Oxidative stress and vascular dysfunction: Potential therapeutic targets and therapies in peripheral artery disease.

Peripheral artery disease (PAD) is the manifestation of atherosclerosis characterized by the accumulation of plaques in the arteries of the lower limbs. Interestingly, growing evidence suggests that the pathology of PAD is multifaceted and encompasses both vascular and skeletal muscle dysfunctions, which contributes to blunted physical capabilities and diminished quality of life. Importantly, it has been suggested that many of these pathological impairments may stem from blunted reduction-oxidation (redox) handling. Of note, in those with PAD, excessive production of reactive oxygen species (ROS) outweighs antioxidant capabilities resulting in oxidative damage, which may have systemic consequences. It has been suggested that antioxidant supplementation may be able to assist in handling ROS. However, the activation of various ROS production sites makes it difficult to determine the efficacy of these antioxidant supplements. Therefore, this review focuses on the common cellular mechanisms that facilitate ROS production and discusses how excessive ROS may impair vascular and skeletal muscle function in PAD. Furthermore, we provide insight for current and potential antioxidant therapies, specifically highlighting activation of the Kelch-like ECH-associated protein 1 (Keap1) - Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway as a potential pharmacological therapy to combat ROS accumulation and aid in vascular function, and physical performance in patients with PAD. Altogether, this review provides a better understanding of excessive ROS in the pathophysiology of PAD and enhances our perception of potential therapeutic targets that may improve vascular function, skeletal muscle function, walking capacity, and quality of life in patients with PAD.

Intake of Sugar and Food Sources of Sugar and Colorectal Cancer Risk in the Multiethnic Cohort Study.

BACKGROUND: The influence of sugar intake on the risk of colorectal cancer (CRC) remains controversial, and there is a need to investigate the heterogeneity of effects among racial and ethnic groups. OBJECTIVES: To examine the association of intake of simple sugars and their food sources with CRC risk according to race/ethnicity in a multiethnic cohort study. METHODS: We analyzed data from 192,651 participants who participated in the Multiethnic Cohort Study comprising African American, Japanese American, Latino, Native Hawaiian, and White older adults living in Hawaii and California with an average follow-up of 19 y. Intakes of total and specific types of sugars and sugary foods were estimated from a quantitative food frequency questionnaire completed by the participants in 1993-1996. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC risk according to quintiles (Q) of sugar and food intakes using Cox models adjusted for potential confounders. RESULTS: As of December 2017, 4403 incident CRC cases were identified. Among all participants, multivariable-adjusted CRC HRs for Q2, Q3, Q4, and Q5 compared with Q1 for total sugars were 1.03 (95% CI: 0.94, 1.13), 1.05 (95% CI: 0.96, 1.16), 1.12 (95% CI: 1.01, 1.24), and 1.13 (95% CI: 1.01, 1.27), respectively. A similar positive association was observed for total fructose, glucose, fructose, and maltose but not for added sugars and sugary foods. The increased risk appeared to be limited to colon cancer and to be strongest among younger participants (i.e., 45-54 y at baseline); an association with CRC was observed for sugar-sweetened beverages in the latter group. Among racial and ethnic groups, increased risk of CRC was most apparent in Latinos. CONCLUSIONS: In this diverse cohort, intakes of total sugar, total fructose, glucose, fructose, and maltose were associated with an increased risk of CRC, and the association was strongest for colon cancer, younger participants, and Latinos.

The EAT-Lancet Diet Index Is Associated with Lower Obesity and Incidence of Type 2 Diabetes in the Multiethnic Cohort.

