Variability In Patient Response Research Articles

Enhancing patient informed consent in elective skin cancer surgeries: a comparative study of traditional and digital approaches in a German public hospital

BackgroundThis study aims to investigate the integration of modern sources of patient information, such as videos, internet-based resources, and scientific abstracts, into the traditional patient informed consent process in outpatient elective surgeries. The goal is to optimize the informed consent experience, enhance patient satisfaction, and promote shared decision making (SDM) between patients and surgeons. By exploring different patient informed consent formats and their impact on patient satisfaction, this research seeks to improve healthcare practices and ultimately enhance patient outcomes. The findings of this study will contribute to the ongoing efforts to improve the informed consent process in public hospitals and advance patient-centred care.MethodsData collection occurred at the day care clinic of a prominent German public hospital, forming an integral component of a prospective clinical investigation. The study exclusively focused on individuals who had undergone surgical intervention for skin cancer. For the purpose of meticulous data examination, the statistical software SPSS version 21 was harnessed. In the course of this study, a chi-square test was aptly employed. Its purpose was to scrutinize the nuances in patient experiences pertaining to informed consent across four distinct categories, viz., oral informed consent discussion (Oral ICD), written informed consent discussion (Written ICD), video-assisted informed consent discussion (video-assisted ICD), and digitally assisted informed consent discussion (digital-assisted ICD). The primary dataset of this inquiry was diligently gathered via a structured questionnaire administered to a targeted cohort of 160 patients. Within this sample, a balanced representation of genders was observed, encompassing 82 males and 78 females. Their collective age span ranged from 18 to 92 years, with an average age of 71 years. A randomized selection methodology was employed to include participants in this study during the period spanning from July 2017 to August 2018.ResultsSignificant differences were observed across the groups for all research questions, highlighting variations in patient responses. Video-assisted and digital-assisted IC were rated as superior in patient satisfaction with information compared to written and oral IC. Demographic profiles of the four study groups were found to be comparable.ConclusionThe findings of this study indicate that the incorporation of digital technologies in the informed consent process can enhance patient understanding during outpatient elective skin cancer surgeries. These results have important implications for increasing patient satisfaction and improving the SDM process within the hospital environment.

Sound waves and solutions: Point-of-care ultrasonography for acute kidney injury in cirrhosis

This article delves into the intricate challenges of acute kidney injury (AKI) in cirrhosis, a condition fraught with high morbidity and mortality. The complexities arise from distinguishing between various causes of AKI, particularly hemodynamic AKI, in cirrhotic patients, who experience hemodynamic changes due to portal hypertension. The term "hepatocardiorenal syndrome" is introduced to encapsulate the intricate interplay among the liver, heart, and kidneys. The narrative emphasizes the often-overlooked aspect of cardiac function in AKI assessments in cirrhosis, unveiling the prevalence of cirrhotic cardiomyopathy marked by impaired diastolic function. The conventional empiric approach involving volume expansion and vasopressors for hepatorenal syndrome is critically analyzed, highlighting potential risks and variable patient responses. We advocate for a nuanced algorithm for AKI evaluation in cirrhosis, prominently featuring point-of-care ultrasonography (POCUS). POCUS applications encompass assessing fluid tolerance, detecting venous congestion, and evaluating cardiac function.

Recent updates in the therapeutic uses of Pembrolizumab: a brief narrative review.

Treatment of cancer has been improved with the discovery of biological drugs that act as immune checkpoint inhibitors. In 2017, FDA designated pembrolizumab, an immune checkpoint inhibitor employed in immunotherapy, as the first tissue-agnostic cancer treatment. To review pembrolizumab's use in oncology, gather and examine the latest discoveries regarding the effectiveness of pembrolizumab in cancer treatment. A literature review was conducted through PubMed(Medline) from January 2015 to December 2023 using "pembrolizumab", "cancer" and "treatment" as search terms. Pembrolizumab demonstrated effectiveness as primary treatment for metastatic nonsmall cell lung cancer, unresectable esophageal cancer, head and neck squamous cell carcinoma and alternative treatment for notable triple-negative breast cancer, biliary, colorectal, endometrial, renal cell, cervical carcinoma, and high microsatellite instability or mismatch repair deficiencies tumors. Pediatric applications include treatment for refractory Hodgkin lymphoma. Evolving research on pembrolizumab allows a deeper clinical understanding, despite challenges as variable patient responses. Pembrolizumab has emerged as a pivotal breakthrough in cancer treatment, improving patient outcomes and safety.

