Standard Of Care For Patients Research Articles

Smart Hospital Management System: Streamlining Healthcare Operations with SQL Integration

This research delves into the development and deployment of a Smart Hospital Management System (HMS), a pivotal solution for enhancing administrative efficiency and elevating patient care standards within healthcare institutions. Motivated by the pressing need to optimize hospital operations, the system seamlessly integrates modules encompassing patient registration, appointment scheduling, medical records management, billing, and inventory control. Leveraging modern technologies, particularly database management systems and web-based platforms, the HMS aims to bolster the efficiency, accuracy, and accessibility of healthcare services while prioritizing data security and regulatory compliance. The study scrutinizes the benefits and challenges associated with HMS adoption, shedding light on its potential impact on healthcare delivery and organizational performance. Furthermore, it underscores the contributions of this work to the research community, delineates future avenues for exploration, and offers insights into the promising prospects of smart healthcare systems.

Cost-effectiveness of sotagliflozin for the treatment of patients with diabetes and recent worsening heart failure.

Aim: To assesses the cost-effectiveness of sotagliflozin for the treatment of patients hospitalized with heart failure and comorbid diabetes. Materials & methods: Ade novo cost-effectiveness model with a Markov structure was created for patients hospitalized for heart failure with comorbid diabetes. Outcomes of interest included hospital readmissions, emergency department visits and all-cause mortality measured over a 30-year time horizon. Baseline event frequencies were derived from published real-world data studies; sotagliflozin's efficacy was estimated from SOLOIST-WHF. Health benefits were calculated quality-adjusted life years (QALYs). Costs included pharmaceutical costs, rehospitalization, emergency room visits and adverse events. Economic value was measured using the incremental cost-effectiveness ratio (ICER). Results: Sotagliflozin use decreased annualized rehospitalization rates by 34.5% (0.228 vs 0.348, difference: -0.120), annualized emergency department visits by 40.0% (0.091 vs 0.153, difference: -0.061) and annualized mortality by 18.0% (0.298 vs 0.363, difference: -0.065) relative to standard of care, resulting in a net gain in QAYs of 0.425 for sotagliflozin versus standard of care. Incremental costs using sotagliflozin increased by $19,374 over a 30-year time horizon of the patient, driven largely by increased pharmaceutical cost. Estimated ICER for sotagliflozin relative to standard of care was $45,596 per QALY. Conclusion: Sotagliflozin is a cost-effective addition to standard of care for patients hospitalized with heart failure and comorbid diabetes.

Overall Survival in Patients with Esophageal Cancer and Clinical Complete Response after Radio Chemotherapy: Should a Watchful Waiting Strategy be the new Standard of Care?

Abstract Background The current standard of care for curative treatment of esophageal cancer (EC) consists of neoadjuvant radio chemotherapy (RCT) followed by resection. However, an organ-sparing approach with a watchful waiting (WW) strategy and resection only in case of cancer recurrence is gaining importance in patients with clinical complete response (cCR) after RCT. Nevertheless, data on overall survival, particularly in subgroups with and without tumor recurrence, is limited. Aims To compare overall survival (OS) rates in patients with cCR based on initial management and at time of recurrence. Methods We retrospectively analyzed data from all patients with EC and cCR to RCT between 01/2014 and 12/2021. OS- and disease-free survival was calculated using Kaplan-Meier survival analysis. Results Of 96 patients with cCR after RCT, 45 underwent resection (47%), and 51 (53%) a WW approach. There were no significant differences in baseline patient or tumor characteristics. In the WW group, 28 patients (55%) had cancer recurrence. Of those, 11 patients (of 28, 39%) underwent either salvage esophagectomy or endoscopic submucosal dissection in curative intent. No significant difference in OS could be detected in patients with WW and either no recurrence or recurrence treated in curative intention (p=0.716). Further, OS was significantly longer in those patients than in patients with primary resection (p=0.031) and WW patients with recurrence and palliative treatment (p<0.001). (Fig 1). Conclusion In a WW concept for patients with EC and cCR after RCT, patients with cancer recurrence can achieve the same OS as patients without recurrence if treated in curative intention. Moreover, OS in both those patient groups was superior to that of patients undergoing direct resection after RCT, supporting a WW approach as at least safe and applicable in clinical practice. Further prospective data are needed to determine the value of WW as standard of care for patients with cCR following neoadjuvant RCT.

