Significance of FSHR and LHCGR gene polymorphisms on clinical outcomes in gonadotropin-releasing hormone antagonist protocol with freeze-all strategy: A case-control study.

Background: Follicle-stimulating hormone receptor (FSHR) and luteinizing hormone/choriogonadotropin receptor (LHCGR) are integral to ovarian function, facilitating follicle development and maturation through their respective hormonal interactions. The influence of receptor polymorphisms on the outcomes of freeze-all cycles remains unclear. Objective: This study investigates the impact of FSHR N680S and LHCGR N312S polymorphisms on clinical outcomes in freeze-all cycles. Materials and Methods: Women undergoing controlled ovarian stimulation for assisted reproductive technology participated in this study. They were administered a gonadotropin-releasing hormone antagonist protocol, with recombinant follicle-stimulating hormone (rFSH) dosages adjusted according to age, body mass index, antral follicle count, and individual hormonal responses. Additionally, human menopausal gonadotropin dosages were tailored based on the LHCGR N312S genetic variant. Results: Analysis revealed no significant differences in age, body mass index, antral follicle count, or marital status across the genotypes of FSHR N680S and LHCGR N312S. However, notable differences were observed in the rFSH dosage required daily and in total among the FSHR polymorphism genotypes. Genotypes of the LHCGR polymorphism correlated with fewer stimulation days. A significant interaction was observed between the 2 polymorphisms concerning total rFSH dosage. Conclusion: The presence of serine in the FSHR polymorphism was associated with higher rFSH dosage requirements. Both FSHR N680S and LHCGR N312S polymorphisms significantly influenced clinical pregnancy and live birth outcomes in freeze-all cycles, underscoring the potential of a pharmacogenomic approach to optimize hormone supplementation in controlled ovarian stimulation protocols during assisted reproductive technology treatments.

Lost dwell time and cycler alarms in inpatient automated peritoneal dialysis at a tertiary care hospital.

BACKGROUND AND AIMS: Dwell time is a critical component of automated peritoneal dialysis (APD) prescription, the stage at which transmembrane mass and fluid transfer occur. Loss of prescribed dwell time (LDT) can negatively influence the efficiency of APD. We investigated the incidence of LDT and related causes using APD in the acute care setting at a tertiary care center. METHODS: Retrospective analysis was conducted of all inpatients receiving APD treatments from 1 December 2021 to 1 June 2023. Patient demographics, comorbidities, laboratory, and treatment data were extracted from electronic medical records and a propriety database. RESULTS: N = 235 cycler treatments completed by 32 patients were included for analysis. The total LDT per treatment exceeding 30 minutes and 60 minutes occurred in 27% and 20% of all treatments. LDT of more than 10 minutes per each cycle exchange occurred in 26%. Session disruptions were caused by slow out-flow (55%), inadequate drain volumes (32%), patient line occlusions (20%), and priming errors (23%). The slow flow alarm requiring user intervention was reported to occur in about one-third of all treatments (31%). CONCLUSION: There was significant LDT and inadequate drain volume seen in about one-quarter and one-third of all inpatient APD treatments respectively. This can impact solute clearance and ultrafiltration.  Slow flow alarms were the most prevalent and the leading cause of LDT followed by inadequate drain volume. Future studies are required to investigate measures to reduce slow drain and improve drain volume in the hospital setting.   .

Emerging lactic acid bacteria bacteriocins as anti-cancer and anti-tumor agents for human health.

Modern cancer diagnostics and treatment options have greatly improved survival rates; the illness remains a major cause of mortality worldwide. Current treatments for cancer, such as chemotherapy, are not cancer-specific and may cause harm to healthy cells; therefore, it is imperative that new drugs for cancer be developed that are both safe and effective. It has been found that lactic acid bacteria (LAB) have the potential to produce bacteriocins, which could potentially offer a promising alternative for cancer treatment. They have been shown in several studies to be effective against cancer cells while having no effect on healthy cells. More research is needed to fully understand the potential of LAB bacteriocins as anti-cancer medicines, to find the appropriate dose and delivery route, and to conduct clinical trials to evaluate the effectiveness and safety of the products in human patients, as is suggested by this work. Furthermore, LAB bacteriocins may evolve into a significant new class of anti-cancer drugs and food products. Patients with cancer may have a safe and effective alternative treatment option in the form of anti-cancer foods and drugs. Therefore, the aim of this study is to provide an in-depth analysis of the recent breakthroughs and potential future technical advancements of significant bacteriocins that are produced by LAB, how these bacteriocins function, and how these bacteriocins may be utilized as an anti-cancer agent. In addition, the current analysis emphasizes the significant constraints and boundaries that bacteriocins face when they are used as an anti-cancer factor.

