Therapeutic Management Of Patients Research Articles

Evolution of therapeutic management of patients with ANCA associated vasculitis in France after licensing Rituximab use

IntroductionIn 2013, rituximab was approved in France for the treatment of ANCA-associated vasculitis (AAV). The aim of the study was to compare the treatment and health events of adult incident patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), included before rituximab approval (over 2010–2012, Group 1) and those included after rituximab approval (over 2014–2017, Group 2).MethodData were extracted from the French National Health Insurance database (SNDS) including outpatient health care consumption and hospital discharge forms. Comparisons between inclusion periods were performed using Wilcoxon and χ² tests. Kaplan-Meier method was used to model the duration of treatment induction, maintenance, and off-drug periods. Fine and Gray tests were used to compare treatment phase durations.ResultsA total of 694 GPA and 283 MPA patients were included in Group 1, while 668 GPA and 463 MPA patients were included in Group 2. Between the two inclusion periods, the proportions of patients treated with rituximab increased in the induction and maintenance phases whereas treatment with azathioprine declined. These proportions remained stable in the case of methotrexate, cyclophosphamide, and glucocorticoid-treated patients. Frequency of first-time hospitalized infections, diabetes and renal failure during the first year after inclusion increased for both groups.Limitations of the studyThis is a retrospective study based on claims data including only 76% of people covered by health insurance in France. The period studied includes the learning phase of using rituximab. This study lacks biological data and precise quantitative analysis for the use of steroids, therefore the criteria for establishing diagnosis and therapeutic choice were unknown.ConclusionsIntroduction of rituximab reduced the use of azathioprine without affecting the use of glucocorticoids or cyclophosphamide.

Patients with Leptomeningeal Carcinomatosis and Hydrocephalus-Feasibility of Combined Ventriculoperitoneal Shunt and Reservoir Insertion for Intrathecal Chemotherapy

Therapeutic management of patients with leptomeningeal carcinomatosis (LC) may require treatment of concomitant hydrocephalus (HC) in addition to intrathecal chemotherapy (ITC). Ventriculoperitoneal shunts (VPS) equipped with a valve for manual deactivation of shunt function and a concomitant reservoir for application of ITC pose an elegant solution to both problems. The present study evaluates indication, feasibility, and safety of such a modified shunt/reservoir design (mS/R). All patients with LC aged ≥ 18 years who had undergone mS/R implantation between 2013 and 2020 at the authors’ institution were further analyzed. ITC was indicated following the recommendation of the neuro-oncological tumor board and performed according to a standardized protocol. Sixteen patients with LC underwent mS/R implantation for subsequent ITC and concomitant treatment of HC. Regarding HC-related clinical symptoms, 69% of patients preoperatively exhibited lethargy, 38% cognitive impairment, and 38% (additional) visual disturbances. Postoperatively, 86% of patients achieved subjective improvement of HC-related symptoms. Overall, postoperative complications occurred in three patients (19%). No patient encountered cancer treatment-related complications. The present study describes a combination procedure consisting of a standard VPS-system and a standard reservoir for patients suffering from LC and HC. No cancer treatment-related complications occurred, indicating straightforward handling and thus safety.

Management of early-stage HER2-positive breast cancer and attitudes towards HER2DX test in Spain: insights from a nationwide survey.

This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer. An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer. The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice. In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

Recommendations and consensus on the therapeutic management of patients with copd exacerbation in the emergency services of Castilla y León (adaptation to 2024 of GOLD 2024 and GesEPOC 2021 Guidelines)

Recommendations and consensus on the therapeutic management of patients with copd exacerbation in the emergency services of Castilla y León (adaptation to 2024 of GOLD 2024 and GesEPOC 2021 Guidelines)

Real-World Treatment Patterns and Healthcare Resource Use for Ulcerative Colitis and Crohn's Disease in Italy.

