Oocyte quality is enhanced by hypoglycosylated FSH through increased cell-to-cell interaction during mouse follicle development.

Macroheterogeneity in follicle-stimulating hormone (FSH) ß-subunit N-glycosylation results in distinct FSH glycoforms. Hypoglycosylated FSH21 is the abundant and more bioactive form in pituitaries of females under 35 years of age, whereas fully glycosylated FSH24 is less bioactive and increases with age. To investigate whether the shift in FSH glycoform abundance contributes to the age-dependent decline in oocyte quality, the direct effects of FSH glycoforms on folliculogenesis and oocyte quality were determined using an encapsulated in vitro mouse follicle growth system. Long-term culture (10-12 days) with FSH21 (10 ng/ml) enhanced follicle growth, estradiol secretion and oocyte quality compared with FSH24 (10 ng/ml) treatment. FSH21 enhanced establishment of transzonal projections, gap junctions and cell-to-cell communication within 24 h in culture. Transient inhibition of FSH21-mediated bidirectional communication abrogated the positive effects of FSH21 on follicle growth, estradiol secretion and oocyte quality. Our data indicate that FSH21 promotes folliculogenesis and oocyte quality in vitro by increasing cell-to-cell communication early in folliculogenesis, and that the shift in in vivo abundance from FSH21 to FSH24 with reproductive aging may contribute to the age-dependent decline in oocyte quality.

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients.

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

The Pharmacogenomics Global Research Network Implementation Working Group: global collaboration to advance pharmacogenetic implementation.

Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.

A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. METHODS: Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689. FINDINGS: Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive). INTERPRETATION: In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy. FUNDING: UK National Institute of Health Research Health Technology Programme.

A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer.

BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-2 Trial: Analysis of the Timing and Causes of Death in Participants Randomised to an Infrapopliteal Vein Bypass or Best Endovascular Treatment First Revascularisation Strategy.

OBJECTIVE: The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-2 trial enrolled participants with chronic limb threatening ischaemia who required an infrapopliteal, with or without a femoropopliteal, revascularisation procedure to restore limb perfusion. Participants randomised to a vein bypass (VB) first revascularisation strategy were over one third more likely than those randomised to a best endovascular treatment (BET) first revascularisation strategy to die from any cause during a median follow up of 40.0 (interquartile range 20.9, 60.6) months. The aim of the present study was to describe the timing and causes of death in BASIL-2 as a first step towards trying to better understand why randomisation to a VB first revascularisation strategy was associated with this excess mortality. METHODS: A 10 person international panel comprising vascular and endovascular surgeons as well as vascular interventional radiologists, who had all been principal investigators in BASIL-2, took part in a modified Delphi consensus exercise to adjudicate the primary cause of death and, in particular, whether the cause was primarily cardiac or non-cardiac. RESULTS: In 151 of 168 deaths (89.9%), the Delphi panel achieved a consensus regarding the cause of death being probably cardiac or non-cardiac. In the BET group, 16 of 77 deaths (21%) were classified as probably cardiac compared with 32 of 91 (35%) in the VB group (unadjusted subdistribution hazard ratio 2.16, 95% confidence interval [CI] 1.20 - 3.87; unadjusted cause specific hazard ratio 2.15, 95% CI 1.19 - 3.90). At the point of randomisation, 64 of 344 (18.6%), 40 of 342 (11.7%), and 37 of 344 (10.8%) participants had a previous myocardial infarction (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG), respectively. There was no evidence of varying treatment effects for cause of death in subgroup analyses of previous PCI, CABG, or MI. CONCLUSION: The excess mortality observed in the VB first revascularisation strategy group in BASIL-2 was largely due to deaths that were adjudicated by the Delphi panel as probably primarily cardiac. These excess cardiac deaths were observed throughout follow up and there was no evidence of non-proportional hazards. Further work is ongoing to try to better understand the reasons for these findings.

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing.

CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.

Use of patient-reported outcome measures for oncology drugs receiving accelerated approval.

Patient-reported outcomes (PROs) represent an important evaluation of health-related quality of life that has become more commonly incorporated into oncology drug clinical trials. The frequency of PRO inclusion as an endpoint in oncology drug clinical trials leading to the initial accelerated approval of a new therapy is not yet known. We conducted a cross-sectional study evaluating all new drug applications submitted to the FDA over the past 10 years (2013-2022) that led to the initial approval of an oncology drug through the accelerated approval process. The objective was to assess whether the trials leading to such an approval included PROs. Between 2013 and 2022, the FDA approved 59 unique drugs for an oncology indication via the accelerated approval pathway, and 35 (59%) included a PRO assessment in the clinical trial. A median of 1 PRO measurement was used in each trial, with 23 different types of PRO assessment tools were used across the 59 new drug applications. In summary, we found that PRO measurements are inconsistently utilized in trials leading to initial accelerated approval of oncology drugs, and there seems to be a lack of harmonization of different PRO measurement tools used across trials.

