Neural correlates of appetite in adolescents.

Appetitive characteristics are associated with child adiposity, but their biological underpinnings are unclear. We sought to investigate the neural correlates of psychometric and behavioral measures of appetitive characteristics in youth. Adolescents (14-18y; 39F, 37M) varying in familial obesity risk and body weight (20% with overweight, 24% with obesity) viewed pictures of high energy-density (ED) foods, low-ED foods and non-foods during fMRI scanning on two separate days. On one day participants consumed a 474 ml preload of water (0 kcal, fasted) and on another (counter-balanced) 474 ml milkshake (480 kcal, fed), before scanning. A multi-item ad libitum meal (ALM) followed scanning. Parents completed Child Eating Behavior Questionnaire (CEBQ) sub-scales assessing food approach and food self-regulation. Caloric compensation was calculated as the percentage of preload intake compensated for by down-regulation of ALM intake in the fed vs. fasted condition. Analyses correcting for multiple comparisons demonstrated that, for the fasted condition, higher CEBQ Food Responsiveness scores were associated with greater activation to high-ED (vs. low-ED) foods in regions implicated in food reward (insula, rolandic operculum, putamen). In addition, higher caloric compensation was associated with greater fed vs. fasted activations in response to foods (vs. non-foods) in thalamus and supramarginal gyrus. Uncorrected analyses provided further support for associations of different measures of appetitive characteristics with brain responses to food cues in each condition. Measures of appetitive characteristics demonstrated overlapping and distinct associations with patterns of brain activation elicited by food cues in fasted and fed states. Understanding the neural basis of appetitive characteristics could aid development of biobehaviorally-informed obesity interventions.

Eligibility for sacubitril/valsartan in heart failure across the ejection fraction spectrum: real-world data from the Swedish Heart Failure Registry.

BACKGROUND: Randomized controlled trials (RCT) generalizability may be limited due to strict patient selection. OBJECTIVE: In a real-world heart failure (HF) population, we assessed eligibility for sacubitril/valsartan based on PARADIGM-HF (sacubitril/valsartan effective)/PARAGON-HF [sacubitril/valsartan effective in mildly reduced ejection fraction (EF)]. METHODS: Outpatients from the Swedish HF Registry (SwedeHF) were analysed. In SwedeHF, EF is recorded as <30, 30-39, 40-49 and ≥50%. In PARAGON-HF, sacubitril/valsartan was effective with EF ≤ 57% (i.e. median). We defined reduced EF/PARADIGM-HF as EF < 40%, mildly reduced EF/PARAGON-HF ≤ median as EF 40-49%, and normal EF/PARAGON-HF > median as EF ≥ 50%. We assessed 2 scenarios: (i) criteria likely to influence treatment decisions (pragmatic scenario); (ii) all criteria (literal scenario). RESULTS: Of 37 790 outpatients, 57% had EF < 40%, 24% EF 40-49% and 19% EF ≥ 50%. In the pragmatic scenario, 63% were eligible in EF < 50% (67% for EF < 40% and 52% for 40-49%) and 52% in EF ≥ 40% (52% for EF ≥ 50%). For the literal scenario, 32% were eligible in EF < 50% (38% of EF < 40%, 20% of EF 40-49%) and 22% in EF ≥ 40% (25% for EF ≥ 50%). Eligible vs. noneligible patients had more severe HF, more comorbidities and overall worse outcomes. CONCLUSION: In a real-world HF outpatient cohort, 81% of patients had EF < 50%, with 63% eligible for sacubitril/valsartan based on pragmatic criteria and 32% eligible based on literal trial criteria. Similar eligibility was observed for EF 40-49% and ≥50%, suggesting that our estimates for EF < 50% may be reproduced whether or not a higher cut-off for EF is considered.

"Real World" Eligibility for Sacubitril/Valsartan in Unselected Heart Failure Patients: Data from the Swedish Heart Failure Registry.

