue were capable of de novo tissue formation and spermatogenesis following xenografting under the back skin of immunocompromised mice. Testes were obtained from normal pre-pubertal colts and dissociated into cell suspensions using trypsin/collagenase digestion. Resulting cell pellets, consisting of both somatic and germ cells, were injected into fascial pockets under the back skin of immunocompromised, castrated mice and maintained for between 1 and 14 months. Mice were killed and grafts were recovered and analyzed. As has been reported for testis cell suspensions from pigs, mice, cattle, and sheep, de novo formation of equine testicular tissue was observed, as evidenced by the presence of seminiferous tubules and an interstitial compartment. There was an increased likelihood of de novo testicular formation as grafting period increased. Using indirect immunofluorescence, we confirmed the presence of spermatogonia in de novo formed seminiferous tubules. However, we found no evidence of meiotic or haploid cells. These results indicate that dissociated pre-pubertal equine testis cells are capable of reorganizing into the highly specialized endocrine and spermatogenic compartments of the testis following ectopic xenografting. However, in spite of the presence of spermatogonia within the seminiferous tubules, spermatogenesis does not occur. Although this technique does allow access to the cells within the seminiferous tubule and interstitial compartments of the equine testis prior to reaggregation, the absence of spermatogenesis will limit its use as a method for the study of testicular function in the horse.

Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium.

Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.

Effectiveness of continuous or intermittent vital signs monitoring in preventing adverse events on general wards: a systematic review and meta-analysis.

BACKGROUND: Vital signs monitoring is an old hospital practice for patient safety but evaluation of its effectiveness is not widespread. We aimed to identify strategies to improve intermittent or continuous vital signs monitoring in general wards; and their effectiveness in preventing adverse events on general hospital wards. METHODS: Publications searched between 1980 and June 2014 in five databases. Main outcome measures were in-hospital death, cardiac arrest, intensive care unit (ICU) transfers, length of stay, identification of physiological deterioration and activation of rapid response systems. RESULTS: Twenty-two studies assessing the effect of continuous (9) or intermittent monitoring (13) and reporting outcomes on 203,407 patients in-hospital wards across 13 countries were included in this review. Both monitoring practices led to early identification of patient deterioration, increased rapid response activations and improvements in timeliness or completeness of vital signs documentation. Innovative intermittent monitoring approaches are associated with modest reduction in in-hospital mortality over intermittent vital signs monitoring in 'usual care'. However, there was no evidence of significant reduction in ICU transfers or other adverse events with either intermittent or continuous monitoring. CONCLUSIONS: This review of heterogeneous monitoring approaches found no conclusive confirmation of improvements in prevention of cardiac arrest, reduction in length of hospital stay, or prevention of other neurological or cardiovascular adverse events. The evidence found to date is insufficient to recommend continuous vital signs monitoring in general wards as routine practice. Future evaluations of effectiveness need to be undertaken with more rigorous methods and homogeneous outcome measurements.

Non-beneficial treatments in hospital at the end of life: a systematic review on extent of the problem.

PURPOSE: To investigate the extent of objective 'non-beneficial treatments (NBTs)' (too much) anytime in the last 6 months of life in routine hospital care. DATA SOURCES: English language publications in Medline, EMBASE, PubMed, Cochrane library, and the grey literature (January 1995-April 2015). STUDY SELECTION: All study types assessing objective dimensions of non-beneficial medical or surgical diagnostic, therapeutic or non-palliative procedures administered to older adults at the end of life (EOL). DATA EXTRACTION: A 13-item quality score estimated independently by two authors. RESULTS OF DATA SYNTHESIS: Evidence from 38 studies indicates that on average 33-38% of patients near the EOL received NBTs. Mean prevalence of resuscitation attempts for advanced stage patients was 28% (range 11-90%). Mean death in intensive care unit (ICU) was 42% (range 11-90%); and mean death rate in a hospital ward was 44.5% (range 29-60%). Mean prevalence of active measures including dialysis, radiotherapy, transfusions and life support treatment to terminal patient was 7-77% (mean 30%). Non-beneficial administration of antibiotics, cardiovascular, digestive and endocrine treatments to dying patients occurred in 11-75% (mean 38%). Non-beneficial tests were performed on 33-50% of patients with do-not-resuscitate orders. From meta-analyses, the pooled prevalence of non-beneficial ICU admission was 10% (95% CI 0-33%); for chemotherapy in the last six weeks of life was 33% (95% CI 24-41%). CONCLUSION: This review has confirmed widespread use of NBTs at the EOL in acute hospitals. While a certain level of NBT is inevitable, its extent, variation and justification need further scrutiny.

Pregnancy outcomes using stallion epididymal sperm stored at 5 °C for 24 or 48 hours before harvest.

The cryopreservation of epididymal sperm can be useful in a variety of circumstances for ensuring genetic preservation of a valued stallion. Although early studies have reported pregnancy rates significantly lower than those achieved with cryopreserved ejaculated sperm, two recent studies report over 60% one-cycle pregnancy rates with epididymal sperm stored for 24 hours at 5 °C before harvest and cryopreservation. The aims of this study were to: (1) attempt to replicate the one-cycle pregnancy rate of over 60% using epididymal sperm cooled and stored within the epididymis for 24 hours before harvest and cryopreservation and (2) evaluate pregnancy outcome with sperm cooled and stored within the epididymis for 48 hours before sperm harvest and cryopreservation. Testicles were obtained from 13 stallions undergoing routine castration. The epididymides were stored at 5 °C for either 24 or 48 hours before sperm harvest and cryopreservation in an egg yolk and dimethylformamide-based freezing extender. Thirteen mares were bred on one cycle with cryopreserved epididymal sperm stored for 24 hours before harvest, and 10 of those 13 mares were also bred on a previous or subsequent cycle with samples from the same stallion that had been stored for 48 hours before harvest. Pregnancy occurred in 7 of the 13 inseminations of sperm stored for 24 hours before harvest, and in 4 of the 10 inseminations of sperm stored for 48 hours before harvest. The pregnancy rate using epididymal sperm stored for 24 hours before harvest is consistent with that of previous reports. In addition, these results provide evidence that pregnancies can be achieved when the epididymides are cooled and stored for 48 hours before sperm harvest and cryopreservation.