Combination of Anti-Angiogenics and Immunotherapies in Renal Cell Carcinoma Show Their Limits: Targeting Fibrosis to Break through the Glass Ceiling?

This review explores treating metastatic clear cell renal cell carcinoma (ccRCC) through current therapeutic modalities-anti-angiogenic therapies and immunotherapies. While these approaches represent the forefront, their limitations and variable patient responses highlight the need to comprehend underlying resistance mechanisms. We specifically investigate the role of fibrosis, prevalent in chronic kidney disease, influencing tumour growth and treatment resistance. Our focus extends to unravelling the intricate interplay between fibrosis, immunotherapy resistance, and the tumour microenvironment for effective therapy development. The analysis centres on connective tissue growth factor (CTGF), revealing its multifaceted role in ccRCC-promoting fibrosis, angiogenesis, and cancer progression. We discuss the potential of targeting CTGF to address the problem of fibrosis in ccRCC. Emphasising the crucial relationship between fibrosis and the immune system in ccRCC, we propose that targeting CTGF holds promise for overcoming obstacles to cancer treatment. However, we recognise that an in-depth understanding of the mechanisms and potential limitations is imperative and, therefore, advocate for further research. This is an essential prerequisite for the successful integration of CTGF-targeted therapies into the clinical landscape.

SMART use of medications for the treatment of adolescent severe obesity: A sequential multiple assignment randomized trial protocol

BackgroundSevere obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their “one-size-fits-all” approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. MethodsThis paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), “SMART Use of Medications for the Treatment of Adolescent Severe Obesity.” The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. ConclusionData from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard “one-size-fits-all” treatments.

Delivering biochemicals with precision using bioelectronic devices enhanced with feedback control.

Precision medicine endeavors to personalize treatments, considering individual variations in patient responses based on factors like genetic mutations, age, and diet. Integrating this approach dynamically, bioelectronics equipped with real-time sensing and intelligent actuation present a promising avenue. Devices such as ion pumps hold potential for precise therapeutic drug delivery, a pivotal aspect of effective precision medicine. However, implementing bioelectronic devices in precision medicine encounters formidable challenges. Variability in device performance due to fabrication inconsistencies and operational limitations, including voltage saturation, presents significant hurdles. To address this, closed-loop control with adaptive capabilities and explicit handling of saturation becomes imperative. Our research introduces an enhanced sliding mode controller capable of managing saturation, adept at satisfactory control actions amidst model uncertainties. To evaluate the controller's effectiveness, we conducted in silico experiments using an extended mathematical model of the proton pump. Subsequently, we compared the performance of our developed controller with classical Proportional Integral Derivative (PID) and machine learning (ML)-based controllers. Furthermore, in vitro experiments assessed the controller's efficacy using various reference signals for controlled Fluoxetine delivery. These experiments showcased consistent performance across diverse input signals, maintaining the current value near the reference with a relative error of less than 7% in all trials. Our findings underscore the potential of the developed controller to address challenges in bioelectronic device implementation, offering reliable precision in drug delivery strategies within the realm of precision medicine.

β-glucan: a potent adjuvant in immunotherapy for digestive tract tumors.

The immunotherapy for gastrointestinal tumors, as a significant research direction in the field of oncology treatment in recent years, has garnered extensive attention due to its potential therapeutic efficacy and promising clinical application prospects. Recent advances in immunotherapy notwithstanding, challenges persist, such as side effects, the complexity of the tumor immune microenvironment, variable patient responses, and drug resistance. Consequently, there is a pressing need to explore novel adjunctive therapeutic modalities. β-glucan, an immunomodulatory agent, has exhibited promising anti-tumor efficacy in preclinical studies involving colorectal cancer, pancreatic cancer, and gastric cancer, while also mitigating the adverse reactions associated with chemotherapy and enhancing patients' quality of life. However, further clinical and fundamental research is warranted to comprehensively evaluate its therapeutic potential and underlying biological mechanisms. In the future, β-glucan holds promise as an adjunctive treatment for gastrointestinal tumors, potentially bringing significant benefits to patients.

