Long-term cognitive and affective consequences of mild traumatic brain injury: comparison with older adults.

OBJECTIVE: Memory and affective processing were compared in young adults with a remote mild traumatic brain injury (mTBI), to healthy younger and older adults. We evaluated memory performance when encoding was done under multi-tasking (divided attention) conditions, likely to exacerbate cognitive and psychological symptoms in mTBI. METHODS: Participants studied pairs of unrelated words under either full or divided attention conditions. Memory for single words (item memory) and for pairs of words (associative memory) was then assessed in sequential independent recognition tests, under full attention. RESULTS: Associative memory was poorer than item memory, and worse when encoding was done under divided than full attention. The decline in recognition accuracy from full to divided attention conditions on the associative memory test was significantly greater in mTBI compared to young adults and was similar in magnitude to that observed in older adults under full attention. Self-reported mental and total fatigue increased significantly as performance on the memory tests, following the divided attention condition, decreased, but only in the mTBI group. CONCLUSIONS: Results show lingering memory deficits, and suggest that cognitive tasks may be experienced as psychologically more demanding in those with a mTBI, even months or years after injury.

Medical student interactions with children in their daily lives.

Learning to communicate effectively with children in clinical interactions can be challenging. This study aimed to determine the extent to which medical students are exposed to children in their daily lives, in order to understand the experience students bring when entering paediatric rotations. METHODS: A cross-sectional survey of medical students entering paediatric rotations from two medical schools was conducted. Students were asked to rate the frequency of their interactions with infants, preschool-aged and school-aged children and their confidence in doing so. RESULTS: 339 out of 476 students participated in this study. Interactions with infants and preschool-aged children were rare, with most students reporting interactions once or two times per year or less (83% and 67%, respectively). Students interacted with school-aged children more frequently (43% most weeks or days). Students who interacted more frequently with children were more confident when entering their paediatric placements. CONCLUSIONS: Medical students have limited exposure to infants and preschool-aged children in their daily lives and this affects their confidence. Supervisors should incorporate activities aimed at building confidence interacting with young children early in clinical attachments.

Longitudinal study of health, disease and access to care in rural Victoria: the Crossroads-II study: methods.

BACKGROUND: High quality, contemporary data regarding patterns of chronic disease is essential for planning by health services, policy makers and local governments, but surprisingly scarce, including in rural Australia. This dearth of data occurs despite the recognition that rural Australians live with high rates of ill health, poor health behaviours and restricted access to health services. Crossroads-II is set in the Goulburn Valley, a rural region of Victoria, Australia 100-300 km north of metropolitan Melbourne. It is primarily an irrigated agricultural area. The aim of the study is to identify changes in the prevalence of key chronic health conditions including the extent of undiagnosed and undermanaged disease, and association with access to care, over a 15 year period. METHODS/DESIGN: This study is a 15 year follow up from the 2000-2003 Crossroads-I study (2376 households participated). Crossroads-II includes a similar face to face household survey of 3600 randomly selected households across four towns of sizes 6300 to 49,800 (50% sampled in the larger town with the remainder sampled equally from the three smaller towns). Self-reported health, health behaviour and health service usage information is verified and supplemented in a nested sub-study of 900 randomly selected adult participants in 'clinics' involving a range of additional questionnaires and biophysical measurements. The study is expected to run from October 2016 to December 2018. DISCUSSION: Besides providing epidemiological and health service utilisation information relating to different diseases and their risk factors in towns of different sizes, the results will be used to develop a composite measure of health service access. The importance of access to health services will be investigated by assessing the correlation of this measure with rates of undiagnosed and undermanaged disease at the mesh block level. Results will be shared with partner organisations to inform service planning and interventions to improve health outcomes for local people.

Large-bore Aspiration Thrombectomy with the FlowTriever System for the Treatment of Pulmonary Embolism: A Large Single-Center Retrospective Analysis.

