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Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0–3 at 365 days (adjusted risk difference 4% [95% CI −4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. National Institute of Neurological Disorders and Stroke and Genentech.

Abstract BACKGROUND Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

Survivors of subarachnoid hemorrhage (SAH) often have learning and memory deficits. This study tested the hypothesis that SAH in rats is associated with similar deficits and that they are due to neuronal injury in the hippocampus. SAH was induced in rats. Behaviour was investigated in the Morris water maze and brain injury by microscopy. Rats with SAH had deficits in spatial learning and working memory and had significantly more fluoro-Jade- and TUNEL-positive neurons in the hippocampus, cerebral cortex and cerebellum. Microthromboemboli in microvessels were more frequent in brains of rats with SAH and deficits there was vasospasm of the anterior and middle cerebral arteries. The amount of cell death in the hippocampus did not appear to be sufficient to cause the observed in the Morris water maze. This suggests that other factors such as dysfunction of neurotransmission or other pathology in hippocampal pathways might contribute to the impairment.

The impact of multiple substance use on the risk of pancreatitis remains underexplored. To systematically review peer-reviewed observational studies assessing the association of multiple substance use with the risk of acute pancreatitis (AP) or chronic pancreatitis (CP) in adults. We conducted a systematic review informed by the Preferred Reporting Items for Systematic Review and Meta-Analyses guideline. EMBASE, MEDLINE, and PsycINFO were searched up to March 2024. Reference lists of included studies were reviewed. From 5205 records identified, 181 relevant records were evaluated in full text. Studies evaluating the association of ⩾2 substances, including tobacco, alcohol, cannabis, and illicit substances, with AP or CP were included. Data were extracted by one reviewer, with quality control by a second reviewer. Quality assessments were independently conducted by two reviewers, with differences resolved by a third. Of 11 included studies, 6 investigated AP as the outcome and 5 examined CP. Among AP studies, 5 comparing smoking and alcohol to alcohol-only use showed high heterogeneity (  = 90.9%), with relative risks (RRs) from 1.40 to 11.40. One study examining cannabis and alcohol versus alcohol found a lower risk of AP in cannabis users. Among CP studies, four comparing smoking and alcohol to alcohol-only use were heterogeneous (  = 81%) with odds ratios 1.21-31.50. Where examined, smoking increases the risk of AP and CP in a dose-dependent fashion. Heavy alcohol users demonstrated a significant increase in CP risk across all smoking categories in one study. Combined alcohol and tobacco use increases pancreatitis risk compared to single substance use, despite heterogeneity in RRs and exposure definitions. Evidence suggests a dose-dependent impact of smoking on pancreatitis risk when added to alcohol. Studies on the impact of a combination of other substance use on pancreatitis risk are needed. CRD42024503677.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.

BackgroundDespite the high workload of mechanical ventilation, there has been a lack of studies on the association between nurse workforce and mortality in mechanically ventilated patients. We evaluated the association of the bed-to-nurse ratio with mortality in ventilated pediatric patients admitted to an intensive care unit (ICU).MethodsWe conducted a nationwide retrospective analysis by using the Korean National Health Insurance database, which categorizes the bed-to-nurse ratio into 9 grades according to the number of beds divided by the number of full-time equivalent registered nurses in a unit. Patients of ages between 28 days and 18 years were enrolled. Multiple admissions and transfers from other hospitals were excluded. We evaluated the odds ratios (ORs) of in-hospital mortality using 4 groups (Grade 1: bed-to-nurse < 0.50, Grade 2: < 0.63, Grade 3: < 0.77, Grade 4 or above > 0.77) with adjustment of patient factors, hospital factors, and treatment requirements.ResultsOf the 27,849 patients admitted to ICU, 11,628 (41.8%) were on mechanical ventilation. The overall in-hospital mortality rates in Grade 1, Grade 2, Grade 3, and Grade 4 or above group were 4.5%, 6.8%, 6.9%, and 4.7%, respectively. The adjusted ORs (95% CI) for in-hospital mortality of mechanically ventilated patients in the Grade 2, Grade 3, and Grade 4 or above compared to those in Grade 1 were 2.73 (95% CI 1.51–4.95), 4.02 (95% CI 2.23–7.26), and 7.83 (4.07–15.07), respectively. However, for patients without mechanical ventilation, the adjusted ORs of in-hospital mortality were not statistically significant.ConclusionIn mechanically ventilated patients, the adjusted mortality rate increased significantly, as the bed-to-nurse ratio of the ICU increased. Policies that limit the number of ventilated patients per nurse should be considered.Trial registration retrospectively registered