PURPOSE: PARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril in patients with heart failure and reduced ejection fraction (HF-REF). How widely applicable sacubitril/valsartan treatment is in unselected patients with HF-REF is not known. We examined eligibility of patients with HF-REF for treatment with sacubitril/valsartan, according to the criteria used in PARADIGM-HF, in the Swedish Heart Failure Registry (SwedeHF). METHODS: Patients were considered potentially eligible if they were not hospitalized, had symptoms (NYHA class II-IV) and a reduced LVEF (≤ 40%), and were prescribed an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a dose equivalent to enalapril ≥ 10 mg daily. In these patients, we evaluated further eligibility according to the main additional PARADIGM-HF inclusion criteria. RESULTS: Of 12,866 outpatients in NYHA functional class II-IV with an LVEF ≤ 40%, 9577 were prescribed at least 10 mg of enalapril (or equivalent) daily. Complete additional data were available for 3099 of these patients (32.4%) and of them 75.5% were potentially eligible for treatment with sacubitril/valsartan. The most common reason for ineligibility was a low natriuretic peptide level (n = 462, 14.9%). Only a small proportion of patients were ineligible due to low eGFR or serum potassium level. Because only 78% of patients were taking ≥ 10 mg enalapril or equivalent daily, only 58.9% of all patients (75.5% of 78%) were eligible for sacubitril/valsartan. CONCLUSIONS: Between 34 and 76% of symptomatic patients with HF-REF in a 'real world' population are eligible for treatment with sacubitril/valsartan, depending on background ACEI/ARB dose. The most common reason for ineligibility is a low natriuretic peptide level.

Determining Physical and Mental Health Conditions Present in Older Adult Refugees: A Mini-Review.

In 2017, there were over 65 million displaced persons at the global level, with approximately 23 million of these people living as refugees around the world. In this same year, the US resettled 53,716 refugees, with the State of Utah receiving 954 of those refugees. Refugees, in general, often face health-related challenges upon resettlement. Since the health of aging refugee men and women is of growing concern, host communities face significant challenges in accommodating the health needs of a diverse refugee population. This study, a review of physical and mental health data from the Utah Department of Health, was undertaken in an effort to ascertain the prevalence of health conditions among refugee men and women 60 years and older arriving in Utah. Findings include information on diseases correlated with increasing age, such as hypertension, decreases in vision, arthritis, and low back pain, which are common among this population of refugees aged 60 years and older. Overall, most of the health conditions assessed affect women and men with a similar prevalence. Some notable exceptions are a history of torture and violence, and a propensity for tobacco use. When dealing with refugee men older than 60 years, providers should consider the psychological ramifications of having endured such atrocities, as well as introduction to evidence-based tobacco cessation programs. When working with refugee women of the same age, an increase in the prevalence of musculoskeletal pain and urinary tract infections should be considered.

Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy.

Children with hypertrophic cardiomyopathy (HCM) experience sudden cardiac death (SCD) and other life-threatening events. We assessed if affected gene and variant burden predict outcomes. Patients <18 years old with primary HCM with a pathogenic variant or variant of uncertain significance in cardiomyopathy genes were included. Association of gene and variant number and type with freedom from major adverse cardiac events (MACE), that is, ICD insertion, myectomy, aborted SCD, transplantation or death, was assessed by Cox regression. A total of 98 of 155 gene-tested patients carried a non-benign variant. The primary affected gene was MYH7 in 35% (MYH7+) and MYBPC3 in 49% (MYBPC3+). MYH7+ patients had earlier disease onset and higher risk of MACE (hazard ratio 2.7, 95% CI 1.3-5.7). Risk of MACE was also higher in patients with multiple variants (n = 16) (HR 2.5, CI: 1.1-5.9) compared to a propensity score-matched single variant subset, after adjustment for primary gene, and in patients with de novo (n = 18) vs inherited variants (HR 5.7, CI: 2.6-12.7). Affected gene (eg, MYH7), higher variant burden and de novo variant status are independently associated with earlier onset and higher frequency of adverse outcomes in pediatric HCM, highlighting the importance of genetic risk stratification in HCM.