Real-world data are used to inform decision-makers and optimise therapeutic management for patients with ulcerative colitis (UC) and Crohn's disease (CD). We analysed data on the epidemiology (by using proxies of prevalence and incidence), patient characteristics, treatment patterns and associated healthcare direct costs for the management of patients with UC and patients with CD in Italy. This retrospective observational study used administrative databases from eight Local Health Units geographically distributed across Italy. Adult patients with a hospitalisation and/or an exemption for UC or CD were included. Study outcomes were summarised descriptively, and limited statistical tests were performed. At baseline, 9255 adults with UC and 4747 adults with CD were included. Mean (standard deviation) age at inclusion was 54.0 (18.4)/48.6 (18.1) years, for UC/CD. The estimated average incidence of UC and CD for the period2013-2020 was 36.5 and 18.7 per 100,000, respectively. The most frequently prescribed drug category for patients with UC/CD was conventional treatment [mesalazine and topical corticosteroids (67.4%/61.1%), immunomodulators and systemic corticosteroids (43.2%/47.7%)], followed by biologic treatments (2.1%/5.1%). The mean annual total direct cost per patient was 7678euro (€), for UC and €6925 for CD. This analysis, carried-out in an Italian clinical setting, may help to optimise therapy for patients with UC and CD and provide relevant clinical practice data to inform decision-makers.

Impact Of PET/CT On Treatment In Patients With Head And Neck Squamous Cell Carcinoma.

<b><br>Introduction:</b> Although PET/CT is effective for staging HNSCC, its impact on patient management is somewhat controversial. For this reason, we considered it necessary to carry out a study in order to verify whether PET/CT helps to improve the prognosis and treatment in patients. This study was designed to address the impact of PET-FDG imaging when used alongside CT in the staging and therapeutic management of patients with HNSCC.</br> <b><br>Material and methods:</b> Data was collected from 169 patients diagnosed with HNSCC with both CT and PET/CT (performed within a maximum of 30 days of each other). It was evaluated whether discrepancies in the diagnosis of the two imaging tests had impacted the treatment.</br> <b><br>Results:</b> The combined use of CT and PET/CT led to a change in the treatment of 67 patients, who represented 39.7% of the sample. In 27.2% of cases, it entailed a change in the type of treatment which the patient received. In 3.0% of the cases, using both diagnostic tests led to modifications of the therapeutic intention of our patients.</br> <b><br>Conclusions:</b> Using PET/CT in addition to the conventional imaging method in staging resulted in more successful staging and more appropriate therapeutic decision-making.</br&gt.

Abstract LB243: Deep learning-based molecular characterization of lung cancers from never smokers using hematoxylin and eosin-stained whole slide images