A Phase 2 Study with Volasertib for Ven-HMA Relapsed/Refractory Acute Myeloid Leukemia Patients Guided By a Predictive Precision Medicine Platform

Introduction Acute myeloid leukemia (AML) represents a significant clinical challenge, with complex genetic heterogeneity that underlies the variable patient response to existing treatment modalities. While molecular features and novel therapeutic options offer promising solutions, their effectiveness is often compromised by inter-patient and intra-leukemia variability, coupled with an overall lack of biomarkers that can reliably inform therapeutic benefit. Consequently, these therapies yield clinical responses limited to only a subset of patients. Predicting a patient's response before initiating therapy optimizes treatment selection by improving the benefit/risk ratio (therapeutic index) and increasing response rates. This helps avoid treating non-responding patients, thereby reducing the occurrence of adverse effects and minimizing the costs associated with ineffective care. Here, we present an actionable strategy in AML that employs an automated, high-throughput, multi-color flow cytometry-based predictive precision medicine platform (PPMP) offering a genetic biomarker-agnostic approach to identify responders to standard-of-care (SOC) treatments and the polo-like kinase 1 (PLK-1) inhibitor volasertib. Clinical validation of the PPMP To date, we have conducted four studies evaluating the PPMP's predictive performance in myelodysplastic syndromes, adult AML, and pediatric AML with several SOC agents. For all studies, pre-induction blood or bone marrow samples were collected from patients then ex vivo treatment responses of individual leukemic cells were assessed using multi-color flow cytometry. The results were validated with the patient's actual clinical response as reported by physicians and indicated high precision-with positive predictive values (PPVs) of 83-100%. These findings help establish a PPMP-based pursuit of investigational therapies to enhance their therapeutic utility in distinct response groups. Case study: Volasertib One application of this approach involves the revival of volasertib, a PLK-1 inhibitor with demonstrated activity in AML, that was discontinued by Boehringer Ingelheim (BI) after failing its Phase 3 study. A BI Phase 2 study showed volasertib combined with low-dose cytarabine (V+LDAC) delivered a complete response (CR) + CR with incomplete count recovery (CRi) rate of 31.0% compared to 13.3% from LDAC monotherapy, and higher overall survival (OS). Similarly, in a global Phase 3 study a CR + CRi rate for V+LDAC (27.7% overall response) compared to Placebo+LDAC (17.1%) was reported. However, the Phase 3 study showed a higher frequency of fatal events with V+LDAC, especially in non-responders, resulting in lower median OS. By accurately pinpointing clinical responders, the integration of PPMP aims to identify those patients deriving clinical benefit (CR or CRi) from volasertib. Clinical trial design We plan on initiating a Phase 2a single-arm, open-label clinical trial in AML with volasertib in Ven-HMA relapsed or refractory patients, while co-developing PPMP as a companion diagnostic to selectively enroll predicted responders in a follow-up Phase 2b study (Figure 1). Intially, 20-30 patients will be enrolled. Once sufficient responders are achieved and certain performance thresholds of the drug sensitivity platform are met, an additional 20-30 patients will be enrolled, utilizing the companion diagnostic to selectively enroll predicted responders. The primary objectives will be focused on efficacy and safety of intravenous volasertib (possibly in combination with another drug) in patients with relapsed/refractory AML. Secondary objectives will include ex vivo response data collection to optimize the diagnostic parameters for the Phase 2b study. Primary Phase 2a endpoints include AML disease response assessment per pre-specified criteria. Secondary endpoints include an assessment of the diagnostic performance characteristic of Notable's drug sensitivity score in predicting in vivo volasertib clinical response. Specific strategies, including tailored dosing, robust infection control, and carefully selecting drug combination partners are designed to mitigate the adverse events observed in BI's Phase 3 trial and maximize volasertib's therapeutic impact regarding both efficacy and safety.