PURPOSE: Evaluate the outcomes of patients undergoing large-bore aspiration thrombectomy for the treatment of pulmonary embolism at a large university medical center. MATERIALS AND METHODS: All patients treated for pulmonary embolism with the FlowTriever System (Inari Medical, Irvine, CA) between September 2019 and January 2023 were retrospectively analyzed. The primary safety and effectiveness outcomes included 7- and 30-day all-cause mortality, major bleeding, procedure-associated clinical decompensation, pulmonary vascular or cardiac injury, and pulmonary artery pressure reduction. Additional outcomes included technical success (completing thrombectomy with the device as intended), changes in hemodynamics and supplemental oxygen requirements, and postprocedural intensive care unit stay. RESULTS: A total of 286 patients were identified. The mean age was 60.5 years, and 90.9% of patients presented with intermediate-risk pulmonary embolism. Technical success was achieved in 96.9% (n = 277) of cases. The average reduction in mean pulmonary arterial pressure was 6.8 mmHg, from 28.7 ± 9.0 to 21.9 ± 8.0 mmHg (p < 0.0001). Two major bleeds (0.7%), 2 pulmonary vascular injuries (0.7%), and 4 (1.4%) procedure-associated decompensations were reported, but no device-related deaths occurred. The mean post-procedure intensive care unit stay was 2.0 ± 4.1 days, and 49.3% of patients had no postprocedural intensive care unit admittance. The overall 7-day and 30-day all-cause mortality rates were 2.4% and 6.7%, respectively, with a 30-day pulmonary embolism-related mortality rate of 3.5%. CONCLUSION: This non-industry-sponsored single-center analysis of large-bore aspiration thrombectomy in a large population corroborates the findings of other studies and confirms that this approach is safe and effective for the treatment high- and intermediate-risk pulmonary embolism. LEVEL OF EVIDENCE IV: Retrospective observational study.

Nonparallelism in MHCIIß diversity accompanies nonparallelism in pathogen infection of lake whitefish (Coregonus clupeaformis) species pairs as revealed by next-generation sequencing.

Major histocompatibility (MHC) immune system genes may evolve in response to pathogens in the environment. Because they also may affect mate choice, they are candidates for having great importance in ecological speciation. Here, we use next-generation sequencing to test the general hypothesis of parallelism in patterns of MHCIIß diversity and bacterial infections among five dwarf and normal whitefish sympatric pairs. A second objective was to assess the functional relationships between specific MHCIIß alleles and pathogens in natural conditions. Each individual had between one and four alleles, indicating two paralogous loci. In Cliff Lake, the dwarf ecotype was monomorphic for the most common allele. In Webster Lake, the skew in the allelic distribution was towards the same allele but in the normal ecotype, underscoring the nonparallel divergence among lakes. Our signal of balancing selection matched putative peptide binding region residues in some cases, but not in others, supporting other recent findings of substantial functional differences in fish MHCIIß compared with mammals. Individuals with fewer alleles were less likely to be infected; thus, we found no evidence for the heterozygote advantage hypothesis. MHCIIß alleles and pathogenic bacteria formed distinct clusters in multivariate analyses, and clusters of certain alleles were associated with clusters of pathogens, or sometimes the absence of pathogens, indicating functional relationships at the individual level. Given that patterns of MHCIIß and bacteria were nonparallel among dwarf and normal whitefish pairs, we conclude that pathogens driving MHCIIß evolution did not play a direct role in their parallel phenotypic evolution.

Safety and efficacy of vemurafenib in end stage renal failure.