Understanding Perioperative Acute Myocardial Ischemia Following Coronary Artery Bypass Grafting.

Surgical revascularization and coronary artery bypass grafting are often pursued as treatment for obstructive coronary artery disease. Despite trends of increased referrals for complex percutaneous coronary intervention, surgical revascularization often remains the standard of care for patients with multivessel or complex coronary artery disease. Myocardial ischemia during the perioperative and postoperative periods during coronary artery bypass grafting remains a challenge. Nuanced consideration is necessary to decide on interventions that include conservative management and percutaneous or repeat surgical revascularization.

Postoperative outcomes after prehabilitation for colorectal cancer patients undergoing surgery: a systematic review and meta-analysis of randomized and nonrandomized studies.

Prehabilitation (PH) is purported to improve patients' preoperative functional status. This systematic review and meta-analysis sought to compare short-term postoperative outcomes between patients who underwent a protocolized PH program and the existing standard of care among colorectal cancer patients awaiting surgery. A search in MEDLINE/PubMed, the Cochrane Library, Embase, Scopus, and CINAHL was conducted to identify relevant articles. Repetitive and exhaustive combinations of MeSH search terms ("prehabilitation," "colorectal cancer," "colon cancer," and "rectal cancer") were used to identify randomized and nonrandomized studies comparing PH versus standard of care for colorectal cancer patients awaiting surgery. The primary outcomes included postoperative morbidity, length of hospital stay, and readmission rates. Seven studies including 1,042 colorectal cancer patients (PH, 382) were included. No significant differences were found in intraoperative outcomes. The postoperative complication rates were comparable between groups (Clavien-Dindo grades I and II: risk ratio, 0.82; 95% confidence interval, 0.62-1.07; P=0.15; Clavien-Dindo grades ≥III: risk ratio, 1.02; 95% confidence interval, 0.72-1.44; P=0.92). There were also no significant differences in length of hospital stay (P=0.21) or the risk of 30-day readmission (P=0.68). Although PH does not appear to improve short-term postoperative outcomes following colorectal cancer surgery, the quality of evidence is impaired by the limited trials and heterogeneity. Thus, further large-scale trials are warranted to draw definitive conclusions and establish the long-term effects of PH.

Carbon monoxide as a cellular protective agent in a swine model of cardiac arrest protocol.

Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50-80% mortality prior to reaching medical care. Despite aggressive supportive care and targeted temperature management (TTM), half of adults do not live to hospital discharge and nearly one-third of survivors have significant neurologic injury. The current treatment approach following cardiac arrest resuscitation consists primarily of supportive care and possible TTM. While these current treatments are commonly used, mortality remains high, and survivors often develop lasting neurologic and cardiac sequela well after resuscitation. Hence, there is a critical need for further therapeutic development of adjunctive therapies. While select therapeutics have been experimentally investigated, one promising agent that has shown benefit is CO. While CO has traditionally been thought of as a cellular poison, there is both experimental and clinical evidence that demonstrate benefit and safety in ischemia with lower doses related to improved cardiac/neurologic outcomes. While CO is well known for its poisonous effects, CO is a generated physiologically in cells through the breakdown of heme oxygenase (HO) enzymes and has potent antioxidant and anti-inflammatory activities. While CO has been studied in myocardial infarction itself, the role of CO in cardiac arrest and post-arrest care as a therapeutic is less defined. Currently, the standard of care for post-arrest patients consists primarily of supportive care and TTM. Despite current standard of care, the neurological prognosis following cardiac arrest and return of spontaneous circulation (ROSC) remains poor with patients often left with severe disability due to brain injury primarily affecting the cortex and hippocampus. Thus, investigations of novel therapies to mitigate post-arrest injury are clearly warranted. The primary objective of this proposed study is to combine our expertise in swine models of CO and cardiac arrest for future investigations on the cellular protective effects of low dose CO. We will combine our innovative multi-modal diagnostic platform to assess cerebral metabolism and changes in mitochondrial function in swine that undergo cardiac arrest with therapeutic application of CO.

Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to...

The impact of pre-, pro- and synbiotics supplementation in colorectal cancer treatment: a systematic review

The impact of pre-, pro- and synbiotics supplementation in colorectal cancer treatment: a systematic review

Real-Time Use of SGLT2i Verified in Pre-dialysis: The RSVP Cross-sectional Study.

The use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in nephrology practice is increasingly becoming standard of care in patients with diabetes or those with proteinuria. The primary outcome was to identify the proportion of pre-dialysis patients with chronic kidney disease (CKD) G3a, G3b, or G4 prescribed an SGLT2i and describe their characteristics. This was a retrospective, multicentric, cross-sectional study of patients with CKD followed at 4 pre-dialysis clinics in the province of Quebec, Canada. We collected data of multiple covariates associated with prescribing SGLT2i in patients over 18 years of age with CKD G3a, G3b, or G4. We then performed a multivariate logistic regression to assess their associations. Of the 874 patients included, 22.7% were prescribed an SGLT2i. Factors most strongly associated included male sex (odds ratio [OR] = 4.88, 95% CI = 2.38-10.03), being prescribed metformin (OR = 4.30, 95% CI = 2.23-8.31), having type 2 diabetes (OR = 4.00, 95% CI = 1.86-8.62), or having an albumin-to-creatinine ratio greater than 300 mg/g (OR = 1.84, 95% CI = 1.08-3.14). The majority of patients (60.4%) had their SGLT2i initiated by the pre-dialysis clinic and the most frequent adverse event was an initial increase in serum creatinine 1 week after starting treatment (33.9%). An increasing number of patients with CKD are being prescribed SGLT2i. Nonetheless, significant disparities in sex, severity of disease, and comorbidities remain. We suggest that specific strategies be put in place to promote prescribing of SGLT2i in women and other at-risk populations, in particular among nephrology teams, to improve patient care.

WhARIO: whole-slide-image-based survival analysis for patients treated with immunotherapy.

Immune checkpoint inhibitors (ICIs) are now one of the standards of care for patients with lung cancer and have greatly improved both progression-free and overall survival, although of the patients respond to the treatment, and some face acute adverse events. Although a few predictive biomarkers have integrated the clinical workflow, they require additional modalities on top of whole-slide images and lack efficiency or robustness. In this work, we propose a biomarker of immunotherapy outcome derived solely from the analysis of histology slides. We develop a three-step framework, combining contrastive learning and nonparametric clustering to distinguish tissue patterns within the slides, before exploiting the adjacencies of previously defined regions to derive features and train a proportional hazards model for survival analysis. We test our approach on an in-house dataset of 193 patients from 5 medical centers and compare it with the gold standard tumor proportion score (TPS) biomarker. On a fivefold cross-validation (CV) of the entire dataset, the whole-slide image-based survival analysis for patients treated with immunotherapy (WhARIO) features are able to separate a low- and a high-risk group of patients with a hazard ratio (HR) of 2.29 ( to 3.56), whereas the TPS 1% reference threshold only reaches a HR of 1.81 ( to 2.69). Combining the two yields a higher HR of 2.60 ( to 3.94). Additional experiments on the same dataset, where one out of five centers is excluded from the CV and used as a test set, confirm these trends. Our uniquely designed WhARIO features are an efficient predictor of survival for lung cancer patients who received ICI treatment. We achieve similar performance to the current gold standard biomarker, without the need to access other imaging modalities, and show that both can be used together to reach even better results.