Digital Nerve Care Forum: Innovative Healthcare Professionals Education on Neuropathy.

Neuropathy is a common complication of diabetes, rarely detected on time, often deprioritized by treating physicians, and hence rarely managed in time, leading to avoidable complications which can be limb and life-threatening. Despite introducing new diagnostic tests, novel potential bio parameters, and a series of relatively small intervention studies utilizing detailed phenotypic profiling, the management of diabetic neuropathy (DN) and painful DN has remained unchanged due to misdiagnosis. The diagnostic complexity of diabetic peripheral neuropathy (DPN), variation in patient response to treatment, and regulatory pressures to meet data-driven quality metrics for diabetes management all likely contributes to the underdiagnosis and treatment of DPN in clinical practice. Educating the primary healthcare providers and diabetic trainers would help improve the number of diagnosed DPN cases as these practitioners lead public health literacy. The digital nerve care forum (NCF) is an educational initiative created by clinical experts and Procter and Gamble (P&G) health academy. Its primary aim is to generate awareness amongst healthcare practitioners (HCPs) about early diagnosis and timely management of DPN. Since its inception in October 2020, NCF has conducted 143 engagements; 39 neuropathy case puzzles, four interactive case-based discussions, two diagnostic workshops, four mentor-mentee nerve talk shows, two intercountry nerve talk shows, two global neuropathy awareness week initiatives, three nerves of steel (Women's Day special engagements), and 17 NCF times (Newsletters). This online forum is hosted on a global HCP education and upskilling platform, MediSage, which offers these educational resources to HCPs worldwide for free. It has helped create a community of 254, 714 HCPs from 86 countries across six continents supported by 30 neuropathy experts from seven countries. With a repeated viewership of 53% of HCPs engaging continuously, NCF empowers this community to improve diabetic patient care. Activities that increase disease awareness and highlight the importance of diabetic nerve health have been the key objectives behind the several educational programs on NCF. To drive this continuum, these digital programs are now becoming more phygital and impactful than ever. Therefore, earlier detection of DPN in at-risk individuals and those with prediabetes or type 2 diabetes is recommended for better management through optimal intervention and lifestyle changes and to prevent future complications of untreated DPN. How to cite this article: Kalra S, Tiwaskar M, Shrestha D, et al. Digital Nerve Care Forum: Innovative Healthcare Professionals Education on Neuropathy. J Assoc Physicians India 2023;71(10):89-92.

Cabozantinib and IL-27 combinatorial therapy for bone-metastatic prostate cancer.

Introduction: Prostate cancer is the second leading cause of cancer-related death among American men. Prostate tumor cells exhibit significant tropism for the bone and once metastasis occurs, survival rates fall significantly. Current treatment options are not curative and focus on symptom management. Immunotherapies are rapidly emerging as a possible therapeutic option for a variety of cancers including prostate cancer, however, variable patient response remains a concern. Chemotherapies, like cabozantinib, can have immune-priming effects which sensitize tumors to immunotherapies. Additionally, lower doses of chemotherapy can be used in this context which can reduce patient side effects. We hypothesized that a combination of chemotherapy (cabozantinib) and immunotherapy [Interleukin-27 (IL-27)] could be used to treat bone-metastatic prostate cancer and exert pro-osteogenic effects. IL-27 is a multi-functional cytokine, which promotes immune cell recruitment to tumors, while also promoting bone repair. Methods: To test this hypothesis, in vivo experiments were performed where syngeneic C57BL/6J mice were implanted intratibially with TRAMP-C2ras-Luc cells that are able to form tumors in bone. Immunotherapy was administered in the form of intramuscular gene therapy, delivering plasmid DNA encoding a reporter gene (Lucia), and/or a therapeutic gene (IL-27). Sonoporation was used to aid gene delivery. Following immunotherapy, the animals received either cabozantinib or a vehicle control by oral gavage. Bioluminescence imaging was used to monitor tumor size over time. Results: Combinatorial therapy inhibited tumor growth and improved survival. Further, RNA sequencing was used to investigate the mechanisms involved. Microcomputed tomography and differentiation assays indicated that the combination therapy improved bone quality by enhancing osteoblast differentiation and inhibiting osteoclast differentiation. Discussion: Our conclusion is that a chemo-immunotherapy approach such as the one examined in this work has potential to emerge as a novel therapeutic strategy for treating bone-metastatic prostate cancer. This approach will enable a significant reduction in chemotherapy-associated toxicity, enhance sensitivity to immunotherapy, and improve bone quality.