BACKGROUND: The EAT-Lancet Commission has developed dietary recommendations, named the EAT-Lancet diet, to promote healthy nutrition and sustainable food production worldwide. OBJECTIVES: We developed an adapted score for the EAT-Lancet diet for participants of the Multiethnic Cohort (MEC) Study and its relation with incidence of obesity and type 2 diabetes (T2D). METHODS: The MEC includes 5 ethnic groups followed since 1993-1996. Anthropometric characteristics and dietary intake were assessed by questionnaire at cohort entry (Qx1) and 10 y later (Qx3). To create the EAT-Lancet index (range: 0-48 points), a 3-point scoring system for 16 food groups standardized to 2500 kcal/d was applied. T2D cases were identified through repeated self-reports and administrative data. In a prospective design, obesity at Qx3 and T2D incidence were evaluated using Cox regression to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) while adjusting for relevant covariates. RESULTS: Among 193,379 MEC participants, the overall mean of the EAT-Lancet index score was 25 ± 4 points and 46,140 new T2D cases were identified. Higher adjusted means were observed in females than males, in participants of Japanese American and Native Hawaiian ancestry, and in those with healthy weight than overweight or obese. Obesity was lower in cohort members with higher EAT-Lancet scores (HR: 0.76; 95% CI: 0.73, 0.79 for tertile 3 compared with 1). Although T2D incidence was 10% lower among participants in the highest (27-42 points) compared with the lowest (9-23 points) EAT-Lancet index tertile (HR: 0.90; 95% CI: 0.88, 0.92), the association was attenuated after BMI adjustment (HR: 0.97; 95% CI: 0.94, 0.99). This inverse association with T2D was restricted to African American and European American participants. CONCLUSIONS: These findings support the hypothesis that adherence to the EAT-Lancet diet is related to a lower risk of obesity, which may be partially responsible for the small reduction in T2D incidence.

Avocado and Guacamole Consumption and Colorectal Cancer Risk: The Multiethnic Cohort Study.

Dietary fiber and phytonutrients can protect against colorectal cancer, yet their consumption is low in the US. Avocados are a potential source of these beneficial nutrients. Therefore, this study aimed to examine the relationship between avocados/guacamole consumption and colorectal cancer risk in the Multiethnic Cohort Study. We assessed avocados/guacamole consumption by using a food frequency questionnaire. We classified participants into three consumer groups: <1 serving/month, 1-3 servings/month, and ≥1 serving/week with one serving defined as ½ avocado or ½ cup. Colorectal cancer cases were ascertained through the Surveillance, Epidemiology and End Results Program cancer registries. Cox proportional hazards models of colorectal cancer were used to calculate hazard ratios and 95% confidence intervals across avocados/guacamole intake groups in each sex overall and by anatomic subsite (i.e., right colon, left colon, and rectum) and race and ethnicity. Of 192,651 eligible participants, 62.8% reported consuming <1 serving/month avocados/guacamole, 26.7% reported 1-3 servings/month, and 10.5% reported ≥1 serving/week. When adjusted for relevant covariates, there was no significant association with incident colorectal cancer overall, for subsites, or within racial and ethnic subgroups (all p for trend ≥ 0.06). In this large prospective cohort study, we did not find that consumption of avocados/guacamole was associated with colorectal cancer risk.

Merkel cell carcinoma recurrence risk estimation is improved by integrating factors beyond cancer stage: A multivariable model and web-based calculator.

BACKGROUND: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis. PURPOSE: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone. METHODS: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors. RESULTS: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years). LIMITATIONS: Lack of an external data set for model validation. CONCLUSION/RELEVANCE: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients.

Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown. PURPOSE: We assessed if delays in ttPORT were associated with inferior outcomes. METHODS: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks. RESULTS: The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs ≤ 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016). LIMITATIONS: The relatively low number of LRRs limited the extent of our multivariable analyses. CONCLUSIONS: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.

Safety and Efficacy of Minoxidil Treatment in Scarring Alopecia: A Scoping Review.