Cardiovascular diseases display etiological and seasonal trend in human population: Evidence from seasonal cardiovascular comorbid diseases (SCCD) index.

Seasonal changes in the human cardiovascular system are known to play an important role in the onset of many diseases. Confounding variables include behavioral and environmental factors; failing to address such variables makes measuring the true temporal impact of these diseases difficult. On the other hand, numerous clinical studies imply that only specific groups of people are more seasonal sensitive and that their maladaptation might contribute to various illnesses. As a result, it is critical to evaluate the etiological and seasonal sensitive patterns of cardiovascular diseases (CVD), which impact the majority of the human population. The hypothesis for this study formulated that cardiovascular and associated illnesses had substantial connections with seasonal and etiological variations. Thus in the present study, 4519 systematic screen-eligible studies were analyzed using data mining to uncover 852 disease association relationships between cardiovascular and associated disorders. A disease ontology-based semantic similarity network (DSN) analysis was performed to narrow down the identified CVDs. Further, topological analysis was used to predict the seven CVDs, including myocardial infarction (MI), in three clusters. Following that, Mann-Kendall and Cox-Stuart analyses were used to investigate the seasonal sensitivity and temporal relationship of these seven CVDs. Finally, temporal relationships were confirmed using LOESS and TBATS, as well as seasonal breakdown utilizing autocorrelation and fast Fourier transform results. The study provides indirect evidence of a severe etiological association among the three cardiovascular diseases, including MI, atrial fibrillation, and atherosclerosis, which are winter season sensitive in most of the world population. Hypertension has two seasonal falls and peaks due to its seasonal nature, that is, summer and winter hypertension. While, heart failure was also identified, with minor temporal trends. Hence, all five diseases could be classified as seasonal cardiovascular comorbid diseases (SCCD). Furthermore, these diseases could be studied for potential common risk factors such as biochemical, genetic, and physiological factors.

Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.

BACKGROUND: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

Integrating pharmacogenomics into precision pain management.

Studies suggest wide heterogeneity in pain management response. Improved methods of pain pharmacotherapy are urgently needed to improve clinical response and safety profile of analgesics. The study or application of how genetics influence response to medications is called pharmacogenomics (PGx). PGx testing is a tool that may support more precise selection and dosing of pain medicines. PGx guidelines exist for drug-gene interactions with high levels of evidence and can be applied in clinical practice for more precise care in patients with cancer. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a publicly funded international consortium of experts who curate published PGx data and create peer-reviewed guidelines on how to translate PGx results into actionable prescribing decisions. Given the immense need to improve pain management, it is important to increase awareness and consider application of CPIC guidelines to pain management strategies. This commentary concisely describes how PGx can be used to aid in more precise applications of pain pharmacotherapy based on the CPIC guidelines.

Global-level population genomics reveals differential effects of geography and phylogeny on horizontal gene transfer in soil bacteria.

Although microorganisms are known to dominate Earth's biospheres and drive biogeochemical cycling, little is known about the geographic distributions of microbial populations or the environmental factors that pattern those distributions. We used a global-level hierarchical sampling scheme to comprehensively characterize the evolutionary relationships and distributional limitations of the nitrogen-fixing bacterial symbionts of the crop chickpea, generating 1,027 draft whole-genome sequences at the level of bacterial populations, including 14 high-quality PacBio genomes from a phylogenetically representative subset. We find that diverse Mesorhizobium taxa perform symbiosis with chickpea and have largely overlapping global distributions. However, sampled locations cluster based on the phylogenetic diversity of Mesorhizobium populations, and diversity clusters correspond to edaphic and environmental factors, primarily soil type and latitude. Despite long-standing evolutionary divergence and geographic isolation, the diverse taxa observed to nodulate chickpea share a set of integrative conjugative elements (ICEs) that encode the major functions of the symbiosis. This symbiosis ICE takes 2 forms in the bacterial chromosome-tripartite and monopartite-with tripartite ICEs confined to a broadly distributed superspecies clade. The pairwise evolutionary relatedness of these elements is controlled as much by geographic distance as by the evolutionary relatedness of the background genome. In contrast, diversity in the broader gene content of Mesorhizobium genomes follows a tight linear relationship with core genome phylogenetic distance, with little detectable effect of geography. These results illustrate how geography and demography can operate differentially on the evolution of bacterial genomes and offer useful insights for the development of improved technologies for sustainable agriculture.