Comprehensive Evaluation of Pathogenesis, Risk Factors and Current Therapeutic Strategies in Melasma: A Clinical and Molecular Perspective

Melasma, an acquired facial hyperpigmentation of a chronic nature, presents a clinical and dermatologic enigma of considerable relevance. This article focuses on a comprehensive review of the underlying pathogenesis of melasma from a molecular and clinical perspective, exploring its multifactorial etiology and the triggering elements that converge in the cascade of biochemical and cellular events that result in its distinctive clinical manifestation. Known risk factors such as excessive sun exposure, hormonal imbalances and genetic predisposition are thoroughly discussed, unraveling their relative contribution and complex interplay in the development of melasma. In addition, a critical analysis is made of current therapeutic strategies, ranging from conventional topical approaches to more advanced modalities such as laser therapy and technology-based treatments. The efficacy, safety and limitations of these modalities are examined, considering variations in patient response and the durability of the results obtained. Ultimately, this article seeks to provide a comprehensive synthesis of contemporary advances in the understanding and management of melasma, with the aspiration of guiding dermatologic health care professionals toward more accurate and individualized approaches in the diagnosis and treatment of this complex skin condition.

Pathological and Therapeutic Advances in Parkinson's Disease: Mitochondria in the Interplay.

Parkinson's disease (PD) is the second most common neurodegenerative illness majorly affecting the population between the ages of 55 to 65 years. Progressive dopaminergic neuronal loss and the collective assemblage of misfolded alpha-synuclein in the substantia nigra, remain notable neuro-pathological hallmarks of the disease. Multitudes of mechanistic pathways have been proposed in attempts to unravel the pathogenesis of PD but still, it remains elusive. The convergence of PD pathology is found in organelle dysfunction where mitochondria remain a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, and mitophagy are under strict regulation by the mitochondrial genome and nuclear genome. These processes aggravate neurodegenerative activities upon alteration through neuroinflammation, oxidative damage, apoptosis, and proteostatic stress. Therefore, the mitochondria have grabbed a central position in the patho-mechanistic exploration of neurodegenerative diseases like PD. The management of PD remains a challenge to physicians to date, due to the variable therapeutic response of patients and the limitation of conventional chemical agents which only offer symptomatic relief with minimal to no disease-modifying effect. This review describes the patho-mechanistic pathways involved in PD not only limited to protein dyshomeostasis and oxidative stress, but explicit attention has been drawn to exploring mechanisms like organelle dysfunction, primarily mitochondria and mitochondrial genome influence, while delineating the newer exploratory targets such as GBA1, GLP, LRRK2, and miRNAs and therapeutic agents targeting them.

Pharmacogenomic Analyses Implicate B Cell Developmental Status and MKL1 as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy.

Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.

Microbial Influences on Immune Checkpoint Inhibitor Response in Melanoma: The Interplay between Skin and Gut Microbiota.

Immunotherapy has revolutionized the treatment of melanoma, but its limitations due to resistance and variable patient responses have become apparent. The microbiota, which refers to the complex ecosystem of microorganisms that inhabit the human body, has emerged as a promising area of research for its potential role in melanoma development and treatment response. Recent studies have highlighted the role of microbiota in influencing the immune system and its response to melanoma, as well as its influence on the development of immune-related adverse events associated with immunotherapy. In this article, we discuss the complex multifactorial mechanisms through which skin and gut microbiota can affect the development of melanoma including microbial metabolites, intra-tumor microbes, UV light, and the immune system. In addition, we will discuss the pre-clinical and clinical studies that have demonstrated the influence of different microbial profiles on response to immunotherapy. Additionally, we will explore the role of microbiota in the development of immune-mediated adverse events.