BACKGROUND: Topical minoxidil (TM) has been a cornerstone in treating various hair loss disorders, while low-dose oral minoxidil (LDOM) is emerging as an effective alternative. Despite their widespread use, there is a notable gap in the literature regarding their use in treating scarring alopecia. OBJECTIVE: This study evaluates the efficacy and safety of TM and LDOM in managing scarring alopecia. METHODS: A systematic literature search identified relevant studies on TM and LDOM use in central centrifugal cicatricial alopecia, frontal fibrosing alopecia, lichen planopilaris, and traction alopecia. Key metrics included disease stabilization, hair thickness improvement, hair regrowth, and side effect profiles. RESULTS: Analysis of the selected studies revealed mixed outcomes. Most participants experienced benefits in terms of disease stabilization and hair regrowth with TM and LDOM. The majority of cases reported good tolerability of the treatment, although some side effects were noted. CONCLUSION: TM and LDOM show promise in scarring alopecia treatment, demonstrating benefits in disease stabilization and hair regrowth. Despite these positive indications, the variability in results and reported side effects underline the need for further research to establish their consistent efficacy and safety profiles in scarring alopecia treatment. J Drugs Dermatol. 2024;23(3):     doi:10.36849/JDD.7743.

Do Death Certificate Errors Decrease as Clinical Experience in an Emergency Department Increases?

BACKGROUND: This study aimed to evaluate the relationship between clinical experience and death certificate (DC) errors by analyzing DCs written by experienced emergency physicians (EPs). METHODS: DCs issued by four experienced EPs over a 10-year period were retrospectively reviewed. DC errors were divided into major and minor errors based on whether they affected the cause of death (COD) determination. The errors were judged through first and second evaluations. Basic information regarding DCs and 10-year changes in DC errors were analyzed. RESULTS: A total of 505 DCs were analyzed, with an average of 34 to 70 for each study year. The number of CODs written in the DCs tended to decrease over time. The presentation of major DC errors did not show a tendency to change over time. However, the sum of the major and minor errors tended to increase over time. Secondary conditions as the underlying COD tended to increase, and the incompatible causal relationships between CODs tended to decrease over time in the detailed analysis of major errors. The increasing tendency for incorrect other significant conditions, incorrect type of accident, incorrect intention of the external cause, no record of the trauma mechanism, and record of the trauma mechanism without another COD were found in the detailed analysis of minor errors. CONCLUSION: DC errors did not decrease as clinical experience increased. Education to reduce DC errors and a feedback process for written DCs are necessary, regardless of clinical experience.

Impact of a game-based interprofessional education program on medical students' perceptions: a text network analysis using essays.

BACKGROUND: The increasing complexity of the healthcare environment and the necessity of multidisciplinary teamwork have highlighted the importance of interprofessional education (IPE). IPE aims to enhance the quality of patient care through collaborative education involving various healthcare professionals, such as doctors, nurses, and pharmacists. This study sought to analyze how game-based IPE activities influence students' perceptions and reflective thinking. It also aimed to identify the shifts in perception and effectiveness caused by this educational approach. METHODS: The study is based on a game-based IPE program conducted at University A, involving medical and nursing students in structured learning and team-based activities. Data were collected using essays written by the students after they had participated in IPE activities. Text network analysis was conducted by extracting key terms, performing centrality analysis, and visualizing topic modeling to identify changes in students' perceptions and reflective thinking. RESULTS: Keywords such as "patient," "thought," "group," "doctor," "nurse," and "communication" played a crucial role in the network, indicating that students prioritized enhancing their communication and problem-solving skills within the educational environment. The topic modeling results identified three main topics, each demonstrating the positive influence of game-based collaborative activities, interprofessional perspectives, and interdisciplinary educational experiences on students. Topic 3 (interdisciplinary educational experience) acted as a significant mediator connecting Topic 1 (game-based collaborative activity experience) and Topic 2 (interprofessional perspectives). CONCLUSION: This study demonstrates that game-based IPE activities are an effective educational approach for enhancing students' team building skills, particularly communication and interprofessional perspectives. Based on these findings, future IPE programs should focus on creating collaborative learning environments, strengthening communication skills, and promoting interdisciplinary education. The findings provide essential insights for educational designers and medical educators to enhance the effectiveness of IPE programs. Future research should assess the long-term impacts of game-based IPE on clinical practice, patient outcomes, and participants' professional development.