Abstract Purpose: This study employs cutting-edge deep learning techniques to comprehensively analyze hematoxylin and eosin-stained (H&E) whole slide images (WSIs) to predict which tumors carry driver gene alterations, mutational signatures, and additional molecular features among lung cancers from never-smokers (LCINS)— the seventh leading cause of cancer death worldwide. Method: A total of 464 H&E-stained WSIs of lung adenocarcinomas from the Sherlock-Lung study were utilized, with 325 WSIs for model training and 139 for testing. Alongside the WSIs, genomic data, including mutations (overall nonsynonymous mutations and driver mutations only), fusions, or copy numbers in driver genes (TP53, KRAS, EGFR, CDKN2A, MDM2, ALK, RBM10), mutational signatures (APOBEC), molecular features (Kataegies, Whole Genome Doubling (WGD) status, Tumor Mutational Burden (TMB)), and specific hotspot driver mutation in EGFR (p.L858R and p.E746_A750del) and KRAS (p.G12C, p.G12V, and p.G12D), were included for all tumors. Each WSI was assigned different labels based on the presence or absence of these genomic alterations or features. We used a customized multilabel binary deep learning model based on ResNet50, a residual convolutional neural network, for analyzing the data. The network was trained from scratch, with an initial epoch set to 100. Results: Our methodology demonstrated high predictive performance, measured by the area under the receiver operating characteristic (AUROC). In the presence or absence category, we achieved high AUROC for detecting any alterations in these driver genes: TP53 (0.81), KRAS (0.92), EGFR (0.93), CDKN2A deletion (0.88), MDM2 amplification (0.94), and ALK fusion (0.86). We also evaluated molecular features, obtaining AUROC scores of 0.79 for WGD status and 0.86 for Kataegies. Moderate AUROC scores were observed for tumors with RBM10 mutations (0.67), high TMB (0.64), and APOBEC signatures (0.56). When focusing on driver mutations only, we achieved high AUROC scores for EGFR (0.88), KRAS (0.84), TP53 (0.93), and RBM10 (0.78). In addition, our model successfully predicted tumors with specific mutations in EGFR (p.L858R = 0.79; p.E746_A750del = 0.77) and KRAS (p.G12C = 0.77). Performance was suboptimal for KRAS p.G12V (0.41) and KRAS p.G12D (0.47). Conclusions: Our deep learning network achieves high prediction scores in identifying tumors with critical driver gene alterations and actionable mutations, holding promise for potential clinical use. In the future, the model could be optimized as a screening assay to guide molecular testing and therapeutic management of patients with LCINS. Citation Format: Monjoy Saha, Tongwu Zhang, Praphulla Bhawsar, Wei Zhao, Jianxin Shi, Soo Ryum Yang, Jonas Almeida, Maria Teresa Landi. Deep learning-based molecular characterization of lung cancers from never smokers using hematoxylin and eosin-stained whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB243.

Abstract CT292: Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases

Abstract Background: Many patients develop brain metastasis during the course of their disease and it represents the cause of death in more than half of them. The prognosis and survival of patients with brain metastases remains poor with limited palliative treatment options. Thus, there is a need to develop new strategies for the therapeutic management of patients with brain metastases. Inflammatory stimuli originating from CNS tumors may increase the permeability of the blood-brain barrier and promote immune cell activation and infiltration into tumors. Several studies have demonstrated now the efficacy of immune checkpoint inhibitors in patients with melanoma with active brain metastases. The modulation of VEGF-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. Lenvatinib is an oral, potent multiple receptor tyrosine kinase inhibitor that selectively inhibits VEGFRs, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and oncogenic pathway-related receptor tyrosine kinases. The combination of lenvatinib and pembrolizumab is approved for patients with metastatic endometrial carcinoma and renal cancer, and it is investigated in other tumor types with promising preliminary results. We hypothesize that pembrolizumab and lenvatinib will be an effective treatment for TNBC, NSCLC, and other solid tumor types with brain metastases by decreasing angiogenic tumor activity and improving antitumor T-cell activity. Methods: This is a single-center, open-label, multi-cohort Phase II study evaluating the efficacy and safety of pembrolizumab in combination with lenvatinib in patients with solid tumors and brain metastases. The study has 3 cohorts: triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other solid tumor types with established or preliminary clinical evidence of efficacy of programmed cell death-1 (PD-1) and angiogenesis inhibitors. Eligible patients will have at least 1 unirraditated or progressing brain metastasis of 0.5-2 cm on brain MRI. The study is conducted using a Simon’s optimal two-stage design, and approximately 87 patients will be enrolled concurrently (n=29 per cohort). Pembrolizumab (200 mg intravenously on Day 1 of each cycle) and lenvatinib (20 mg orally once daily) are administered in 21-day cycles for a maximum of 24 months. The primary endpoint is intracranial objective response rate at 4 months as assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Exploratory analyses will include evaluation of tissue and blood-based immune-related correlates of response to the pembrolizumab and lenvatinib combination. The first patient was enrolled in January 2022 and accrual of patients is ongoing (NCT05064280). Citation Format: Ecaterina E. Dumbrava, Emma J. Montazari, Uyen M. Vu, Tiantian Cai, Mehmet Altan, Nuhad K. Ibrahim, Debra N. Yeboa, Jing Li, Frederick F. Lang, Gisela Sanchez, Isabella C. Glitza, Barbara J. O'Brien, Rashmi K. Murthy, Jianbo Wang, Tanisha T. Darko, Denisse Velazquez, Komal Shah, Funda Meric-Bernstam, Hussein Tawbi, Jordi Rodon. Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT292.