Clinical genetic testing in pediatric cardiomyopathy: Is bigger better?

BACKGROUND: For clinical genetic testing of cardiomyopathy (CMP), current guidelines do not address which gene panels to use: targeted panels specific to a CMP phenotype or expanded (panCMP) panels that include genes associated with multiple phenotypic subtypes. AIM: Our objective was to assess the clinical utility of targeted versus panCMP panel testing in pediatric CMPs. METHODS: 151 pediatric patients with primary hypertrophic (n = 66), dilated (n = 64), restrictive (n = 8), or left-ventricular non-compaction (n = 13) CMP who underwent clinical genetic panel testing at a single centre were included. PanCMP (n = 47) and targeted panel testing (n = 104) were compared for yield of pathogenic variants and variants of unknown significance (VUS). RESULTS: Pathogenic variants were identified in 26% of patients, 42% had indeterminate results (only VUS detected), and 32% had negative results. Yield was lower (15%) in panCMP vs. targeted panel testing (32%) (P = .03) in all CMP subtypes. VUS detection was higher with panCMP (87%) than targeted panel testing (30%) (P <.0001). PanCMP panel testing only identified pathogenic variants in genes that overlapped targeted panels. CONCLUSION: PanCMP testing did not increase diagnostic yield compared to targeted panel testing. Until accuracy of variant interpretation with panCMP panels improves, targeted panels may be suitable for clinical testing in pediatric CMP.

Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia.

A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50=1.0µM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50>20µM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin.

Caloric compensation in preschool children: Relationships with body mass and differences by food category.

Maintaining a healthy weight may involve compensating for previously consumed calories at subsequent meals. To test whether heavier children demonstrated poorer caloric compensation across a range of conditions, and to explore whether compensation failure was the result of inadequate adjustment of overall intake or specific over-consumption of highly palatable, high energy-density 'junk' foods, we administered two compensation tests to a sample of 4-5 y olds. For Test A, preloads varied only in carbohydrate content and were organoleptically indistinguishable (200 ml orange-flavored beverage [0 kcal vs. 200 kcal]). For Test B, the preloads varied substantially in both macronutrient composition and learned gustatory cues to caloric content (200 ml water [0 kcal] vs. 200 ml strawberry milkshake [200 kcal]). Each preload was followed 30 min later by a multi-item ad-libitum meal containing junk foods (chocolate cookies, cheese-flavored crackers) and core foods (fruits and vegetables, bread rolls, protein foods). Testing took place at the children's own school under normal lunch-time conditions. Children were weighed and measured. Caloric compensation occurred in both tests, in terms of total, junk and core food intake (RMANOVA, all p < 0.01). Higher BMI z scores were associated with greater average caloric compensation (r = -0.26; p < 0.05), such that overweight/obese children showed least compensation (41%), children over the 50th centile the next least (59%), and children under the 50th centile (80%) the most. For Test A only, obese/overweight children compensated less well than normal-weight children in terms of junk food intake (RMANOVA preload-by-weight group interaction p < 0.05), with no significant effect for core foods. Our results suggest that caloric compensation is consistently poorer in heavier children, and that overweight/obese children's preferences for junk foods may overwhelm intake regulation mechanisms within meals containing those foods.

Paracervical block as pain treatment during second-trimester medical termination of pregnancy: an RCT with bupivacaine versus sodium chloride.