Antibiotic impregnated catheters and intrathecal antibiotics for CSF shunt infection prevention in children undergoing low-risk CSF shunt surgery

BackgroundCerebrospinal fluid (CSF) shunts allow children with hydrocephalus to survive and avoid brain injury (J Neurosurg 107:345-57, 2007; Childs Nerv Syst 12:192-9, 1996). The Hydrocephalus Clinical Research Network implemented non-randomized quality improvement protocols that were shown to decrease infection rates compared to pre-operative prophylactic intravenous antibiotics alone (standard care): initially with intrathecal (IT) antibiotics between 2007–2009 (J Neurosurg Pediatr 8:22-9, 2011), followed by antibiotic impregnated catheters (AIC) in 2012–2013 (J Neurosurg Pediatr 17:391-6, 2016). No large scale studies have compared infection prevention between the techniques in children. Our objectives were to compare the risk of infection following the use of IT antibiotics, AIC, and standard care during low-risk CSF shunt surgery (i.e., initial CSF shunt placement and revisions) in children.MethodsA retrospective observational cohort study at 6 tertiary care children’s hospitals was conducted using Pediatric Health Information System + (PHIS +) data augmented with manual chart review. The study population included children ≤ 18 years who underwent initial shunt placement between 01/2007 and 12/2012. Infection and subsequent CSF shunt surgery data were collected through 12/2015. Propensity score adjustment for regression analysis was developed based on site, procedure type, and year; surgeon was treated as a random effect.ResultsA total of 1723 children underwent initial shunt placement between 2007–2012, with 1371 subsequent shunt revisions and 138 shunt infections. Propensity adjusted regression demonstrated no statistically significant difference in odds of shunt infection between IT antibiotics (OR 1.22, 95% CI 0.82–1.81, p = 0.3) and AICs (OR 0.91, 95% CI 0.56–1.49, p = 0.7) compared to standard care.ConclusionIn a large, observational multicenter cohort, IT antibiotics and AICs do not confer a statistically significant risk reduction compared to standard care for pediatric patients undergoing low-risk (i.e., initial or revision) shunt surgeries.

Automatic classification and segmentation of blast cells using deep transfer learning and active contours.

Acute lymphoblastic leukemia (ALL) presents a formidable challenge in hematological malignancies, necessitating swift and precise diagnostic techniques for effective intervention. The conventional manual microscopy of blood smears, although widely practiced, suffers from significant limitations including labor-intensity and susceptibility to human error, particularly in distinguishing the subtle differences between normal and leukemic cells. To overcome these limitations, our research introduces the ALLDet classifier, an innovative tool employing deep transfer learning for the automated analysis and categorization of ALL from White Blood Cell (WBC) nuclei images. Our investigation encompassed the evaluation of nine state-of-the-art pre-trained convolutional neural network (CNN) models, namely VGG16, VGG19, ResNet50, ResNet101, DenseNet121, DenseNet201, Xception, MobileNet, and EfficientNetB3. We augmented this approach by incorporating a sophisticated contour-based segmentation technique, derived from the Chan-Vese model, aimed at the meticulous segmentation of blast cell nuclei in blood smear images, thereby enhancing the accuracy of our analysis. The empirical assessment of these methodologies underscored the superior performance of the EfficientNetB3 model, which demonstrated exceptional metrics: a recall specificity of 98.5%, precision of 95.86%, F1-score of 97.16%, and an overall accuracy rate of 97.13%. The Chan-Vese model's adaptability to the irregular shapes of blast cells and its noise-resistant segmentation capability were key to capturing the complex morphological changes essential for accurate segmentation. The combined application of the ALLDet classifier, powered by EfficientNetB3, with our advanced segmentation approach, emerges as a formidable advancement in the early detection and accurate diagnosis of ALL. This breakthrough not only signifies a pivotal leap in leukemia diagnostic methodologies but also holds the promise of significantly elevating the standards of patient care through the provision of timely and precise diagnoses. The implications of this study extend beyond immediate clinical utility, paving the way for future research to further refine and enhance the capabilities of artificial intelligence in medical diagnostics.