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.

Potentially actionable pharmacogenetic variants and symptom control medications in oncology.

PURPOSE: We estimated the prevalence of potentially actionable pharmacogenetic (PGx) variants related to symptom control medications (SCMs) based on institutional prescribing patterns and correlated presenting symptoms with SCM prescribing. METHODS: This was a retrospective study of adult ambulatory cancer patients undergoing electronic distress screening (EDS) within 90 days of intake to the cancer hospital. We estimated the proportion prescribed SCM(s) with PGx evidence within 90 days of intake. Those with potentially actionable variants were estimated using population frequency data from 1000 genomes. The expected number at risk of altered drug response was estimated. The associations between symptom scores and SCM(s) were estimated with logistic regression and threshold analyses performed with receiver operating characteristic (ROC) curves. RESULTS: Of 6985 patients, 3222 (46%) received ≥ one SCM. Of these, 2760 (86%) received SCM(s) with PGx evidence for CYP2B6, CYP2C19, CYP2D6, or SLC6A4; 2719 (84%) received a drug metabolized by CYP2D6, most commonly hydrocodone (40.4%), ondansetron (35.6%), oxycodone (24.2%), and/or tramadol (7.1%). Based on this, about one quarter were expected to have altered metabolism and/or drug response. One third were prescribed two or more SCMs with PGx evidence. About half reported at least one severe symptom, which significantly correlated with SCM prescribing (p < 0.001). Threshold scores were identified that highly correlated with SCM prescribing for anxiety, depression, nausea, neuropathy, pain, and sleep. CONCLUSION: About half presented with significant symptom burden, which highly correlated with SCM prescribing. Most received SCMs with PGx evidence. Preemptive PGx testing for these variants should be evaluated in prospective trials to evaluate the impact on symptom control.

Infusion techniques for peripheral arterial thrombolysis.