STUDY QUESTION: Can paracervical block (PCB) administered before the onset of pain decrease women's pain experience during second-trimester medical termination of pregnancy (MToP)? SUMMARY ANSWER: There were no clinically significant differences between groups receiving PCB with bupivacaine or saline with regard to the highest and lowest pain intensity, morphine consumption or induction-to abortion interval. WHAT IS KNOWN ALREADY: The most common side effect of misoprostol is pain; nevertheless, there are sparse studies in pain and pain treatment during MToP, especially in second-trimester abortion. Pain reported in second-trimester medical abortion is often intense, and peaks when the fetal expulsion occurs. STUDY DESIGN, SIZE, DURATION: A double-blinded RCT was carried out from May 2012 until April 2015. A power calculation was based on a previous pilot study showing that the proportion of women with severe pain [visual analogue scale (VAS) ≥7] was 63%. A clinically significant reduction was considered to yield 35% with severe pain, and with a power of 80% and significance level of 5% (two-sided) 112 women were needed. Accounting for a 20% drop-out rate, a total of 140 women were needed. The primary outcome, pain intensity measured as any VAS ≥7, was analysed using a generalized estimating equations model. The level of significance was set to P < 0.05 two-sided. A computer generated randomization list with block size of 10 was used. The treatment allocation was placed in a sealed, opaque, envelope and picked consecutively. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 589 women attending a gynaecological clinic had a second-trimester abortion during the study period and 276 were invited to participate. A total of 113 women undergoing abortion from 13 weeks of gestation and above were recruited, of which 55 were randomly allocated to receive a PCB with bupivacaine and 58 a PCB with sodium chloride 1 h after the first dose of misoprostol. The full analysis set (FAS) population was defined as all randomized women that had at least one value for any of the outcomes (n = 102). The per-protocol (PP) population was defined as a subset of the FAS excluding patients with major protocol deviations or without a value for the primary outcome (n = 99). Pain was measured by VAS at misoprostol initiation (baseline) and repeated every 30 min until fetal expulsion. The primary outcome was the highest VAS pain intensity at any time point. MAIN RESULTS AND THE ROLE OF CHANCE: The highest pain intensity, did not show any differences at a cut-off of VAS ≥7 [risk ratio (RR): 1.1; 95% confidence interval (CI): 0.9-1.5; P = 0.0.292]. In the PP analyses, there were 75% women in the bupivacaine group and 64% in the sodium chloride group with VAS ≥7 (RR: 1.2; 95% CI: 0.9-1.5; P = 0.235). Most women did not experience pain at the misoprostol start, 19 women scored a VAS of >0, ranging from 1 to 4 with a mean of 1.8 and median of 2 (P = 1.000). Immediately prior to PCB, 61 women scored a VAS of >0, from 1 to 10 with a mean of 2.0 and median of 1 (P = 0.771). There was a 48% loss of VAS scores at the time of expulsion and the remaining scores did not differ between groups (RR: 1.5; 95% CI: 0.9-2.5). A subgroup analysis of primipara did not show any difference in highest pain intensity VAS ≥7 (RR: 1.2; 95% CI: 0.9-1.6; P = 0.283). No statistically significant differences were observed between groups with regard to the highest and lowest (P = 553 and 0.182) pain intensity and morphine consumption (P = 0.772). Side effects were reported by 28 women (14 women in each group), with no differences between groups. Most common was nausea and vomiting in connection to morphine injection. LIMITATIONS, REASONS FOR CAUTION: Nearly 60% of the invited women did not want to participate in the study (fear of needles and fear of receiving the placebo) therefore women who tolerate pain may have been overrepresented in the study population. Data collection was stopped, in error, when 113 participants had been recruited. The loss to follow-up was, however, only 11 women (10%), which was lower than expected but intrinsically the study did not fully reach the intended number of women, which may have influenced the results. In addition, the obstetrical and gynaecological background of participating women differs. The participants were informed that they had a 50% chance of receiving a PCB with active substance, which could theoretically have affected their expectations and pain experience (placebo effect). The frequent attention at VAS scoring and the overall care provided may also have affected the participants in a positive way, and helped women to feel supported and more relaxed during the abortion. WIDER IMPLICATIONS OF THE FINDINGS: The highest pain intensity was severe (VAS: 7-10) among 65-75% of the participants, as reported for first-trimester medical abortion; however, the maximal pain scores remain high despite the PCB. There is, therefore, a clear need for more optimal pain treatment but only limited data exist on pain treatment during MToP over all gestational lengths. As PCB was well tolerated, did not cause any serious side effects and had no negative impact on the abortion process and efficacy, another approach may be worth exploring, namely PCB given on demand at the onset of painful contractions. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Swedish Research Council (grant no: 2012-2844), ALF (Karolinska Institutet - Stockholm County Council, Agreement on Medical Research and Training) funding, the Karolinska Institutet, Stockholm South General Hospital, and Swedish Nurses in the Area of Pain - SSOS together with GlaxoSmithKline. None of the authors have any conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov (identifier: NCT01617564) and The EudraCT (number: 2010-020780-21) and was approved by The Regional Ethical Review Board at Karolinska Institutet (dnr: 2007/1277-31/2 and 2010/410-31/1). TRIAL REGISTRATION DATE: Clinical trial registration was done in May 2012 before initiation of patient recruitment. DATE OF FIRST PATIENT'S ENROLMENT: 29 May 2012.