A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms.

Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

The Impact of Prior Single-Gene Testing on Comprehensive Genomic Profiling Results for Patients with Non-Small Cell Lung Cancer.

Tissue-based broad molecular profiling of guideline-recommended biomarkers is advised for the therapeutic management of patients with non-small cell lung cancer (NSCLC). However, practice variation can affect whether all indicated biomarkers are tested. We aimed to evaluate the impact of common single-gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) test outcomes and results in NSCLC. Oncologists who ordered SGT for guideline-recommended biomarkers in NSCLC patients were prospectively contacted (May-December 2022) and offered CGP (DNA and RNA sequencing), either following receipt of negative SGT findings, or instead of SGT for each patient. We describe SGT patterns and compare CGP completion rates, turnaround time, and recommended biomarker detection for NSCLC patients with and without prior negative SGT results. Oncologists in > 80 community practices ordered CGP for 561 NSCLC patients; 135 patients (27%) first had negative results from 30 different SGT combinations; 84% included ALK, EGFR and PD-L1, while only 3% of orders included all available SGTs for guideline-recommended genes. Among patients with negative SGT results, CGP was attempted using the same tissue specimen 90% of the time. There were also significantly more CGP order cancellations due to tissue insufficiency (17% vs. 7%), DNA sequencing failures (13% vs. 8%), and turnaround time > 14days (62% vs. 29%) than among patients who only had CGP. Forty-six percent of patients with negative prior SGT had positive CGP results for recommended biomarkers, including targetable genomic variants in genes beyond ALK and EGFR, such as ERBB2, KRAS (non-G12C), MET (exon 14 skipping), NTRK2/3, and RET . For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency.

The Role of Inflammatory Biomarkers in Mediating the Effect of Inflammatory Bowel Disease on nonmalignant Digestive System Diseases: A Multivariable Mendelian Randomized Study.

While observation studies have shown a positive correlation between inflammatory bowel disease (IBD) and the risk of nonmalignant digestive system diseases, a definitive causal relationship has not yet been clearly established. Mendelian randomization (MR) was employed to investigate the potential causal association between genetic susceptibility to IBD and nonmalignant gastrointestinal diseases. Genetic variants were extracted as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis, which included 12,194 cases of Crohn's disease (CD) and 28,072 control cases of European ancestry. The GWAS for ulcerative colitis (UC) included 12,366 UC and 33,609 control cases of European ancestry. All IVs reached genome-wide significance (GWAS p value <5 × 10-8). Summary-level data for acute pancreatitis (AP), irritable bowel syndrome (IBS), gastroesophageal reflux disease, cholelithiasis, and CeD (celiac disease) were obtained from the GWAS meta-analysis and the FinnGen dataset. Summary-level data on relevant inflammatory factors were provided by the International Genetic Consortium. Univariate MR analysis was conducted using inverse variance weighting as the primary method for estimating causal effects. Multivariate MR analyses were also performed to detect possible mediators. Genetic susceptibility to UC was associated with an increased risk of AP (OR = 1.08; 95% CI = 1.03-1.13; p=0.002) and IBS odds ratio (OR] = 1.07; 95% confidence interval (CI] = 1.03-1.11; (p < 0.001). In terms of potential mediators, interleukin 6 (IL-6) had a driving effect on the association between UC and AP. There was no apparent evidence of increased risk with CD. Meanwhile, genetic susceptibility to CD increases the risk of CeD (OR = 1.14; 95% CI = 1.03-1.25; p=0.01). The evidence suggests that UC is associated with an elevated risk of AP and IBS, and IL-6 may be responsible in AP. CD is associated with an increased risk of developing CeD. Implementing a proactive monitoring program for assessing the risk of gastrointestinal diseases in UC patients, particularly those with elevated IL-6 levels, may be of interest. In addition, the presence of AP and IBS may indicate the presence of UC. Preventing CeD is an essential consideration in the therapeutic management of patients with CD.

