Antibody-Drug Conjugates and Ocular Toxicity: Nursing, Patient, and Organizational Implications for Care.

BACKGROUND: Antibody-drug conjugates (ADCs) are a novel class of drugs with rapidly expanding oncology indications across solid and hematologic malignancies. OBJECTIVES: This article provides an overview of ADCs with a high risk of ocular reactions and guidance for oncology nurses to help mitigate risk and identify toxicities for prompt management. METHODS: This review presents updated evidence, manufacturer recommendations, and clinical guidance about three ADCs with a risk of overall ocular reactions exceeding 40%, as well as strategies to prepare patients for treatment, prevent reactions, and respond to presenting ocular toxicities. FINDINGS: ADCs can cause a range of ocular reactions from mild dry eye to severe and dose- limiting corneal adverse reactions and vision loss. Oncology nurses and other members of the interprofessional team can perform focused clinical assessment, provide patient education about self-management and prevention, and coordinate surrounding eye care for patients receiving treatment with ADCs.

An Evidence-Based Review of the Safety and Efficacy of Remote Chemotherapy Verification.

In response to the nursing shortage and the emergence of telehealth opportunities, the Oncology Nursing Society used an evidence-based approach to examine current literature and trends for the two-person independent double ch.

Regulation of vascular angiotensin II type 1 and type 2 receptor and angiotensin-(1-7)/MasR signaling in normal and hypertensive pregnancy.

Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II (Ang II), although the renin-angiotensin-aldosterone system (RAAS) is upregulated. Preeclampsia (PE) is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg), and dysregulation of angiotensin biosynthesis and signaling have been implicated. Ang II activates vascular Ang II type-1 receptor (AT1R) and Ang II type-2 receptor (AT2R), while angiotensin-(1-7) promotes Ang-(1-7)/MasR signaling. The role of AT1R in vasoconstriction and the activated cellular mechanisms are well-characterized. The sensitivity of vascular AT1R to Ang II and consequent activation of vasoconstrictor mechanisms decrease during Norm-Preg, but dramatically increase in HTN-Preg. Placental ischemia in late pregnancy could also initiate the release of AT1R agonistic autoantibodies (AT1AA) with significant impact on endothelial dysfunction and activation of contraction pathways in vascular smooth muscle including [Ca2+]c and protein kinase C. On the other hand, the role of AT2R and Ang-(1-7)/MasR in vascular relaxation, particularly during Norm-Preg and PE, is less clear. During Norm-Preg, increases in the expression/activity of vascular AT2R and Ang-(1-7)/MasR promote the production of endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor leading to generalized vasodilation. Aortic segments of Preg rats show prominent endothelial AT2R staining and increased relaxation and NO production in response to AT2R agonist CGP42112A, and treatment with AT2R antagonist PD123319 enhances phenylephrine-induced contraction. Decreased vascular AT2R and Ang-(1-7)/MasR expression and receptor-mediated mechanisms of vascular relaxation have been suggested in HTN-Preg animal models, but their role in human PE needs further testing. Changes in angiotensin-converting enzyme-2 (ACE2) have been observed in COVID-19 patients, and whether ACE2 influences the course of COVID-19 viral infection/immunity in Norm-Preg and PE is an intriguing area for research.

Effects of Adding Lean Red Meat to a U.S.-Style Healthy Vegetarian Dietary Pattern on Gut Microbiota and Cardiovascular Risk Factors in Young Adults: a Crossover Randomized Controlled Trial.

BACKGROUND: Limited research evidence exists on the effects of red meat on gut microbiota in human adults. OBJECTIVE: We aim to assess the effects of consuming a Healthy U.S.-Style Dietary Pattern (HDP), without or with unprocessed or processed lean red meats, on gut microbiota and fecal short-chain fatty acid (SCFA) levels in healthy young adults. Secondary outcomes are cardiovascular disease risk factors. METHODS: We conducted a randomized, controlled, crossover trial with 3 3-wk dietary interventions, each separated by a 5-wk washout period with habitual dietary intake. Nineteen participants (8 females, age 26 ± 4 y old, BMI 23 ± 3 kg/m2) consumed 3 study diets in random order: 1) healthy lacto-ovo vegetarian diet (LOV); 2) LOV plus 3 ounces/d of cooked unprocessed lean red meat (URM); and 3) LOV plus 3 ounces/d of cooked processed lean red meat (PRM). Fecal and fasting blood samples were collected before and during the last 2 wk of each intervention. We measured fecal bacterial community structure using 16S rRNA amplicon sequencing (V4 region, primers 515F-806R). Community diversity, structure, and taxonomic composition were computed using Mothur v.1.44.3. RESULTS: The addition of unprocessed or processed lean red meats to a LOV HDP did not influence short-term changes in bacterial taxonomic composition. Independent of red meat intake, the HDP led to changes in 23 bacteria; reductions in serum total cholesterol (TC) and LDL-C concentrations; but no changes in fecal SCFA, serum triglycerides, HDL-C concentrations, TC/HDL-C ratio, or blood pressures. With data from all 3 diet interventions combined, changes in some bacteria were associated with improvements in TC, LDL-C, triglycerides, and HDL-C concentrations, and TC/HDL-C ratio. CONCLUSIONS: Healthy young adults who adopt an HDP that may be vegetarian or omnivorous, including lean red meat, experience short-term changes in gut microbial composition, which associate with improvements in multiple lipid-related cardiovascular risk factors. NCT03885544, https://clinicaltrials.gov/ct2/show/NCT03885544?cond=NCT03885544&draw=2&rank=1.