Impact of intravenous accessibility and prehospital epinephrine use on survival outcomes of adult nontraumatic out-of-hospital cardiac arrest patients.

BACKGROUND: This study compared out-of-hospital cardiac arrest (OHCA) patient outcomes based on intravenous (IV) access and prehospital epinephrine use. METHODS: A retrospective study in Ulsan, South Korea, from January 2017 to December 2022, analyzed adult nontraumatic OHCA cases. Patients were grouped: Group 1 (no IV attempts), Group 2 (failed IV access), Group 3 (successful IV access without epinephrine), and Group 4 (successful IV access with epinephrine), with comparisons using logistic regression analysis. RESULTS: Among 2,656 patients, Group 4 had significantly lower survival to hospital discharge (adjusted OR 0.520, 95% CI 0.346-0.782, p = 0.002) and favorable neurological outcomes (adjusted OR 0.292, 95% CI 0.140-0.611, p = 0.001) than Group 1. Groups 2 and 3 showed insignificant survival to hospital discharge (adjusted OR 0.814, 95% CI 0.566-1.171, p = 0.268) and (adjusted OR 1.069, 95% CI 0.810-1.412, p = 0.636) and favorable neurological outcomes (adjusted OR 0.585, 95% CI 0.299-1.144, p = 0.117) and (adjusted OR 1.075, 95% CI 0.689-1.677, p = 0.751). In the shockable rhythm group, Group 3 had better survival to hospital discharge (adjusted OR 1.700, 95% CI 1.044-2.770, p = 0.033). CONCLUSIONS: Successful IV access with epinephrine showed worse outcomes in both rhythm groups than no IV attempts. Outcomes for failed IV and successful IV access without epinephrine were inconclusive. Importantly, successful IV access without epinephrine showed favorable survival to hospital discharge in the shockable rhythm group, warranting further research into IV access for fluid resuscitation in shockable rhythm OHCA patients.

Mesenchymal Stem Cell Therapy in Alopecia Areata: Visual and Molecular Evidence from a Mouse Model.

Recent studies have highlighted the potential of Mesenchymal Stem Cells (MSCs) as an alternative treatment for Alopecia Areata (AA) due to their immunosuppressive properties. While MSCs have shown promise in cell experiments, their effectiveness in vivo remains uncertain. This study aims to validate local administration of MSC therapy's efficacy in AA treatment through animal experiments. AA was induced through Interferon-gamma (IFN-γ) administration in mice, and MSC treatment (MSCT)'s effects were assessed visually and through tissue analysis. The MSC-treated group showed more hair regrowth compared to the control (CTL) group. MSCT notably reduced local inflammatory cytokines (JAK1, JAK2, STAT1, STAT3, IFN-γR, IL-1ß, IL-16, IL-17α, and IL-18) in AA-induced mice's skin, but systemic cytokine levels remained unchanged. Furthermore, MSC treatment normalized the expression of Wnt/ß-catenin signaling pathway genes (LEF1 and ß-catenin) and growth factors (FGF7 and FGF2), which are crucial for hair cycle regulation. This study lays the groundwork for further exploring MSCs as a potential treatment for AA, but more research is needed to fully understand their therapeutic potential.

Smoking and pancreatic cancer: a sex-specific analysis in the Multiethnic Cohort study.