A Qualitative Examination of the Preferred Language for Patients Discussing Genital Psoriasis With the Physician

Background Psoriasis is a chronic inflammatory disease that may affect the genitalia in up to 60% of patients. This is a significant concern to patients; however, they may be too embarrassed to report genital involvement or seek help for it spontaneously. Information on preferred language that would put patients more at ease discussing disease in sensitive areas is lacking. Objective To address language as a barrier to care in patients with psoriasis by identifying preferred terminology when discussing genital involvement of the disease with physicians. Methods A qualitative study was performed that consisted of one-on-one interviews with patients with psoriasis; thematic analysis was used to analyze the data. Results Themes included (1) personal experience with genital psoriasis; (2) timespan between genital psoriasis symptom onset and diagnosis; (3) patient–provider communication; (4) patient–provider preference, and (5) patient terminology preference. Conclusion Our study highlights providers’ failure to ask psoriasis patients about genital involvement of the disease and variation in patient response on preferred language when discussing sensitive topics. Dermatologists may need to be cognizant of the patient’s comfort level using verbal and nonverbal communication and tailor their approach to the individual.

RYK Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients.

Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients.

Modern Interventions for Pediatric Atopic Dermatitis: An Updated Pharmacologic Approach.

Pediatric atopic dermatitis (AD) has historically challenged dermatologists given the variable response of patients to treatment and limited available therapeutic options, often with significant potential side effects. Over the last decade, targeted treatments including dupilumab and Janus kinase (JAK) inhibitors have emerged as significant treatment advances. An updated therapeutic approach for incorporating these new practice-changing medications can help clinicians manage these challenging patients. In this review, we discuss emerging topical and systemic (oral and injectable) treatments in pediatric AD, including topical PDE4 inhibitors and tapinarof, oral JAK inhibitors, and injected biologics including IL-4Rα inhibitor dupilumab, IL-13 inhibitor tralokinumab, IL-13Rα inhibitor lebrikizumab, IL-31Rα inhibitor nemolizumab, and IL-5Rα inhibitor benralizumab. We also review experimental agents in early clinical trials, such as targeted microbiome transplant lotions/antimicrobials, which may gain relevance in AD treatment. Finally, we propose a therapeutic approach for pediatric AD that incorporates newer therapies including dupilumab and JAK inhibitors, recognizing that these agents may not be universally available or approved. Further trials that include pediatric patients, especially head-to-head studies among therapeutic classes, are needed to clarify the role of emerging treatments.

Time constant to determine PEEP levels in mechanically ventilated COVID-19 ARDS: a feasibility study

BackgroundWe hypothesized that the measured expiratory time constant (TauE) could be a bedside parameter for the evaluation of positive end-expiratory pressure (PEEP) settings in mechanically ventilated COVID-19 patients during pressure-controlled ventilation (PCV).MethodsA prospective study was conducted including consecutively admitted adults (n = 16) with COVID-19-related ARDS requiring mechanical ventilation. A PEEP titration using PCV with a fixed driving pressure of 14 cmH2O was performed and TauE recorded at each PEEP level (0 to 18 cmH2O) in prone (n = 29) or supine (n = 24) positions. The PEEP setting with the highest TauE (TauEMAX) was considered to represent the best tradeoff between recruitment and overdistention.ResultsTwo groups of patterns were observed in the TauE plots: recruitable (R) (75%) and nonrecruitable (NR) (25%). In the R group, the optimal PEEP and PEEP ranges were 8 ± 3 cmH2O and 6–10 cmH2O for the prone position and 9 ± 3 cmH2O and 7–12 cmH2O for the supine position. In the NR group, the optimal PEEP and PEEP ranges were 4 ± 4 cmH2O and 1–8 cmH2O for the prone position and 5 ± 3 cmH2O and 1–7 cmH2O for the supine position, respectively. The R group showed significantly higher optimal PEEP (p < 0.004) and PEEP ranges (p < 0.001) than the NR group. Forty-five percent of measurements resulted in the most optimal PEEP being significantly different between the positions (p < 0.01). Moderate positive correlation has been found between TauE vs CRS at all PEEP levels (r2 = 0.43, p < 0.001).ConclusionsTauE may be a novel method to assess PEEP levels. There was wide variation in patient responses to PEEP, which indicates the need for personalized evaluation.