Meat Consumption and Gut Microbiota: a Scoping Review of Literature and Systematic Review of Randomized Controlled Trials in Adults.

Emerging research indicates the importance of gut microbiota in mediating the relationship between meat intake and human health outcomes. We aimed to assess the state of available scientific literature on meat intake and gut microbiota in humans (PROSPERO, International Prospective Register of Systematic Reviews, CRD42020135649). We first conducted a scoping review to identify observational and interventional studies on this topic. Searches were performed for English language articles using PubMed, Cochrane Library, Scopus, and CINAHL (Cumulated Index to Nursing and Allied Health Literature) databases from inception to August 2021 and using keywords related to meat (inclusive of mammalian, avian, and aquatic subtypes) and gut microbiota. Of 14,680 records, 85 eligible articles were included in the scoping review, comprising 57 observational and 28 interventional studies. One prospective observational study and 13 randomized controlled trials (RCTs) were identified in adults without diagnosed disease. We included the 13 RCTs, comprising 18 comparisons, in the systematic review to assess the effects of higher and lower intakes of total meat and meat subtypes on the gut microbiota composition. The bacterial composition was differentially affected by consuming diets with and without meat or with varied meat subtypes. For example, higher meat intake tended to decrease population sizes of genera Anerostipes and Faecalibacterium, but it increased the population size of Roseburia across studies. However, the magnitude and directionality of most microbial responses varied, with inconsistent patterns of responses across studies. The data were insufficient for comparison within or between meat subtypes. The paucity of research, especially among meat subtypes, and heterogeneity of findings underscore the need for more well-designed prospective studies and full-feeding RCTs to address the relationships between and effects of consuming total meat and meat subtypes on gut microbiota, respectively.

Urinary bladder recurrences following ureteroscopic biopsies of upper tract urothelial cancers: a multi-centre observational study with genomic assessment for clonality.

BACKGROUND AND AIMS: Urinary bladder recurrences (UBRs) after radical nephroureterectomy (RNUx) are a known challenge in patients with upper-tract urothelial cancers (UTUCs). We aim to assess factors associated with UBR and clonal-relatedness with resected UTUC. METHODS: Patients who underwent RNUx for UTUC between 1998 and 2015 in five institutions were identified. Clonal relatedness between primary UTUC and subsequent UBR in a sub-cohort was assessed using next-generation sequencing. A Kaplan-Meier curve was used to assess differences in UBR between two groups (with or without ureteroscopic biopsy). RESULTS: Of 267 patients with complete records, 73 (27.3%) had UBR during follow-up. The five-year UBR-free survival in all patients was 64.7%. The five-year UBR-free-survival was inferior in patients who underwent URS biopsy compared with patients who did not undergo ureteroscopic biopsy (49.9% vs 76.4%, p < 0.001). History of bladder tumour (HR, 95% CI; 2.94, 1.73-5.00, p < 0.001), ureteroscopic biopsy (HR, 95% CI; 2.21, 1.38-3.53, p = 0.001) and preoperative urine cytology ≥C3 (HR, 95% CI; 2.06, 1.24-3.40, p = 0.005) were independently associated with UBR. Patients with ureteroscopic biopsy (n = 3/5) showed identical mutational changes for common genes (TP53 and FGFR3) between primary UTUC and subsequent UBR. CONCLUSIONS: Ureteroscopic biopsy of UTUC is a significant risk factor for UBR. Qualitative clonality assessment showed identical mutational signatures between primary UTUC and UBR.

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing.

NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases - 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.