Plasmodium Vivax in a Healthy, Young Immigrant Male.

A young immigrant male presented to the hospital with multiple complaints and was found to be in septic shock with symptomatic anemia. After an extensive workup, the patient was found to have malaria, a disease caused by the bite of an infected mosquito. This case outlines the pertinent findings, relevant diagnostic tests, and appropriate treatment for a patient with malaria secondary to Plasmodium vivax. It also demonstrates the importance of social and travel history, especially when evaluating our immigrant populations.

Implications of Family-Oriented Psychotherapy for Hereditary Angioedema Management: A Case Series.

The role of psychotherapy in the management of chronic conditions has been widely explored and supported. The current approach to the utilization of family-oriented psychotherapy in treatment plans is individualized to the patient and focused on the development of personal coping skills alongside identifying and changing negative thoughts, emotions, and behaviors. Alleviation of symptom burden, improvement in psychiatric co-morbidities like anxiety and depression, and enhancement of quality of life have all been found to be associated with incorporating family-oriented psychotherapy in the management of chronic conditions. In contrast, heritable conditions, such as hereditary angioedema (HAE), have not been the center of extensive research. Heritable conditions introduce a new category of stressors that require management like the anxiety of a parent, a sibling, a child, or another family member decompensating at the same time as oneself. Family-centered psychotherapy focuses on discussing the stressors of the family unit and the development of coping strategies to prevent the time course of one family member's condition from exacerbating another family member's condition. This model has been utilized for families with separate chronic conditions, but its role and effectiveness in managing inherited conditions have room for investigation. This paper presents a case series on a family engaging in family-centered psychotherapy for HAE.

Aflatoxin removal and biotransformation aptitude of food grade bacteria from milk and milk products- at a glance.

Microorganisms are the only entities in the biosphere with an incomparable ability to employ diverse organic and inorganic compounds for growth and convert it to simple form that is no longer harmful to human health and environment. Food grade microorganisms such as lactic acid bacteria, bifidobacteria, propionibacteria as well as several yeast species are associated with food fermentation processes as well as have gained probiotic status owing to their noteworthy offerings in health stimulation as a natural gut microbiota in animals and humans. However, as biological agents little is known about their application for bioremediation and biotransformation aptitude. In context to this, aflatoxin M1 is a class of mycotoxins often associated with milk through consumption of fungus contaminated feed & fodders by cattle and well documented for their adverse health effects. Therefore, current review summarizes significance of aflatoxins present in milk and dairy products in human life, their source, types & health implications; food grade bacteria including probiotic strains and their mechanism of action involved in the removal of aflatoxin; and last section discusses the outcome of major studies showing aflatoxin reduction potential of food grade bacteria in milk and milk based products.

Chronic Myelomonocytic Leukemia and Atypical Chronic Myeloid Leukemia: A National Analysis.

BACKGROUND: Myelodysplastic/myeloproliferative overlap syndromes (MDS/MPN) are rare blood cancers characterized by concomitant myeloid hyperplasia and dysplasia. These heterogenous disorders include chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). METHODS: Using two large national cancer databases to examine a total of 15,704 CMML and 702 aCML patients, we report the largest study to date on the incidence, survival and demographic characteristics of CMML and aCML in the United States. RESULTS: Overall age-adjusted incidence of CMML and aCML was 0.63 per 100,000 Americans per year and 0.03 per 100,000 per year, respectively. CMML incidence in the U.S. was noted to rise steadily in the years between 2001 and 2019. Median patient age was 75 and 72 years for CMML and aCML, and the majority of CMML and aCML patients were male (62.9% and 62.0%) and White (90.1% and 86.3%). Median OS was 17.4 months for CMML, and 15.2 months for aCML. Multivariate Cox regression demonstrated features associated with reduced survival, including increasing age, comorbidities, Medicaid insurance status, and low-income residential zip code, highlighting survival disparities in underinsured and socioeconomically disadvantaged patients. In CMML, Black race was associated with inferior survival, while female sex, management at an academic center, and later calendar-year of diagnosis were associated with improved OS. CONCLUSION: These findings underscore the need to better understand the biological basis for such differences in survival and reflect the importance of access to specialized care for patients with these rare disorders.