PURPOSE: To examine whether the detrimental smoking-related association with pancreatic cancer (PC) is the same for women as for men. METHODS: We analyzed data from 192,035 participants aged 45-75 years, enrolled in the Multiethnic Cohort study (MEC) in 1993-1996. We identified PC cases via linkage to the Hawaii and California Surveillance, Epidemiology, and End Results Program cancer registries through December 2017. RESULTS: During a mean follow-up of 19.2 years, we identified 1,936 incident PC cases. Women smokers smoked on average less than men smokers. In multivariate Cox regression models, as compared with sex-specific never smokers, current smokers had a similar elevated risk of PC for women, hazard ratio (HR) 1.49 (95% CI 1.24, 1.79) and as for men, HR 1.48 (95% CI 1.22, 1.79) (pheterogeneity: 0.79). Former smokers showed a decrease in risk of PC for men within 5 years, HR 0.74 (95% CI 0.57, 0.97) and for women within 10 years after quitting, HR 0.70 (95% CI 0.50, 0.96), compared with their sex-specific current smokers. Both sexes showed a consistent, strong, positive dose-response association with PC for the four measures (age at initiation, duration, number of cigarettes per day, number of pack-years) of smoking exposure among current smokers and an inverse association for years of quitting and age at smoking cessation among former smokers (all ptrend's < 0.001). CONCLUSION: Although MEC women smoke on average less than their men counterparts, the smoking-related increase in PC risk and the benefits of cessation seem to be of similar magnitudes for women as for men.

Attenuated reactive hyperemia after prolonged sitting is associated with reduced local skeletal muscle metabolism: insight from artificial intelligence.

Blunted post-occlusive reactive hyperemia (PORH) after prolonged sitting (PS) has been used as evidence of microvascular dysfunction. However, it has not been determined if confounding variables are responsible for the reduction in PORH after PS. Therefore, the purpose of this study was to examine the PS-mediated changes in cardiovascular and metabolic factors that affect PORH using artificial intelligence (AI). We hypothesized that calf muscle metabolic rate (MMR) is attenuated after PS, which may reduce tissue hypoxia during an arterial occlusion (i.e., oxygen deficit) and PORH. Thirty-one subjects (male = 13, female = 18) sat for 2.5 h. A rapid-inflation cuff was placed around the thigh above the knee to generate an arterial occlusion. PORH was represented by the reoxygenation rate (RR) of the near-infrared spectroscopy (NIRS) tissue oxygenation index (TOI) after 5-min of arterial occlusion. An artificial intelligence model (AI) defined the stimulus-response relationship between the oxygen deficit (i.e., ΔTOI and TOI deficit), and RR with 65 previous PORH recordings. If the AI predicts the experimental RRs, then the change in RR is related to the change in the oxygen deficit. RR (Δ -0.27 ± 0.55 lnTOI%·s-1, P = 0.001), MMR (Δ -0.46 ± 0.61 lnTOI%·s-1, P < 0.001), ΔTOI (Δ -0.34 ± 0.62 lnTOI%, P < 0.001), and the TOI deficit (Δ -0.42 ± 0.68 lnTOI%·s, P < 0.001) were reduced after PS. In addition, strong linear associations were found between MMR and the TOI deficit (r2 = 0.900, P < 0.001) and ΔTOI (r2 = 0.871, P < 0.001). Furthermore, the AI accurately predicted the RRs pre- and post-PS (P = 0.471, P = 0.328, respectively). Therefore, blunted PORH after PS may be caused by attenuated MMR and not microvascular dysfunction.NEW & NOTEWORTHY Prolonged sitting reduces lower leg skeletal muscle metabolic rate in healthy individuals. Artificial intelligence revealed that impaired post-occlusive reactive hyperemia after prolonged sitting is related to a reduced stimulus for vasodilation and may not be evidence of microvascular dysfunction. Current post-occlusive reactive hyperemia protocols may be insufficient to assess micro- and macrovascular function after prolonged sitting.