Atrial Fibrillation in Wolff Parkinson White (WPW) Syndrome: Case Report and Review of the Literature

The occurrence of atrial fibrillation (AF) transmitted to the ventricles by an accessory pathway is a rare, potentially serious arrhythmia. The risk of ventricular fibrillation is a fatal complication that can be increased by certain medications such as digitalis. AF can be the initial presentation of WPW syndrome, in which case it is often poorly tolerated. We report the case of a 42-year-old patient with no particular history, who consulted for palpitations that appeared at rest, a few hours previously; systolic blood pressure was 80 mm Hg without signs of shock. The ECG showed rapid AF with wide QRS. After reduction by external electric shock, the post-ictal ECG was in favor of WPW syndrome. The initial assessment was quickly carried out, and the patient was treated with a combination of two antiarrhythmic drugs. The occurrence of rhythm disturbances requires an etiological assessment on which the specific treatment will depend. In WPW syndrome, stratification of the individual risk of sudden death is essential in the therapeutic management of patients.

Prediction of lymph node status in patients with surgically treated head and neck squamous cell carcinoma via neck lavage cytology: A pilot study.

Neck dissection is a standardized surgical procedure for patients with head and neck squamous cell carcinoma (HNSCC) and plays a critical role in the choice of adjuvant treatment based on histopathological findings. Saline irrigation is routinely performed at the end of surgery. However, this irrigant is not used for diagnostic purposes. Intraoperative irrigation of the neck dissection wound was performed in 56 patients with HNSCC (N=93 neck dissections), and the cytological suspension obtained was processed via the liquid-based cytology (LBC) technique, Papanicolaou staining, and immunocytochemical staining. Microscopic preparations were screened for the presence of tumor cells and classified as positive, borderline, or negative. These results were correlated with the histopathological and clinical data. Neck lavage LBC demonstrated high diagnostic value in detecting lymph node metastases (N+) with extracapsular spread (ECS), with a specificity, sensitivity, negative predictive value, and positive predictive value of 93.1%, 100%, 100%, and 80%, respectively. Tumor cells were detected in 4.8% of N- cases, 20% of N+ cases without ECS, and 100% of N+ cases with ECS. Receiver operating characteristic curve analysis showed an area under the curve of 0.8429 for the prediction of N+ (p<.0001) and 0.9658 for the prediction of N+ with ECS (p<.0001). Differential lavage cytology can provide valid and rapid information on the lymph node status in patients with HNSCC and showed an excellent correlation with histopathology. Thus, neck lavage LBC may facilitate faster and more reasonable planning of adjuvant treatment and help improve the therapeutic management of patients with HNSCC.

French Society for Biological Psychiatry and Neuropsychopharmacology (AFPBN) guidelines for the management of patients with partially responsive depression and treatment-resistant depression: Update 2024

IntroductionThe purpose of this update is to add newly approved nomenclatures and treatments as well as treatments yet to be approved in major depressive disorder, thus expanding the discussions on the integration of resistance factors into the clinical approach. MethodsUnlike the first consensus guidelines based on the RAND/UCLA Appropriateness Method, the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) developed an update of these guidelines for the management of partially responsive depression (PRD) and treatment-resistant depression (TRD). The expert guidelines combine scientific evidence and expert clinicians’ opinions to produce recommendations for PRD and TRD. ResultsThe recommendations addressed three areas judged as essential for updating the previous 2019 AFPBN guidelines for the management of patients with TRD: (1) the identification of risk factors associated with TRD, (2) the therapeutic management of patients with PRD and TRD, and (3) the indications, the modalities of use and the monitoring of recent glutamate receptor modulating agents (esketamine and ketamine). ConclusionThese consensus-based guidelines make it possible to build bridges between the available empirical literature and clinical practice, with a highlight on the ‘real world’ of the clinical practice, supported by a pragmatic approach centred on the experience of specialised prescribers in TRD.