Successful transcatheter occlusion of an anomalous pulmonary vein with dual drainage to the left atrium.

We describe a case of a scimitar syndrome "variant" where dual drainage existed from the right upper and middle pulmonary veins to the inferior vena cava and left atrium. Device closure of the anomalous vein at the level of the connection to the IVC was successful in achieving diversion of pulmonary venous flow to the left atrium. Vigilance during work-up of anomalous pulmonary venous drainage (whether isolated or associated with other cardiac defects that may be amenable to device closure) is important to define the presence of dual connections to the left atrium, in which case a less-invasive transcatheter approach may be feasible.

Exploring the preferences of traditional versus Western medicine in the Spiti Valley region of India: A qualitative approach.

Background: Traditional healing practices are prevalent in rural and mountainous areas of India where Western medicine is not accessible. WHO guidelines recommend integration of traditional and Western medicine to meet rural primary care needs. We explored three dimensions of rural patients' decision-making and satisfaction with their medical care: pregnancy-related concerns, pediatric care for children under five, and acute injuries. Methods: We conducted a qualitative study using a phenomenological approach in India's Spiti Valley between August and October 2023. Sixteen individuals, age 18 years and older, participated in one-on-one interviews. The interviews were transcribed from Hindi into English, reviewed for accuracy by a native speaker, and imported into Dedoose software. Data were analyzed using inductive coding. Findings: Multiparous women aged 35-44 were concerned about pregnancy complications, leading them to choose Western medicine despite access and cost barriers. Pediatric illness requiring urgent care at night was a concern for women with children under five. Those in the injuries group reported having to travel for care beyond basic first aid. Overall, concerns were about limited access to some services locally, as well as costs of travel, medical procedures, and medications when services were obtained beyond the local area. Interpretation: All participants considered their traditional healer their first point of contact for medical care. A number of Western medical services were not available locally. These findings suggest a need to strengthen access to and integration of Western and traditional medical care in rural settings in India.

Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent.

The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.

Impact of COVID-19 Social Distancing Mandates on Gastrointestinal Pathogen Positivity: Secondary Data Analysis.