BACKGROUND: Serine-threonine inhibitors, such as vemurafenib, are being used increasingly in cancer treatment, and the toxicity and therapeutic benefit need to be balanced carefully both before and during treatment. CASE PRESENTATION: A patient with metastatic melanoma and end stage renal failure who was on peritoneal dialysis was treated with the serine-threonine kinase inhibitor, vemurafenib. After 5 months of treatment, a substantial response to vemurafenib was observed using imaging, but when he developed a prolonged QTc interval (common toxicity criteria (CTC) grade 3), treatment was interrupted. Vemurafenib was restarted at a reduced dose when the QTc interval returned to normal. The patient has had a significant response to vemurafenib and continued on treatment for 12 months after beginning the therapy. CONCLUSION: This is the first reported case of end stage renal failure in a patient who is taking vemurafenib. Although the patient developed QTc prolongation, it appears to be asymptomatic, and was managed with dose reduction. This case highlights the need for closer QTc monitoring at the start and during treatment.

Digitally Based Blood Pressure Self-Monitoring Program That Promotes Hypertension Self-Management and Health Education Among Patients With Low-Income: Usability Study.

BACKGROUND: According to evidence-based clinical guidelines, adults with hypertension are advised to self-monitor their blood pressure (BP) twice daily. Self-measured BP monitoring is a recommended strategy for improving hypertension management. OBJECTIVE: We aimed to determine the feasibility and acceptability of a digitally based BP self-monitoring program that promotes hypertension self-management and health education among low-income patients. We hypothesized that the program would be highly feasible and acceptable and that at least 50% of the patients would use the monitor at the rate required for the reimbursement of the device's cost (16 days of measurements in any 30-day period). METHODS: Withings BPM Connect was deployed to patients at Family Health Centers of San Diego. Program elements included training, SMS text message reminders, and physician communication. Compliance, use, mean BP, and BP control status were calculated. A Kaplan-Meier time-to-event analysis was conducted to compare time to compliance between a strict definition (≥16 days in any rolling 30-day window) and a lenient definition (≥1 day per week for 4 consecutive weeks). A log-rank test was performed to determine whether the difference in time to compliance between the definitions was statistically significant. Mean systolic BP (SBP) and diastolic BP (DBP) before the intervention and after the intervention and mean change in SBP and DBP across patients were calculated. Paired sample t tests (2-tailed) were performed to assess the changes in SBP and DBP from before to after the intervention. RESULTS: A total of 179 patients received the monitors. The mean changes in SBP and DBP from before to after the intervention were +2.62 (SE 1.26) mm Hg and +3.31 (SE 0.71) mm Hg, respectively. There was a statistically significant increase in both SBP and DBP after the intervention compared with before the intervention (P=.04 and P<.001). At the first and last measurements, 37.5% (63/168) and 48.8% (82/168) of the patients had controlled BP, respectively. During the observation period, 83.3% (140/168) of the patients had at least 1 controlled BP measurement. Use decreased over time, with 53.6% (90/168) of the patients using their monitor at week 2 and only 25% (42/168) at week 11. Although only 25.6% (43/168) achieved the strict definition of compliance, 42.3% (71/168) achieved the lenient definition of compliance. The median time to compliance was 130 days for the strict definition and 95 days for the lenient definition. The log-rank test showed a statistically significant difference in time to compliance between the compliance definitions (P<.001). Only 26.8% (45/168) complied with the measurement rate that would result in device cost reimbursement. CONCLUSIONS: Few patients used the monitors at a rate that would result in reimbursement, raising financial feasibility concerns. Plans for sustaining costs among low-income patients need to be further evaluated.

Cloning of the broadly effective wheat leaf rust resistance gene Lr42 transferred from Aegilops tauschii.

The wheat wild relative Aegilops tauschii was previously used to transfer the Lr42 leaf rust resistance gene into bread wheat. Lr42 confers resistance at both seedling and adult stages, and it is broadly effective against all leaf rust races tested to date. Lr42 has been used extensively in the CIMMYT international wheat breeding program with resulting cultivars deployed in several countries. Here, using a bulked segregant RNA-Seq (BSR-Seq) mapping strategy, we identify three candidate genes for Lr42. Overexpression of a nucleotide-binding site leucine-rich repeat (NLR) gene AET1Gv20040300 induces strong resistance to leaf rust in wheat and a mutation of the gene disrupted the resistance. The Lr42 resistance allele is rare in Ae. tauschii and likely arose from ectopic recombination. Cloning of Lr42 provides diagnostic markers and over 1000 CIMMYT wheat lines carrying Lr42 have been developed documenting its widespread use and impact in crop improvement.

Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment.

BACKGROUND: The temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth. METHODS: C57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays. RESULTS: The distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth. CONCLUSIONS: Despite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

Renewed: Protocol for a randomised controlled trial of a digital intervention to support quality of life in cancer survivors.

INTRODUCTION: Low quality of life is common in cancer survivors. Increasing physical activity, improving diet, supporting psychological well-being and weight loss can improve quality of life in several cancers and may limit relapse. The aim of the randomised controlled trial outlined in this protocol is to examine whether a digital intervention (Renewed), with or without human support, can improve quality of life in cancer survivors. Renewed provides support for increasing physical activity, managing difficult emotions, eating a healthier diet and weight management. METHODS AND ANALYSIS: A randomised controlled trial is being conducted comparing usual care, access to Renewed or access to Renewed with brief human support. Cancer survivors who have had colorectal, breast or prostate cancer will be identified and invited through general practice searches and mail-outs. Participants are asked to complete baseline measures immediately after screening and will then be randomised to a study group; this is all completed on the Renewed website. The primary outcome is quality of life measured by the European Organization for Research and Treatment of Cancer QLQ-c30. Secondary outcomes include anxiety and depression, fear of cancer recurrence, general well-being, enablement and items relating to costs for a health economics analysis. Process measures include perceptions of human support, intervention usage and satisfaction, and adherence to behavioural changes. Qualitative process evaluations will be conducted with patients and healthcare staff providing support. ETHICS AND DISSEMINATION: The trial has been approved by the NHS Research Ethics Committee (Reference 18/NW/0013). The results of this trial will be published in peer-reviewed journals and through conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN96374224; Pre-results.

Hypothesis: a simple algorithm to distinguish between hypoaldosteronism and renal aldosterone resistance in patients with persistent hyperkalemia.

AIM: Many patients with hyperkalemia have a readily identifiable cause, which leads to appropriate management. In others, particularly those with a reduced glomerular filtration rate, differentiating between (relative) hypoaldosteronism (HA) and renal aldosterone resistance (RAR) can be problematic. The aim of this study was to see if a plasma aldosterone to potassium algorithm could be defined which would help identify patients with hyperkalemia owing to suboptimal levels of aldosterone, thereby validating treatment with 9-alpha-fluhydrocortisone, instead of cation exchange resins, if more conservative treatment fails. METHODS: A literature search for, and analysis of, studies providing details of plasma aldosterone and plasma potassium in normals (made hyperkalemic)and patients with a plasma potassium >5.3 mmol/L, and a contemporaneous plasma aldosterone. RESULTS: One study was found in which normals were made significantly hyperkalemic (to 6.3 mmol/L). These subjects, while on a high sodium, low potassium (western) diet (n = 5), provided an arbitrary definition of a simple aldosterone to potassium algorithm for diagnosis (factored aldosterone (FAldo) = plasma aldosterone/(plasma K - 4.2)). The limit for FAldo is set at 280(pmol/L) or 10(ng/dL): results below the limit suggest HA; above the limit, RAR. This algorithm was then tested against, and, when plasma potassium was greater than 5.3, found to be consistent with, reported patients with confirmed HA (n = 33) and pseudohypoaldosteronism (n = 23). The ratios in reported patients with renal failure (n = 43) were consistent with either HA (n = 30) or RAR(n = 13). HYPOTHESIS: In hyperkalemic patients a plasma aldosterone to potassium algorithm may help distinguish HA from RAR, thereby guiding therapy.