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Background There is a lack of nationwide studies on critically ill patients’ health disparity under the National Health Insurance (NHI) system. We evaluated health disparities in intensive care unit (ICU) admission, outcomes, and readmission in impoverished children. Methods We conducted a retrospective cohort study using a national database from the Korean NHI and Medical Aid Program (MAP). MAP supports the population whose household income is lower than 40% of the median Korean household income. We defined poverty as being a MAP beneficiary and compared the poverty and non-poverty groups. Patients between 28 days and 18 years old who were admitted to the ICU were included. Hospital mortality and readmission were analyzed with adjustment for patient characteristics, hospital type, and management procedures. Results Out of 17,893 patients, 1153 (6.4%) patients were in poverty. The age-standardized ICU admission rate was higher in the poverty group (126.9 vs. 80.2 per 100,000 person-years). There was more age-standardized mortality in the poverty group (11.8 vs. 4.3 per 100,000 person-years). Patients in the poverty group did not have a statistically different risk of adjusted in-hospital mortality to those in the non-poverty group (odds ratio: 1.15, confidence interval [CI]: 0.84–1.55) but had a higher readmission rate (hazard ratio 1.25, CI 1.09–1.42). Conclusion Under the NHI system, the disparity in pediatric critical care outcomes according to poverty is not definite, but the healthcare disparity in pre- and post-hospital care is a concern. Further studies are required to improve pre- and post-hospital healthcare quality of impoverished children.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) characterized by a hallmark translocation of t (11; 14). CD10 negativity has been used to differentiate MCL from other NHL types; however, recently, there has been an increase in the number of reported cases of CD10-positive MCL. This warrants further investigation into this rarer immunophenotype and its clinical significance. BCL6, which is a master transcription factor for the regulation of cell proliferation and key oncogene in B cell lymphomagenesis, has been reported to have co-expression with CD10 in MCL. The clinical significance of this aberrant antigen expression remains unknown. We conducted a systematic review by searching four databases and selected five retrospective analyses and five case series. Two survival analyses were conducted to determine if BCL6 positivity conferred a survival difference: 1. BCL6+ vs. BCL6− MCL. 2. BCL6+/CD10+ vs. BCL6−/CD10+ MCL. Correlation analysis was conducted to determine if BCL6 positivity correlated with the Ki67 proliferation index (PI). Overall survival (OS) rates were performed by the Kaplan–Meier method and log-rank test. Our analyses revealed that BCL6+ MCL had significantly shorter overall survival (median OS: 14 months vs. 43 months; p = 0.01), BCL6+/CD10+ MCL had an inferior outcome vs. BCL6+/CD10− MCL (median OS: 20 months vs. 55 months p = 0.1828), BCL6+ MCL had significantly higher percentages of Ki67% (Ki67% difference: 24.29; p = 0.0094), and BCL6 positivity had a positive correlation with CD10+ status with an odds ratio 5.11 (2.49, 10.46; p = 0.0000286). Our analysis showed that BCL6 expression is correlated with CD10 positivity in MCL, and BCL6 expression demonstrated an inferior overall survival. The higher Ki67 PI in BCL6+ MCL compared to BCL6− MCL further supports the idea that the BCL6+ immunophenotype may have prognostic value in MCL. MCL management should consider incorporating prognostic scoring systems adjusted for BCL6 expression. Targeted therapies against BCL6 may offer potential therapeutic options for managing MCL with aberrant immunophenotypes.

Diabetes mellitus requires continuous self-management to prevent complications. Patients frequently rely on online resources and mobile apps for diabetes-related information; however, these often lead to information overload, limited personalization, and difficulty in navigation. Generative artificial intelligence (AI) chatbots may address these challenges by providing accessible, personalized, and responsive guidance. This study aimed to explore the potential role of generative AI chatbots in diabetes management through a 2-part qualitative evaluation. Part 1 examined patients' information needs, user experiences, and expectations. Part 2 investigated specialists' perspectives on the practical utility of generative AI chatbots in supporting diabetes self-management. By incorporating perspectives from both patients and specialists, the study aimed to identify appropriate boundaries for the involvement of generative AI chatbots, reflecting the needs and expectations of both stakeholder groups. This study was conducted using DTalksBot, a generative AI chatbot powered by GPT-4 (OpenAI) and enhanced with retrieval-augmented generation. In Part 1, we aimed to understand the experiences, needs, and expectations of patients with diabetes. To achieve this, 24 participants engaged in structured chatbot sessions, completed postinteraction surveys, and participated in in-depth interviews. Data were analyzed using thematic and content analysis to identify patterns in user queries and experiences. In part 2, we invited 4 family medicine specialists to assess the accuracy of DTalksBot's responses by reviewing conversation logs and to share expert insights on the future role of generative AI chatbots in diabetes management. In part 1, a total of 24 patients submitted a total of 643 questions, which were categorized into 4 primary themes: personalized health advice and guidance (n=281, 44.6%), complications and comorbidities (n=174, 27.1%), medication and treatment exploration (n=111, 17.3%), and mental health management and support (n=30, 4.7%). Patients emphasized the advantages of generative AI chatbots over traditional information sources, including faster access to reliable content, reduced cognitive burden, and the ability to comfortably discuss sensitive topics. In part 2, specialists recognized the generative AI chatbots' value in answering routine inquiries, but noted limitations in contextual accuracy, real-time data integration, and response personalization. Generative AI chatbots showed promise as complementary tools for diabetes self-management by offering accessible, reliable, and tailored support. This formative evaluation provides empirical evidence on how generative AI chatbots can address patient information needs and complement existing health care resources. To maximize utility, future generative AI chatbots need to integrate real-time health data, enhance contextual relevance, and align with clinical workflows to ensure safety, trust, and broader applicability.