BACKGROUND: Acute gastrointestinal (GI) illnesses are of the most common problems evaluated by physicians and some of the most preventable. There is evidence of GI pathogen transmission when people are in close contact. The COVID-19 pandemic led to the sudden implementation of widespread social distancing measures in the United States. There is strong evidence that social distancing measures impact the spread of SARS-CoV-2, and a growing body of research indicates that these measures also decrease the transmission of other respiratory pathogens. OBJECTIVE: This study aims to investigate the impact of COVID-19 social distancing mandates on the GI pathogen positivity rates. METHODS: Deidentified GI Panel polymerase chain reaction test results from a routinely collected diagnostic database from January 1, 2019, through August 31, 2020, were analyzed for the GI pathogen positivity percentage. An interrupted time series analysis was performed, using social distancing mandate issue dates as the intervention date. The following 3 target organisms were chosen for the final analysis to represent different primary transmission routes: adenovirus F40 and 41, norovirus GI and GII, and Escherichia coli O157. RESULTS: In total, 84,223 test results from 9 states were included in the final data set. With the exception of E coli O157 in Kansas, Michigan, and Nebraska, we observed an immediate decrease in positivity percentage during the week of social distancing mandates for all other targets and states. Norovirus GI and GII showed the most notable drop in positivity, whereas E coli O157 appeared to be least impacted by social distancing mandates. Although we acknowledge the analysis has a multiple testing problem, the majority of our significant results showed significance even below the .01 level. CONCLUSIONS: This study aimed to investigate the impact of social distancing mandates for COVID-19 on GI pathogen positivity, and we discovered that social distancing measures in fact decreased GI pathogen positivity initially. The use of similar measures may prove useful in GI pathogen outbreaks. The use of a unique diagnostic database in this study exhibits the potential for its use as a public health surveillance tool.

Strategies to increase rural maternal utilization of skilled health personnel for childbirth delivery in low- and middle-income countries: a narrative review.

BACKGROUND: Skilled attendance at birth is considered key to accomplishing Sustainable Development Goal (SDG) 3.1 aimed at reducing maternal mortality. Many maternal deaths can be prevented if a woman receives care by skilled health personnel. Maternal utilization of skilled health delivery services in rural areas in low- and middle-income countries is 70% compared to 90% in urban areas. Previous studies have found community-based interventions may increase rural maternal uptake of skilled health delivery services, but evidence is lacking on which strategies are most effective. OBJECTIVE: To review the effectiveness of community-based strategies to increase rural maternal utilization of skilled health personnel for childbirth delivery in low-and middle-income countries. METHODS: We conducted a narrative review. PubMed, CINAHL, Cochrane Library, and PsycINFO databases were searched for articles from database inception through 13 November 2019. Key search terms were pre-determined. Information was extracted on studies meeting our inclusion criteria: cluster and randomized trials, rural setting, reproductive aged women, community engagement, low- and middle-income countries. Studies were considered effective if statistically significant (p < 0.05). A narrative synthesis was conducted. RESULTS: Ten cluster randomized trials out of 5,895 candidate citations met the inclusion criteria. Strategies included home-based visits, women's groups, and combined approaches. Out of the ten articles, only three studies were found to significantly increase maternal uptake of skilled health personnel for delivery, and each used a different strategy. The results are inconclusive as to which strategies are most effective. Limitations of this review include heterogeneity and generalizability of studies. CONCLUSIONS: This research suggests that different strategies may be effective at improving maternal utilization of skilled health personnel for delivery in certain rural settings while ineffective in others. More research is warranted to better understand the context in which strategies may be effective and under what conditions.

Incidence Rate and Risk Factors Associated with Travelers' Diarrhea in International Travelers Departing from Utah, USA.