Poultry Consumption and Human Health: How Much Is Really Known? A Systematically Searched Scoping Review and Research Perspective.

This scoping review was conducted to systematically search and chronicle scientific literature pertinent to poultry intake and human health. The protocol (uploaded to Open Science Framework, https://osf.io/2k7bj/) was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews guidelines. Articles with observational and experimental research, narrative and systematic reviews, and meta-analyses were included. Among 13,141 articles identified, 525 met inclusion criteria. Among these 525 articles, 212 focused on cancer morbidity and mortality; 41 on cardiovascular disease (CVD) morbidity and mortality; 52 on CVD risk factors; 32 on type 2 diabetes mellitus (T2DM) morbidity and mortality; 33 on T2DM risk factors; and 42 on body weight and body composition. An "Other" category (181 articles) included nutrient status, psychological well-being/mental health, cognition, microbiome, chronic kidney disease, nonalcoholic fatty liver disease, skin disorders, and fertility, among others. Among the 525 included articles, 366 were observational, 64 were experimental, and 76 were reviews and meta-analyses. Eighty-three percent of articles focused on adults or older adults. A paucity of research exists to support poultry as health-promoting foods, with most research only indirectly assessing poultry intake compared with other foods of interest (e.g., red meats or plant-based protein foods). No randomized controlled trials and only 1% of OBS assessed the influence of processed poultry intake on human health. In the future, the relative health effects of consuming poultry will be compared with a widening array of traditional and new protein-rich food products, necessitating the need for research to assess poultry as foods of choice. Science and health professionals, the poultry industry, and the public will benefit from new observational and experimental research to address cutting-edge scientific, public policy, and consumer topics pertinent to poultry intake and human health.

Red and processed meat intakes and cardiovascular disease and type 2 diabetes mellitus: An umbrella systematic review and assessment of causal relations using Bradford Hill's criteria.

Observational research suggests higher red and processed meat intakes predict greater risks of developing or dying from cardiovascular diseases (CVD) and type 2 diabetes mellitus (T2DM), but this research limits causal inference. This systematic review of reviews utilizes both observational and experimental research findings to infer causality of these relations. Reviews from four databases were screened by two researchers. Reviews included unprocessed red meat (URM), processed meat (PM), or mixed URM + PM intake, and reported CVD or T2DM outcomes. Twenty-nine reviews were included, and causality was inferred using Bradford Hill's Criteria. Observational assessments of CVD outcomes and all meat types consistently reported weak associations while, T2DM outcomes and PM and Mixed URM + PM assessments consistently reported strong associations. Experimental assessments of Mixed URM + PM on CVD and T2DM risk factors were predominately not significant which lacked coherence with observational findings. For all meat types and outcomes, temporality and plausible mechanisms were established, but specificity and analogous relationships do not support causality. Evidence was insufficient for URM and T2DM. More experimental research is needed to strengthen these inferences. These results suggest that red and processed meat intakes are not likely causally related to CVD but there is potential for a causal relationship with T2DM.

An update on the safety of olaparib for treating ovarian cancer.

INTRODUCTION: PARP inhibitors have dramatically improved outcomes for ovarian cancer patients, transforming oncologists' armamentarium and fueling hope for more cures and longer survival. AREAS COVERED: The recent PARP inhibitor randomized trials of FDA approved PARP inhibitors for ovarian cancer, olaparib, rucaparib and niraparib, and implications for clinical care are discussed with a focus on toxicity and risks. PARP adds NAD polymers to DNA-binding proteins, improving survival of cells after DNA damage, and acting as a scaffold for important DNA Damage Response (DDR) enzymes. If this system is inhibited, PARP activation cannot support DNA repair when there is synthetic lethality from BRCA mutations or homologous repair dysfunction (HRD), and the accumulation of DNA damage can kill cancer and lead to the catastrophic complications of MDS/AML. Although the risk of AML can be a < 1% risk, the incidence of MDS/AML presently approaches 10% in patients with BRCA mutations, multiple prior lines of platinum therapy, and protracted exposure to PARP inhibitors. EXPERT OPINION: PARP inhibitors are a well-tolerated and exciting new class of agents that improve survival despite the risk of AML. Understanding of the biology has led to optimal use and potential new strategies for overcoming PARP resistance.

Continuing the sequence? Towards an economic evaluation of whole genome sequencing for the diagnosis of rare diseases in Scotland.

Novel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost-benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts.

Effects of Total Red Meat Intake on Glycemic Control and Inflammatory Biomarkers: A Meta-Analysis of Randomized Controlled Trials.