Meta-analysis of the effect of preoperative breast MRI on the surgical management of ductal carcinoma in situ.

BACKGROUND: MRI has been used increasingly in the diagnosis and management of women with invasive breast cancer. However, its usefulness in the preoperative assessment of ductal carcinoma in situ (DCIS) remains questionable. A meta-analysis was conducted to examine the effects of MRI on surgical treatment of DCIS by analysing studies comparing preoperative MRI with conventional preoperative assessment. METHODS: Using random-effects modelling, the proportion of women with various outcomes in the MRI versus no-MRI groups was estimated, and the odds ratio (OR) and adjusted OR (adjusted for study-level median age) for each model were calculated. RESULTS: Nine eligible studies were identified that included 1077 women with DCIS who had preoperative MRI and 2175 who did not. MRI significantly increased the odds of having initial mastectomy (OR 1·72, P = 0·012; adjusted OR 1·76, P = 0·010). There were no significant differences in the proportion of women with positive margins following breast-conserving surgery (BCS) in the MRI and no-MRI groups (OR 0·80, P = 0·059; adjusted OR 1·10, P = 0·716), nor in the necessity of reoperation for positive margins after BCS (OR 1·06, P = 0·759; adjusted OR 1·04, P = 0·844). Overall mastectomy rates did not differ significantly according to whether or not MRI was performed (OR 1·23, P = 0·340; adjusted OR 0·97, P = 0·881). CONCLUSION: Preoperative MRI in women with DCIS is not associated with improvement in surgical outcomes.

Antenatal predictors and body composition of large-for-gestational-age newborns: perinatal health outcomes.

OBJECTIVE: To compare body composition of large-for-gestational-age (LGA) with appropriate-for-gestational-age (AGA) newborns and to identify antenatal predictors of LGA. STUDY DESIGN: This cross-sectional study included 536 term, singleton infants. Anthropometric measurements were performed within 48 h of birth and included determination of body fat percentage (%BF) by air displacement plethysmography. Associations were investigated using logistic regression. RESULT: LGA infants had greater %BF (P<0.001) compared with AGA infants. Significant predictors of LGA infants included parity (odds ratio (OR)=1.98, (95% confidence interval (CI) 1.00, 4.02)), paternal height (OR=1.08, (95% CI 1.03, 1.14)), maternal pregravid weight (65 to 74.9 kg: OR=2.77, (95% CI 1.14, 7.06)) and gestational weight gain (OR=1.09, 95% CI (1.03, 1.16)). Gestational diabetes mellitus was not associated with LGA infants (P=0.598). CONCLUSION: Paternal height, parity, maternal pregravid weight and gestational weight gain were strongly associated with LGA infants. These results may allow early prediction and potential modification, thereby optimising clinical outcomes.

Cardiovascular pharmacogenomics: expectations and practical benefits.

Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Pharmacogenomics is the study of genetic determinants of interindividual variation in drug response and aims to facilitate personalized medicine, through genotype-informed drug and dose selection, to maximize drug efficacy and/or minimize adverse drug reactions. Despite high expectations, no cardiovascular pharmacogenomic association is currently in widespread clinical practice; evidential, logistical, financial, and knowledge implementation barriers exist. Nevertheless, VKORC1, CYP2C9, and CYP4F2 variants have been associated with warfarin dose requirements, and CYP2C19 variants have been associated with perturbed antiplatelet response to clopidogrel. However, at present, controversy exists over the clinical utility of these genetic associations. There is an increased risk of simvastatin-induced muscle toxicity in SLCO1B1*5 carriers, ADRB1 and ADRA2C polymorphisms are associated with differential response to bucindolol, and rare congenital arrhythmia gene variants have been identified in drug-induced torsade de pointes. Practical benefits are still anticipated, but much work remains.

Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney-pancreas transplant recipients.

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney-pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add-on test to qualitative polyoma NAT for the diagnosis of BK virus-associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10(3) serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1-99.8) and specificity 79.1% (95%: CI 67.4-88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8-57.7%) and 98.6% (95% CI: 98.3-99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85-0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add-on test to qualitative polyomavirus NAT for kidney and kidney-pancreas transplant recipients at risk of BKVAN.

The emerging pathophysiology of age-related testicular degeneration with a focus on the stallion and an update on potential therapies.

Studies in laboratory rodents are shedding light on the pathophysiology of testicular ageing and now suggest a complicated basis for age-related declines in testicular function. A highly significant contributor to infertility may involve failure of specific and complex testicular microenvironments (niches) comprised of a variety of cellular and molecular components. Our laboratory has applied testis tissue xenografting to the study of testicular ageing in the stallion. Using this technique, we have confirmed that the disease is tissue autologous. As would be expected from a tissue autologous disease, hormonal and non-hormonal therapies designed to drive the function of the diseased testis are ineffective. However, we have some evidence that contact with young, normal testicular tissue may improve the condition of aged, degenerate testes. Perhaps, paracrine factors from young testicular cells may partially restore a young microenvironment and allow for the maintenance of testicular function. These findings form the basis for future studies designed to determine whether cells, genes or proteins from a normal testis can aid the function of a degenerate testis.