Moderate dose of dietary nitrate improves skeletal muscle microvascular function in patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease characterized by compromised lower-extremity blood flow that impairs walking ability. We showed that a moderate dose of dietary nitrate in the form of beetroot juice (BRJ, 0.11 mmol/kg) can improve macrovascular function and maximal walking distance in patients with PAD. However, its impacts on the microcirculation and autonomic nervous system have not been examined. Therefore, we investigated the impacts of this dose of dietary nitrate on skeletal muscle microvascular function and autonomic nervous system function and further related these measurements to 6-min walking distance, pain-free walking distance, and exercise recovery in patients with PAD. Patients with PAD (n = 10) ingested either BRJ or placebo in a randomized crossover design. Heart rate variability, skeletal muscle microvascular function, and 6-min walking distance were performed pre- and post-BRJ and placebo. There were significant group × time interactions (P < 0.05) for skeletal muscle microvascular function, 6-min walking distance, and exercise recovery, but no changes (P > 0.05) in heart rate variability or pain-free walking distance were noted. The BRJ group demonstrated improved skeletal muscle microvascular function (∆ 22.1 ± 7.5 %·min-1), longer 6-min walking distance (Δ 37.5 ± 9.1 m), and faster recovery post-exercise (Δ -15.3 ± 4.2 s). Furthermore, changes in skeletal muscle microvascular function were positively associated with changes in 6-min walking distance (r = 0.5) and pain-free walking distance (r = 0.6). These results suggest that a moderate dose of dietary nitrate may support microvascular function, which is related to improvements in walking distance and claudication in patients with PAD.

Change in the inflammatory potential of diet over 10 years and subsequent mortality: the Multiethnic Cohort Study.

Dietary inflammatory potential assessed by the Dietary Inflammatory Index (DII®) has been associated with health outcomes. However, longitudinal changes in the DII in relation to health outcomes rarely have been studied. This study aimed to examine change in the DII score over 10 years and its association with subsequent mortality in the Multiethnic Cohort. The analysis included 56 263 African American, Japanese American, Latino, Native Hawaiian and White participants who completed baseline (45-75 years) and 10-year follow-up surveys, including a FFQ. Mean energy-adjusted DII (E-DII) decreased over 10 years in men (from -0·85 to -1·61) and women (from -1·80 to -2·47), reflecting changes towards a more anti-inflammatory diet. During an average follow-up of 13·0 years, 16 363 deaths were identified. In multivariable Cox models, compared with anti-inflammatory stable individuals, risk of all-cause mortality was increased with pro-inflammatory change in men (hazard ratio (HR) = 1·13, 95 % CI 1·03, 1·23) and women (HR = 1·22, 95 % CI 1·13, 1·32). Per one-point increase in E-DII score over time, HR was 1·02 (95 % CI 1·00, 1·03) for men and 1·06 (95 % CI 1·04, 1·07) for women (P for heterogeneity < 0·001). While no heterogeneity by race and ethnicity was observed for men, the increased risk per one-point increase among women was stronger in non-Whites than in Whites (P for heterogeneity = 0·004). Our findings suggest that a change towards a more pro-inflammatory diet is associated with an increased risk of mortality both in men and women, and that the association is stronger in women, especially non-White women, than in men.

Characteristics of patients who visited emergency departments for headache in South Korea: A descriptive cross-sectional study.

OBJECTIVE: This study aimed to describe the characteristics of adult patients who visit emergency departments (EDs) for non-traumatic headache in South Korea. BACKGROUND: Little is known about East Asian patients who visit EDs for headache. METHODS: This observational, descriptive, cross-sectional study retrospectively analyzed 2019 National Emergency Department Information System data, including age, sex, co-occurring fever, symptom duration, insurance type, transportation mode, ED level, triage level, ED visit time, specialist consultations at the ED, disposition from the ED, and outcomes. The proportion of patients with a life-threatening secondary headache and the diagnostic codes were investigated. RESULTS: A total of 227,288 patients were observed in this study, accounting for 2.2% (227,288/10,238,360) of all ED visits. Females (63.1%; 143,493/227,288) visited EDs more than males, and patients aged 50-60 years (21.0%; 47,637/227,288) visited most frequently. A total of 61.5% (93,789/151,494) of ED visits were within 24 h after headache onset, and 57.6% (131,056/227,288) of visits were assigned to non-urgent triage levels. The most frequent discharge codes were "R51: Headache (not better specified)" from the ED and ward, and "I60: Subarachnoid hemorrhage" from the intensive care unit. The rate of migraine diagnosis was 7.2% (16,471/227,288). A total of 3.1% (7153/227,288) of patients were diagnosed with life-threatening secondary headaches, most commonly subarachnoid hemorrhage (1.2%; 2744/227,288) and cerebral infarction (0.6%; 1341/227,288). CONCLUSIONS: In South Korea, the characteristics of patients who visited the ED for non-traumatic headache were not very different from those in existing studies; however, patients tended to visit EDs early and be classified as non-urgent, and emergency physicians tended to enter the diagnosis code "R51: Headache (not better specified)", resulting in a much lower rate of migraine diagnoses. Non-urgent early visitors coded with "R51" may include those who have not yet been diagnosed with primary headache and have not been treated, but who need further research. TRIAL REGISTRATION: Not applicable.