Our objective was to conduct a systematic review and meta-analysis to assess the effects of total red meat (TRM) intake on glycemic control and inflammatory biomarkers using randomized controlled trials of individuals free from cardiometabolic disease. We hypothesized that higher TRM intake would negatively influence glycemic control and inflammation based on positive correlations between TRM and diabetes. We found 24 eligible articles (median duration, 8 weeks) from 1172 articles searched in PubMed, Cochrane, and CINAHL up to August 2019 that included 1) diet periods differing in TRM; 2) participants aged ≥19 years; 3) included either men or women who were not pregnant/lactating; 4) no diagnosed cardiometabolic disease; and 5) data on fasting glucose, insulin, HOMA-IR, glycated hemoglobin (HbA1c), C-reactive protein (CRP), or cytokines. We used 1) a repeated-measures ANOVA to assess pre to post diet period changes; 2) random-effects meta-analyses to compare pre to post changes between diet periods with ≥ vs. <0.5 servings (35g)/day of TRM; and 3) meta-regressions for dose-response relationships. We grouped diet periods to explore heterogeneity sources, including risk of bias, using the National Heart, Lung, and Blood Institute's Quality Assessment of Controlled Interventions Studies. Glucose, insulin, and HOMA-IR values decreased, while HbA1c and CRP values did not change during TRM or alternative diet periods. There was no difference in change values between diet periods with ≥ vs. <0.5 servings/day of TRM [weighted mean differences (95% CIs): glucose, 0.040 mmol/L (-0.049, 0.129); insulin, -0.710 pmol/L (-6.582, 5.162); HOMA-IR, 0.110 (-0.072, 0.293); CRP, 2.424 nmol/L (-1.460, 6.309)] and no dose response relationships (P > 0.2). Risk of bias (85% of studies were fair to good) did not influence results. Total red meat consumption, for up to 16 weeks, does not affect changes in biomarkers of glycemic control or inflammation for adults free of, but at risk for, cardiometabolic disease. This trial was registered at PROSPERO as 2018 CRD42018096031.

Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed.

PURPOSE: Oesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. METHODS: The effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. RESULTS: EGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. CONCLUSION: Gefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.

Hypersensitivity Reactions: Priming Practice Change to Reduce Incidence in First-Dose Rituximab Treatment.

BACKGROUND: Strategies to reduce hypersensitivity reaction (HSR) incidence with rituximab include premedications and slow titration. Literature is lacking on the priming method used when preparing rituximab IV lines and the potential impact on HSR incidence. OBJECTIVES: The primary objective is to evaluate HSR incidence in titrated first-dose rituximab infusions when priming IV lines with rituximab, as compared to priming with diluent. METHODS: A retrospective, comparative, descriptive study with two arms (rituximab- versus diluent-primed) was conducted. Variables were HSR incidence in relation to priming method, age, sex, diagnosis, and premedications. For patients with HSR, severity, time to onset, and infusion rate were examined. FINDINGS: HSR incidence was significantly higher in the diluent- versus the drug-primed arm. Other significant findings included higher HSR incidence in women and lower HSR incidence in patients premedicated with dexamethasone.

Aripiprazole Lauroxil NanoCrystal® Dispersion Technology (Aristada Initio®).

Nonadherence to antipsychotic medications for the treatment of schizophrenia is a widely recognized concern, leading to poorer clinical outcomes and higher treatment costs. Long-acting injectable (LAI) antipsychotics offer an extended dosing interval option for patients, although the current options may require an oral overlap at initiation. Aripiprazole lauroxil is an LAI that offers multiple dosing options but requires oral treatment overlap during initiation for the first 21 consecutive days. As an alternative to oral overlap, a novel nano-crystalline milled dispersion delivery system of aripiprazole lauroxil was recently approved as a one-day regimen to be added to aripiprazole lauroxil treatment.

Combined linkage and association analysis of classical Hodgkin lymphoma.

The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL.

HIV in Orthopaedic Surgery.

The emergence of HIV in the United States has had important implications in the surgical setting. This blood-borne pathogen poses risks to both the surgeon and the patient undergoing an orthopaedic procedure. Although there has been research regarding the likelihood of orthopaedic surgeons contracting HIV during a surgical procedure, the correlation of HIV with postoperative prognosis has not been extensively examined. Because HIV-positive patients may be immunodeficient, they are at increased risk for certain postoperative complications, especially infection. Orthopaedic surgeons should have a thorough understanding of the effects of this disease on patients to optimize preoperative decision making, intraoperative care, and postoperative recovery.