Prognostic value of the systemic immune-inflammation index in patients with acute respiratory distress syndrome: A retrospective study

BackgroundInflammation is critical in the etiology and progression of acute respiratory distress syndrome (ARDS). This study aims to rigorously assess the predictive capacity of systemic immune-inflammation index (SII) in determining the outcomes of patients with ARDS. MethodsPatient data were extracted from version 2.2 of the Medical Information Mart for Intensive Care IV (MIMIC-IV). The Receiver Operating Characteristic (ROC) curve was deployed to determine the optimal cutoff value for the SII, facilitating the stratification of participants into distinct cohorts based on SII levels. The relationship between SII and survival outcomes was rigorously evaluated using Cox proportional hazards models. The association between SII and patient survival was rigorously examined using Cox proportional-hazard models. The impact of varying SII levels on mortality was quantitatively assessed through these models, with the results articulated as hazard ratios (HRs) and 95% confidence intervals (CIs). Three distinct models were formulated for this analysis: Model 1 employed univariate Cox regression to relate SII with mortality; Model 2 introduced adjustments for age and sex; and Model 3 extended these adjustments to include age, sex, race, SAPS II, APSIII, Hemoglobin, Albumin, Pneumonia, SpO2, and SBP. ResultsPost-application of the inclusion criteria, a cohort of 976 eligible patients was delineated for detailed examination. Univariate analysis focusing on 30-day mortality within the SII ≥1694, the hazard ratio (HR) was 1.42 (95% confidence interval (CI): 1.11, 1.81). However, after adjusting for confounding factors such as age, sex, race, Simplified Acute Physiology Score II (SAPS II), Acute Physiology Score (APS) III, Hemoglobin, Albumin, Pneumonia, SpO2, and Systolic Blood Pressure (SBP), an SII value of ≥1694 was identified as an independent and significant risk factor for mortality in patients with ARDS, with an HR of 1.38 (95% CI: 1.08–1.77, P = 0.0016). This trend was consistent for 90-day and one-year mortality rates. ConclusionsSII surfaced as an autonomous determinant of mortality in ARDS patients, affirming its status as an accessible and dependable prognostic indicator for individuals newly diagnosed with this critical condition. Additional research is imperative to further elucidate the prognostic implications of SII in the therapeutic management of patients with ARDS.

Clinical characteristics, diagnosis, treatment and outcomes of patients living with HIV and co-infected with tuberculosis and histoplasmosis: a 5-y retrospective case series.

In Latin America, tuberculosis (TB) and histoplasmosis are two of the most frequent opportunistic infections affecting people living with human immunodeficiency virus (HIV). However, there are limited data on the clinical characteristics and outcomes of patients with concurrent TB and histoplasmosis infections. This was a retrospective observational study to describe the clinical, epidemiological and laboratory characteristics and outcomes of 21 patients living with HIV (PLHIV) who were diagnosed with concurrent histoplasmosis and TB between 2017 and 2021 in Guatemala City, Guatemala. Most patients were male and were newly diagnosed with HIV. All patients had advanced HIV disease (AHD). They presented with a median CD4 count of 20cells/µl. The most common symptoms reported by the patients were fever, weight loss, cough and diarrhoea. Twelve patients died within 6months of baseline evaluation, for a mortality rate of 57.1%. PLHIV with concurrent TB and histoplasmosis infections are characterised by AHD, predominantly presenting with disseminated forms of these infections and with unspecific symptoms and signs. This evidence calls for early HIV and opportunistic infection screening and insights into the challenges and opportunities for the efficient diagnostic and therapeutic management of patients with AHD with concurrent histoplasmosis and TB infections.

Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.

Current Challenges and Controversies in Colorectal Carcinoma Pathologic Staging-A Practical Guide.

The pathologic assessment of colorectal carcinoma specimens plays a crucial role in the therapeutic management of patients and disease prognostication. The TNM staging system is used globally and is a critical component of colorectal carcinoma pathology reporting. However, our experience informs us that there are significant variations in the assignment of the TNM stage, both between pathologists and between hospital centers. We identify several potential reasons for this, among them suboptimal gross and microscopic assessment of colorectal resection specimens and, later, nonuniformity in applying criteria set forth in pathologic TNM staging guidelines. In addition, some defining characteristics of the staging system remain poorly defined. We aim to enlist those issues with potential remedies to improve reproducibility and, therefore, multidisciplinary discussion.

Optimized Pre-analytical Handling Protocol for Blood-Based Biomarkers of Alzheimer's Disease.

The therapeutic management of patients with Alzheimer's disease (AD) has been hindered by poor diagnostic accuracy. As such, there is an unmet clinical need for tools that can detect and diagnose the disease in its early stages. Compared with cerebrospinal fluid (CSF)-based biomarkers or positron emission tomography(PET), the use of reliable blood-based biomarkers could offer an accessible and minimally invasive method of streamlining diagnosis in the clinical setting. However, the influence of pre-analytical processing and sample handling parameters on the accurate measurement of protein biomarkers is well established, especially for AD CSF-based biomarkers. In this chapter, we provide recommendations for an optimal sample handling protocol for the analysis of blood-based biomarkers specifically for amyloid pathology in AD.

Prevalence of extended-spectrum beta-lactamases producing isolates obtained from patients of pediatric critical care unit in a tertiary care hospital

Background: Over the past decades, antibiotic-resistant Gram-negative bacteria commonly Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae have increased significantly. These microorganisms have great clinical importance because they increase hospital stay of the patients in the intensive care unit (ICU) leading to high morbidity and mortality. Because of their role in increasing morbidity and mortality, this study was performed to isolate extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacilli screened by phenotypical method and further projected into molecular characterization by polymerase chain reaction. Aims and Objectives: The aims and objectives are to isolate the Gram-negative multidrug-resistant strains from clinically suspected bacterial infections in patients of neonatal, sick newborn, and pediatric ICU and to study antibiotic sensitivity pattern of isolated Gram-negative multidrug-resistant strains with special reference to molecular characterization. Materials and Methods: A total of 100 Gram-negative bacilli were isolated. Screening of ESBL positivity was done by double-disk synergy test (combined disc test method). Their antibiogram profile was interpreted. With the use of designed primers, 26 ESBL isolates each of E. coli and Klebsiella spp. were processed for molecular analysis of beta-lactamase family genes TEM and CTX-M. Results: Within the 100 samples, majority of the isolates (45%) were Klebsiella spp. and 40% was E. coli isolates. Highest ESBL-producing organisms were observed within E. coli (65%). Prevalence bla-TEM gene was highest followed by bla-CTX-M. These ESBL-producing organisms were found to be resistant to multiple classes of antibiotics. With extensive ESBL surveillance and proper usage of antibiotics, this threatening rise of antibiotic resistance can be mitigated. Conclusion: Gram-negative isolates showed high resistance to commonly used antibiotics. Significant proportions of them were MDR strains. Such high antibiotic resistance is associated with significant morbidity and mortality among pediatric population. MDR along with possession of ESBL associated resistance genes among Gram-negative bacilli pose a serious problem in therapeutic management of patients. Our study signifies that there is a high probability of Gram- negative bacilli to be multi-drug resistant and ESBL positive and earliest detection of such cases should be made.