The Evolving Treatment Landscape of Merkel Cell Carcinoma.

OPINION STATEMENT: Merkel cell carcinoma (MCC) has a high risk of recurrence and requires unique treatment relative to other skin cancers. The patient population is generally older, with comorbidities. Multidisciplinary and personalized care is therefore paramount, based on patient preferences regarding risks and benefits. Positron emission tomography and computed tomography (PET-CT) is the most sensitive staging modality and reveals clinically occult disease in ~ 16% of patients. Discovery of occult disease spread markedly alters management. Newly diagnosed, localized disease is often managed with sentinel lymph node biopsy (SLNB), local excision, primary wound closure, and post-operative radiation therapy (PORT). In contrast, metastatic disease is usually treated systemically with an immune checkpoint inhibitor (ICI). However, one or more of these approaches may not be indicated. Criteria for such exceptions and alternative approaches will be discussed. Because MCC recurs in 40% of patients and early detection/treatment of advanced disease is advantageous, close surveillance is recommended. Given that over 90% of initial recurrences arise within 3 years, surveillance frequency can be rapidly decreased after this high-risk period. Patient-specific assessment of risk is important because recurrence risk varies widely (15 to > 80%: Merkelcell.org/recur) depending on baseline patient characteristics and time since treatment. Blood-based surveillance tests are now available (Merkel cell polyomavirus (MCPyV) antibodies and circulating tumor DNA (ctDNA)) with excellent sensitivity that can spare patients from contrast dye, radioactivity, and travel to a cancer imaging facility. If recurrent disease is locoregional, management with surgery and/or RT is typically indicated. ICIs are now the first line for systemic/advanced MCC, with objective response rates (ORRs) exceeding 50%. Cytotoxic chemotherapy is sometimes used for debulking disease or in patients who cannot tolerate ICI. ICI-refractory disease is the major problem faced by this field. Fortunately, numerous promising therapies are on the horizon to address this clinical need.

Feasibility and safety of exercise during chemotherapy in people with gastrointestinal cancers: a pilot study.

PURPOSE: Sarcopenia is a poor prognostic factor in cancer patients, and exercise is one of the treatments to improve sarcopenia. However, there is currently insufficient evidence on whether exercise can improve sarcopenia in patients with advanced cancers. This study examined the feasibility of exercise in advanced gastrointestinal (GI) cancer patients treated with palliative chemotherapy. METHODS: Between 2020 and 2021, 30 patients were enrolled in a resistance and aerobic exercise program for six weeks. The exercise intervention program (EIP) consisted of low, moderate, and high intensity levels. Patients were asked to select the intensity level according to their ability. The primary endpoint was the feasibility of the EIP measured by compliance during the six weeks. A compliance of over 50% was considered acceptable. The secondary endpoints were changes in weight and muscle mass, safety, quality of life (QoL) and overall survival (OS). RESULTS: The median age of the study's participants was 60 (30-77). The total compliance to the EIP was 63.3% (19/30 patients). Sixteen (53.3%) patients had a compliance of over 80%. The attrition rate was 30.0% (9/30). The mean exercise time was 41.4 min, and the aerobic exercise was 92.3% and the resistant exercise was 73.7%, and both exercise was 66.5%. Most patients performed the moderate intensity level exercises at home or near their home. The mean skeletal muscle index (SMI) was 43.5 cm2/m2 pre-chemotherapy and 42.2 cm2/m2 after six weeks of chemotherapy, with a decrease of -1.2 ± 2.8 cm2/m2 (-3.0%) (p = 0.030). In the poor compliance group, the mean SMI decrease was -2.8 ± 3.0 cm2/m2 which was significantly different (p = 0.033); however, in the good compliance group, the mean SMI decrease was -0.5 ± 2.5 cm2/m2 which was maintained over the six weeks (p = 0.337). The good compliance group had a significantly longer median OS compared with the poor compliance group (25.3 months vs. 7.9 months, HR = 0.306, 95% CI = 0.120-0.784, p = 0.014). The QoL showed a better score for insomnia (p = 0.042). There were no serious adverse events. CONCLUSIONS: The EIP during palliative chemotherapy in advanced GI cancer patients showed good compliance. In the good compliance group, muscle mass and physical functions were maintained for six weeks. The EIP was safe, and the QoL was maintained. Based on this study, further research in exercise intervention in advanced cancer patients is needed. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is KCT 0005615 (CRIS, https://cris.nih.go.kr/cris/en/ ); registration date, 23rd Nov 2020.