Routine Functional Testing or Standard Care in High-Risk Patients after Percutaneous Coronary Intervention.

This review aimed to collate the available evidence on outcomes following routine functional stress testing vs standard of care (i.e. symptom-guided stress testing) in high-risk patients following percutaneous coronary intervention (PCI). The most recent pragmatic POST-PCI trial provided randomized evidence showing that routine functional stress testing post-PCI did not lead to a reduction in 2-year ischemic cardiovascular events or all-cause mortality, as compared to a symptom-guided standard-of-care approach. This was also true for sub-analyses including multivessel or left main disease, diabetics, as well as following imaging or physiology guided PCI. In the absence of a change in their clinical or functional status suggestive of stent failure, post-PCI routine periodic stress testing in stable patients on guideline-directed medical therapy is currently not recommended by American clinical practice guidelines. While evidence on the cost-effectiveness of routine stress testing strategy is scarce, physician, payer, and policy-level interventions to reduce inappropriate use of routine functional testing need to be addressed.

Pre-operative Stereotactic Radiosurgery for Patients with One to Four Brain Metastases: A Single-Arm Phase 2 Trial Outcome Analysis (NCT03398694)

Abstract Background Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10-15% local failure. Targeting a resection cavity is imprecise, thus pre-operative radiosurgery where the target is well defined may be superior, however, the efficacy of pre-operative SRS has not yet been tested in a clinical trial. Methods We conducted a phase II, single-arm trial of pre-operative SRS followed by surgical resection in patients with 1-4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing gamma knife or linear accelerator as per RTOG-9005 dosing criteria24 based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, primary endpoint of 6-month LC was 100% (95% CI: 0.891-1.000; p=0.005). Secondary endpoints, presented as medians, were overall-survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions Our data confirms superior local control in patients who received pre-operative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of pre-operative SRS.

Effects of a combined exercise and dietary intervention on body composition, physical functioning and fatigue in patients with ovarian cancer: results of the PADOVA trial.

Guidelines recommend to include exercise and dietary advice in standard care for patients with cancer, based on evidence primarily derived from patients with breast cancer. Its applicability to patients with ovarian cancer is uncertain due to differences in patient characteristics and treatments. The PADOVA trial examined the effectiveness of a combined exercise and dietary intervention on fat-free mass (FFM), physical functioning, and fatigue. In total, 81 patients with ovarian cancer were randomised to the exercise and dietary intervention (n = 40) or control (n = 41) group. Measurements were performed before chemotherapy, after chemotherapy, and 12 weeks later. FFM was assessed by bioelectrical impedance analysis, and physical functioning and fatigue were assessed using questionnaires. Intervention effects were assessed on an intention-to-treat basis using linear mixed models. FFM and physical functioning increased, and fatigue decreased significantly over time in both groups. No significant difference between the groups were found for FFM (β = -0.5 kg; 95% CI = -3.2; 2.1), physical functioning (β = 1.4; 95% CI = -5.4; 8.3) and fatigue (β = 0.7; 95% CI = -1.5; 2.8). During treatment, both groups improved in FFM, physical functioning, and fatigue. The intervention group, however, did not demonstrate additional benefits compared to the control group. This highlights the need for caution when extrapolating findings from different cancer populations to patients with ovarian cancer.

Respiratory Syncytial Virus Infection in Older Adults: An Update.

Respiratory syncytial virus (RSV) infection represents one of the most common infections during childhood, with significant morbidity and mortality in newborns and in the early years of life. RSV is a common infection throughout all age groups, largely undetected and underestimated in adults, with a disproportionately high impact in older individuals. RSV infection has a wide range of clinical presentations, from asymptomatic conditions to acute pneumonia and severe life-threatening respiratory distress, including exacerbations of underlying chronic conditions. Overall, the incidence of RSV infections requiring medical attention increases with age, and it is highest among persons ≥70years of age. As a consequence of a combination of an aging population, immunosenescence, and the related increased burden of comorbidities, high-income countries are at risk of developing RSV epidemics. The standard of care for RSV-infected patients remains supportive, including fluids, antipyretics, and oxygen support when needed. There is an urgent need for antivirals and preventive strategies in this population, particularly in individuals at higher risk of severe outcomes following RSV infection. In this review, we describe prevention and treatment strategies for RSV illnesses, with a deep focus on the novel data on vaccination that has become available (Arexvy, GSK, and Abrysvo, Pfizer) for older adults.