BACKGROUND: Acute limb ischaemia usually is caused by a blood clot blocking an artery or a bypass graft. Severe acute ischaemia will lead to irreversible damage to muscles and nerves if blood flow is not restored in a few hours. Once irreversible damage occurs, amputation will be necessary and the condition can be life-threatening. Infusion of clot-busting drugs (thrombolysis) is a useful tool in the management of acute limb ischaemia. Fibrinolytic drugs are used to disperse blood clots (thrombi) to clear arterial occlusion and restore blood flow. Thrombolysis is less invasive than surgery. A variety of techniques are used to deliver fibrinolytic agents. This is an update of a review first published in 2004. OBJECTIVES: To compare the effects of infusion techniques during peripheral arterial thrombolysis for treatment of patients with acute limb ischaemia. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries to 20 October 2020. We undertook reference checking to identify additional studies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing infusion techniques for fibrinolytic agents in the treatment of acute limb ischaemia. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. We assessed the risk of bias in included trials using the Cochrane 'Risk of bias' tool. We evaluated certainty of evidence using GRADE. For dichotomous outcomes, we calculated the odds ratio (OR) with the corresponding 95% confidence interval (CI). We were not able to carry out meta-analyses due to clinical heterogeneity, so we have reported the results and performed the comparisons narratively. The main outcomes of interest were amputation-free survival or limb salvage, amputation, mortality, vessel patency, duration of thrombolysis, and complications such as cerebrovascular accident and major and minor bleeding. MAIN RESULTS: Nine studies with a total of 671 participants are included in this update. Trials covered a variety of infusion techniques, dosage regimens, and adjunctive agents. We grouped trials according to types of techniques assessed (e.g. intravenous and intra-arterial delivery of the agent, 'high-' and 'low-dose' regimens of the agent, continuous infusion and 'forced infusion' of the agent, use of adjunctive antiplatelet agents). We assessed the certainty of evidence as very low to low due to the limited power of individual studies to deliver clinically relevant results, small and heterogeneous study populations, use of different inclusion criteria by each study in terms of severity and duration of ischaemia, considerably different outcome measures between trials, and use of different fibrinolytic agents. This heterogeneity prevented pooling of data in meta-analyses. No regimen has been shown to confer benefit in terms of amputation-free survival (at 30 days), amputation, or death. For vessel patency, complete success was more likely with intra-arterial (IA) than with intravenous (IV) infusion (odds ratio (OR) 13.22, 95% confidence interval (CI) 2.79 to 62.67; 1 study, 40 participants; low-certainty evidence); radiological failure may be more likely with IV infusion (OR 0.02, 95% CI 0.00 to 0.38; 1 study, 40 participants; low-certainty evidence). Due to the small numbers involved in each arm and design differences between arms, it is not possible to conclude whether any technique offered any advantage over another. None of the treatment strategies clearly affected complications such as cerebrovascular accident or major bleeding requiring surgery or blood transfusion. Minor bleeding complications were more frequent in systemic (intravenous) therapy compared to intra-arterial infusion (OR 0.03, 95% CI 0.00 to 0.56; 1 study, 40 participants), and in high-dose compared to low-dose therapy (OR 0.11, 95% CI 0.01 to 0.96; 1 study, 63 participants). Limited evidence from individual trials appears to indicate that high-dose and forced-infusion regimens reduce the duration of thrombolysis. In one trial, the median duration of infusion was 4 hours (range 0.25 to 46) for the high-dose group and 20 hours (range 2 to 46) for the low-dose group. In a second trial, treatment using pulse spray was continued for a median of 120 minutes (range 40 to 310) compared with low-dose infusion for a median of 25 hours (range 2 to 60). In a third trial, the median duration of therapy was reduced with pulse spray at 195 minutes (range 90 to 1260 minutes) compared to continuous infusion at 1390 minutes (range 300 to 2400 minutes). However, none of the studies individually showed improvement in limb salvage at 30 days nor benefit for the amputation rate related to the technique of drug delivery. Similarly, no studies reported a clear difference in occurrence of cerebrovascular accident or major bleeding. Although 'high-dose' and 'forced-infusion' techniques achieved vessel patency in less time than 'low-dose' infusion, more minor bleeding complications may be associated (OR 0.11, 95% CI 0.01 to 0.96; 1 study, 72 participants; and OR 0.48, 95% CI 0.17 to 1.32; 1 study, 121 participants, respectively). Use of adjunctive platelet glycoprotein IIb/IIIa antagonists did not improve outcomes, and results were limited by inclusion of participants with non-limb-threatening ischaemia. AUTHORS' CONCLUSIONS: There is insufficient evidence to show that any thrombolytic regimen provides a benefit over any other in terms of amputation-free survival, amputation, or 30-day mortality. The rate of CVA or major bleeding requiring surgery or blood transfusion did not clearly differ between regimens but may occur more frequently in high dose and IV regimens. This evidence was limited and of very low certainty. Minor bleeding may be more common with high-dose and IV regimens. In this context, thrombolysis may be an acceptable therapy for patients with marginally threatened limbs (Rutherford grade IIa) compared with surgery. Caution is advised for patients who do not have limb-threatening ischaemia (Rutherford grade I) because of risks of major haemorrhage, cerebrovascular accident, and death from thrombolysis.

100 days outcome of severe wasting in hospitalised infants <6 months of age.

OBJECTIVE: To assess the outcome of severe wasting in infants below 6 months of age. DESIGN: A prospective observational study conducted between January 2017 and October 2018. SETTING: A medical college-affiliated hospital in Eastern Delhi, catering mainly to the urban poor population. PARTICIPANTS: All children with severe wasting (weight-for-length Z-score (WLZ) < -3 sd) between 1 and 6 months of age, requiring hospitalisation. RESULTS: Out of fifty children enrolled, during hospitalisation, forty-two (84 %) recovered (WLZ > -3 sd) and discharged; the median (interquartile range (IQR)) duration of stay was 9·5 (6·5, 13·0) d. After 100 d of enrolment, sustained cure (WLZ > -2 SD) could be achieved in only fifteen (30 %) infants, while another fourteen (28 %) recovered from severe wasting, but remained in moderately wasted state (WLZ between -2 and -3 sd). Overall, there were three (6 %) deaths (all during first week of hospitalisation); three (6 %) relapses and fifteen (30 %) defaulters (5, 5, 2, 1 and 2 defaulted during hospitalisation at day 15, day 60, day 75 and day 90, respectively). CONCLUSIONS: The overall recovery rate from severe wasting in infants below 6 months of age was below the acceptable levels. In order to achieve better long-term outcome, community linkage services after discharge from hospital are required for supervised feeding, close monitoring and supportive care.