Initiation of the Pharmacogenetics of Capecitabine in Morocco

Introduction: The pharmacogenetics of anticancer drugs is of paramount importance in minimizing their side effects and increasing their efficacy. When applied to capecitabine, the result is that variation in patient responses has been largely linked to different genetic polymorphisms of dihydropyrimidine dehydrogenase (DPD), which explained in many cases, the onset of toxicity of this medication in patients. Failure of this enzyme is known to be responsible for a high incidence of serious or fatal side effects. In this study conducted on Moroccan patients under treatment with capecitabine at usual doses at the Fez University Hospital, the first in Africa and Morocco, we are looking for the presence of four variants of the DPD gene (DPYD): T486A on exon 5 (rs666523971), c.1679T&gt; G (p.I560S; rs55886062; allele DPYD * 13) on exon 13, c.1905 + 1G&gt; A (IVS14 + 1G&gt; A; rs3918290; allele DPYD * 2A) on the splice site near exon 14 and the c.2846A&gt; T mutation (p.D949V; rs67376798) on exon 22. We will therefore seek to establish the cause-and-effect relationship between this toxicity and the presence of these variants in his patients, which will allow us to avoid the dangerous prescription of capecitabine in patients carrying these polymorphisms. Methods: This prospective study is carried out at the Laboratory of Medical Genetics of the CHU Hassan II Fez and spread over a period of 3 years. Patient recruitment was carried out by the oncology department of CHU Hassan II-Fès. All recruited patients are treated with capecitabine. A total of 64 patients were tested. Blood samples (5 ml) were obtained from each one of them after their consent, and DNA was extracted. The study of these four polymorphisms was carried out by PCR sequencing. Results and Discussion: We have studied 64 patients taking capecitabine. Their median age was 50, and the mean age was 50 and 79, with extremes of 25 and 78 years. The sex ratio F / M was 0,60. Different levels of toxicity have been developed in patients ranging from simple vomiting to IVdegree hand and foot syndrome and second-degree neuropathy involving total discontinuation of treatment. These mutations were not found in the patients. Thus it would be interesting to enlarge the sample size, look for these polymorphisms and others on other exons of the DPYD gene, and try to understand the cause of this increased incidence of capecitabine toxicity in the Moroccan population. Conclusion: Capecitabine-based chemotherapy caused adverse effects with varying levels in its patients. The SNPs on the DPYD gene sought were not found in this Moroccan sample. It is desirable to screen more patients and to search for other SNPs to understand the toxicity of capecitabine in relation to the DPYD gene. This will make it possible to adjust the dosage of this drug, increase its effectiveness and minimize its toxicity.

An off-the-shelf multi-well scaffold-supported platform for tumour organoid-based tissues

Complex 3D bioengineered tumour models provide the opportunity to better capture the heterogeneity of patient tumours. Patient-derived organoids are emerging as a useful tool to study tumour heterogeneity and variation in patient responses. Organoid cultures typically require a 3D microenvironment that can be manufactured easily to facilitate screening. Here we set out to create a high-throughput, “off-the-shelf” platform which permits the generation of organoid-containing engineered microtissues for standard phenotypic bioassays and image-based readings. To achieve this, we developed the Scaffold-supported Platform for Organoid-based Tissues (SPOT) platform. SPOT is a 3D gel-embedded in vitro platform that can be produced in a 96- or 384-well plate format and enables the generation of flat, thin, and dimensionally-defined microgels. SPOT has high potential for adoption due to its reproducible manufacturing methodology, compatibility with existing instrumentation, and reduced within-sample and between-sample variation, which can pose challenges to both data analysis and interpretation. Using SPOT, we generate cultures from patient derived pancreatic ductal adenocarcinoma organoids and assess the cellular response to standard-of-care chemotherapeutic compounds, demonstrating our platform's usability for drug screening. We envision 96/384-SPOT will provide a useful tool to assess drug sensitivity of patient-derived organoids and easily integrate into the drug discovery pipeline.