Tenecteplase Versus Alteplase in Acute Ischemic Stroke in Chinese Patients: Protocol for the ORIGINAL Study

BACKGROUND Tenecteplase, a bioengineered variant of alteplase, is a new alternative thrombolytic agent. The ORIGINAL study aims to evaluate the efficacy and safety of tenecteplase versus standard care in Chinese patients with acute ischemic stroke within 4.5 hours of symptom onset. METHODS This is a multicenter phase III study that employs a randomized (1:1), active‐controlled, parallel‐group, prospective, open‐label, blinded–end point design. Adult participants (aged ≥18 years) with acute ischemic stroke who are eligible for intravenous thrombolysis within 4.5 hours of symptom onset according to current guideline recommendations are recruited from ≈55 neurology clinics/stroke centers throughout China. RESULTS The primary objective of the ORIGINAL study is to demonstrate the noninferiority of tenecteplase (0.25 mg/kg) to alteplase (0.9 mg/kg) on the basis of the proportion of patients who achieve a modified Rankin Scale score of 0 or 1 on day 90, that is, a favorable functional outcome. The prespecified noninferiority risk ratio margin is 0.937. Secondary end points include other functional outcomes and the following safety end points: adjudicated symptomatic intracerebral hemorrhage (up to 36 hours after the end of study drug administration) based on the European Cooperative Acute Stroke Study III definition; all‐cause death within 90 days; and the proportion of patients with a modified Rankin Scale score of 5 or 6 on day 90. CONCLUSIONS It is anticipated that the results of this study will contribute to the growing body of evidence for the noninferiority of tenecteplase to alteplase given within 4.5 hours of acute ischemic stroke symptom onset and support a new indication for tenecteplase in China. Clinical Trial Registration Information NCT04915729 ( https://clinicaltrials.gov/study/NCT04915729 )

HOSPITAL MANAGEMENT SYSTEM BASED ON WEB

Hospital Management Systems (HMS) represent a key advancement in healthcare technology designed to revolutionize operational efficiency, raise standards of patient care and ensure compliance with regulatory protocols. This paper explores the multifaceted functions of HMS, highlighting its role in automating administrative tasks, supporting real-time access to patient data, and facilitating seamless communication between healthcare professionals. Drawing on current research and practical implementations, we delve into the transformative potential of HMS, particularly in the context of recent innovations in telemedicine, data analytics, and remote monitoring systems. In our research, we present SIMRS, a robust hospital management information system developed using the waterfall method, strategically focused on the systematic improvement of hospital operations. By automating key processes such as patient registration, appointment scheduling, payment and inventory management, SIMRS optimizes hospital workflows and ultimately improves patient care delivery. In addition, we examine the empirical evidence that shows the significant impact of management systems and leadership traits on the quality of care in hospital settings, and highlight the indispensable role of effective leadership and management frameworks. Next, we discuss the technical foundations of HMS and highlight the integration of various programming languages and database management systems such as HTML, CSS, JavaScript, PHP, MySQL, and MongoDB. This cross-disciplinary approach underscores the synergy between technological innovation and healthcare management, paving the way for a more efficient patient- centered healthcare ecosystem. In summary, this research illuminates the transformative potential of HMS to revolutionize healthcare operations, improve patient outcomes and optimize resource allocation, advocating for its widespread adoption to shape the future of healthcare delivery. Key Words: JavaScript, MySql, HMS, Electronic Health Records, Telehealth

Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. Mirum Pharmaceuticals.