A preliminary study about the potential risks of the UV-weathered microplastic: The proteome-level changes in the brain in response to polystyrene derived weathered microplastics.

The growing use of plastic materials has resulted in a constant increase in the risk associated with microplastics (MPs). Ultra-violet (UV) light and wind break down modify MPs in the environment into smaller particles known as weathered MPs (WMPs) and these processes increase the risk of MP toxicity. The neurotoxicity of weathered polystyrene-MPs remains unclear. Therefore, it is important to understand the risks posed by WMPs. We evaluated the chemical changes of WMPs generated under laboratory-synchronized environmentally mimetic conditions and compared them with virgin MPs (VMPs). We found that WMP had a rough surface, slight yellow color, reduced molecular weight, and structural alteration compared with those of VMP. Next, 2 µg of ∼100 µm in size of WMP and VMP were orally administered once a day for one week to C57BL/6 male mice. Proteomic analysis revealed that the WMP group had significantly increased activation of immune and neurodegeneration-related pathways compared with that of the VMP group. Consistently, in in vitro experiments, the human brain-derived microglial cell line (HMC-3) also exhibited a more severe inflammatory response to WMP than to VMP. These results show that WMP is a more profound inflammatory factor than VMP. In summary, our findings demonstrate the toxicity of WMPs and provide theoretical insights into their potential risks to biological systems and even humans in the ecosystem.

White Rice Consumption and Risk of Colorectal Cancer Among Japanese Americans: The Multiethnic Cohort Study.

BACKGROUND: White rice is a staple food for Japanese, a population at high risk for colorectal cancer (CRC). We investigated the association between white rice intake and CRC among Japanese Americans in the Multiethnic Cohort (MEC) study. METHODS: The MEC study is a prospective study established in Hawaii and California in 1993-1996. Usual dietary intake was assessed using a validated quantitative food frequency questionnaire at baseline. Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for quartiles of intake and to perform trend tests across sex-specific quartiles with adjustment for relevant confounders. RESULTS: We identified 1,553 invasive CRC cases among 49,136 Japanese Americans (23,595 men and 25,541 women) during a mean follow-up of 19 years. White rice consumption was not associated with overall CRC incidence in men (Ptrend = 0.11) or women (Ptrend = 0.56). After excluding participants with a history of diabetes, the inverse associations were significant for CRC (Ptrend = 0.03, HR for quartile 4 [Q4] vs quartile 1 [Q1], 0.81; 95% CI, 0.64-1.03) and tumors of the distal colon (Ptrend = 0.006, HR for Q4 vs Q1, 0.66; 95% CI, 0.44-0.99) among men but not women. CONCLUSION: White rice consumption was not associated with an increased risk of overall CRC among Japanese Americans. An inverse association was observed with risk of CRC and distal colon cancer in men without a history of diabetes.