Whole-genome sequencing of three ciprofloxacin-resistant Salmonella Reading (ST93) strains, an emerging Salmonella serovar in the poultry sector of Pakistan.

In this study, we performed whole-genome sequencing of three ciprofloxacin-resistant Salmonella Reading strains isolated from poultry meat. Genomes of S. Reading strains contained an average of 4.81 Mbp size with 52.1% GC. The isolates exhibited blaOXA-10, aac [6']-Iaa, aadA1, cmlA1, qnrS1, and tetA resistance genes and IncX1 and IncX2 plasmids.

Acute Kidney Injury after Cardiac Surgery.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CS-AKI) remains a vexing issue. Clinical trials for the prevention of CS-AKI have been disappointing despite enormous initial enthusiasm based on experimental data. SUMMARY: The schism in experimental and clinical data has triggered a relook at our understanding of CS-AKI and the experimental and preclinical models. In this review, we discuss the therapeutic targets of major clinical trials. KEY MESSAGES: The silver lining in the midst is the standardization of anesthetic and perioperative care proposed by national societies. Implementation of the KDIGO bundle is a reasonable option to decrease the incidence of CS-AKI despite lack of proven robust benefits.

NCCN Guidelines® Insights: Systemic Mastocytosis, Version 3.2024.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Polycythemia vera: past, present and future.

There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2-mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.

Shaping immunity against infectious diseases with multivalent DNA vaccines.

Immunization has dramatically transformed human and animal health. Since its earliest days, vaccination has served as a fundamental strategy for infectious disease prevention, providing population-level coverage for childhood diseases and seasonal infections, and serving as a rapid response to pandemic pathogens. Yet, there is continued circulation of endemic, emerging, and reemerging pathogens for which there are no licensed prophylactic measures. The successes of nucleic acid technologies during the COVID-19 pandemic, exemplified in the first two licensed mRNA vaccines [1] and the first DNA vaccine receiving emergency use authorization for human use [2], are reinvigorating vaccine development to tackle this urgent unmet need. The inherent stability of DNA offers advantageous features such as thermostability and extended shelf life. These characteristics are pivotal for transport and storage in resource-constrained environments, like low and middle-income countries. Furthermore, the ability to encode large transgenes and well-established modular assembly pipelines are key attributes of DNA-based platforms. This versatility extends to combination strategies of individual DNA vaccines as a multivalent drug product. Multivalent synthetic DNA vaccines are therefore emerging as part of the exciting nucleic acid-based vaccine landscape as a strategy to induce robust and durable immunity in diverse global populations.

Clonal Hematopoiesis in Patients With Human Immunodeficiency Virus and Cancer.

BACKGROUND: Cancer-related deaths for people with human immunodeficiency virus (PWH) are increasing due to longer life expectancies and disparately poor cancer-related outcomes. We hypothesize that advanced biological aging contributes to cancer-related morbidity and mortality for PWH and cancer. We sought to determine the impact of clonal hematopoiesis (CH) on cancer disparities in PWH. METHODS: We conducted a retrospective study to compare the prevalence and clinical outcomes of CH in PWH and people without HIV (PWoH) and cancer. Included in the study were PWH and similar PWoH based on tumor site, age, tumor sequence, and cancer treatment status. Biological aging was also measured using epigenetic methylation clocks. RESULTS: In 136 patients with cancer, PWH had twice the prevalence of CH compared to similar PWoH (23% vs 11%, P = .07). After adjusting for patient characteristics, PWH were 4 times more likely than PWoH to have CH (odds ratio, 4.1 [95% confidence interval, 1.3-13.9]; P = .02). The effect of CH on survival was most pronounced in PWH, who had a 5-year survival rate of 38% if they had CH (vs 59% if no CH), compared to PWoH who had a 5-year survival rate of 75% if they had CH (vs 83% if no CH). CONCLUSIONS: This study provides the first evidence that PWH may have a higher prevalence of CH than PWoH with the same cancers. CH may be an independent biological aging risk factor contributing to inferior survival for PWH and cancer.

Interobserver agreement and risk of malignancy using the International Academy of Cytology Yokohama System for reporting breast FNA biopsy in a liquid-based exclusive cohort.

BACKGROUND: Per the College of American Pathologist's National Breast Fine Needle Aspiration Biopsy (FNAB) Practice Survey, ∼40% of laboratories use liquid-based cytology (LBC) for breast FNAB. The reproducibility of the International Academy of Cytology Yokohama System (YS) for reporting breast FNAB on LBC was explored. DESIGN: Breast FNAB specimens submitted as LBC only (all ThinPrep) between January 2017 and January 2021 were retrieved. Cases without histopathologic follow-up were excluded. Clinical and radiologic information was collected. One cytologist and six cytopathologists rendered diagnoses per YS. All reviewers were blinded to the original diagnosis and histopathologic follow-up. The risk of malignancy was calculated. Concordance rates were calculated by a weighted Cohen Kappa score (κ). RESULTS: Review of 110 cases demonstrated substantial to near-perfect agreement between each reviewer (κ = 0.73-0.91) and follow-up histopathology (κ = 0.66-0.85). The agreement was lowest in the inadequate (κ = 0.05) and atypical (κ = 0.04) categories. The lack of concordance in the atypical category was common in cases with low cellularity or incomplete structural features. The risk of malignancy for inadequate, benign, atypical, suspicious for malignancy, and malignant categories were 12.5% (2/16), 3% (2/65), 67%, (8/12) 100% (1/1), and 100% (16/16). CONCLUSION: Interobserver agreement is excellent using the five YS categories in LBC. Lack of cellularity and incomplete architectural features were barriers to perfect agreement. Established pitfalls in the interpretation of LBC were cause for atypical diagnoses. Continuous training and education are recommended to avoid misdiagnosis because of the nonconventional cytomorphologic features of LBC and to improve inadequate and atypical rates within YS.

In vivo delivery of engineered synthetic DNA-encoded SARS-CoV-2 monoclonal antibodies for pre-exposure prophylaxis in non-human primates.

COVID-19 remains a major public health concern. Monoclonal antibodies have received emergency use authorization (EUA) for pre-exposure prophylaxis against COVID-19 among high-risk groups for treatment of mild to moderate COVID-19. In addition to recombinant biologics, engineered synthetic DNA-encoded antibodies (DMAb) are an important strategy for direct in vivo delivery of protective mAb. A DMAb cocktail was synthetically engineered to encode the immunoglobulin heavy and light chains of two different two different Fc-engineered anti-SARS-CoV-2 antibodies. The DMAbs were designed to enhance in vivo expression and delivered intramuscularly to cynomolgus and rhesus macaques with a modified in vivo delivery regimen. Serum levels were detected in macaques, along with specific binding to SARS-CoV-2 spike receptor binding domain protein and neutralization of multiple SARS-CoV-2 variants of concern in pseudovirus and authentic live virus assays. Prophylactic administration was protective in rhesus macaques against signs of SARS-CoV-2 (USA-WA1/2020) associated disease in the lungs. Overall, the data support further study of DNA-encoded antibodies as an additional delivery mode for prevention of COVID-19 severe disease. These data have implications for human translation of gene-encoded mAbs for emerging infectious diseases and low dose mAb delivery against COVID-19.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer.

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

Use of the Afirma Xpression Atlas for cytologically indeterminate, Afirma Genomic Sequencing Classifier suspicious thyroid nodules: Clinicopathologic analysis with postoperative molecular testing.

OBJECTIVES: Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules. METHODS: Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available. RESULTS: Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27). CONCLUSIONS: Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test.