Despite knowledge on the causes and prevention strategies for travelers' diarrhea (TD), it continues to be one of the most common illnesses experienced by U.S. international travelers. However, studies of risk factors associated with TD among U.S. travelers are limited. In this study, we aimed to determine the incidence rate of TD, the proportion of travelers who experience TD, and to identify risk factors associated with TD. In this cross-sectional study, we collected and analyzed data from anonymous posttravel questionnaires submitted by international travelers recruited during their pretravel visit at two travel clinics in Salt Lake City, Utah, from October 2016 to March 2020. Of 571 travelers who completed posttravel surveys, 484 (85%) answered the TD question, of which 111 (23%) reported TD, for an incidence rate of 1.1 episodes per 100 travel-days (95% confidence interval [CI]: 0.9-1.4). In a multivariable model, visiting Southeast Asian (odds ratio [OR]: 2.60; 95% CI: 1.45-4.72) and African (OR: 2.06; 95% CI: 1.09-3.93]) WHO regions, having 10 or more individuals in the group (OR: 3.91; 95% CI: 1.50-11.32]), longer trip duration (OR: 1.01; 95% CI: 1.00-1.02), visiting both urban and rural destinations (OR: 1.94; 95% CI: 1.01-3.90), and taking medications/supplements to prevent TD (OR: 2.74; 95% CI: 1.69-4.47) were statistically significantly associated with increased odds of reporting TD. TD continues to be common in international travelers from the United States. Our findings provide insights regarding travelers' behaviors regarding TD in international travelers from high-income countries and shows the need for additional research into prevention strategies for travelers' diarrhea.

EPIC: an evaluation of the psychological impact of early-phase clinical trials in cancer patients.

BACKGROUND: Anxiety and depression in patients with cancer is associated with decreased quality of life and increased morbidity and mortality. However, these are often overlooked and untreated. Early-phase clinical trials (EPCTs) recruit patients with advanced cancers who frequently lack future treatment options, which may lead to increased anxiety and depression. Despite this, EPCTs do not routinely consider psychological screening for patients. PATIENTS AND METHODS: This prospective observational study explored levels of anxiety and depression alongside impact of trial participation in the context of EPCTs. The Hospital Anxiety and Depression Scale and the Brief Illness Perceptions Questionnaire were completed at the point of EPCT consent, the end of screening and at pre-specified time points thereafter. RESULTS: Sixty-four patients (median age 56 years; median Eastern Cooperative Oncology Group performance status 1) were recruited. At consent, 57 patients returned questionnaires; 39% reported clinically relevant levels of anxiety whilst 18% reported clinically relevant levels of depression. Sixty-three percent of patients experiencing psychological distress had never previously reported this. Males were more likely to be depressed (P = 0.037) and females were more likely to be anxious (P = 0.011). Changes in anxiety or depression were observed after trial enrolment on an individual level, but not significant on a population level. CONCLUSIONS: Patients on EPCTs are at an increased risk of anxiety and depression but may not seek relevant support. Sites offering EPCTs should consider including psychological screening to encourage a more holistic approach to cancer care and consider the sex of individuals when tailoring psychological support to meet specific needs.

Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1.

The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents and inhibitors of tubulin assembly (IC50 = 1-2 µM). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regiochemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (IC50 > 40 µM), as anticipated in this pure protein assay.

Travel-Related Behaviors and Health Outcomes of Adolescents Compared with Adults on Short-Term International Service Missions.

With an increasing number of adolescents participating in international travel, little is known about travel-related behaviors and health risks in this age group. In the years 2015-2016, we conducted an anonymous, posttravel, questionnaire-based survey with the aim to compare self-reported practices and travel-related symptoms between adolescents (< 18 years old, N = 87) and adults (≥ 18 years old, N = 149) who came to our travel clinic before their humanitarian missions. They had the same pretravel health education, and traveled together to perform similar activities. In univariate analysis, compared with adults, we found that adolescents reported less prior international travel (P < 0.001), more often wore long-sleeved clothing for malaria prevention (P < 0.001) but less often for sun protection (P = 0.009), more often used insect repellents (P = 0.011), and less often had diarrhea (P = 0.024). All other practices and health outcomes were similar between the groups. Multivariate analyses using Bayesian network show strong associations between adults and prior travel experience, and not wearing long-sleeve clothing for malaria prevention. We also found strong associations between prior international travel and sustaining an injury, and having jet lag, as well as between taking malaria prophylaxis and not having diarrhea. Overall, most practices and health outcomes were similar between age groups. Adolescent age and lack of prior international travel experience did not have significant impacts on practices and health outcomes. Our findings highlight the need for more effective strategies to improve the behaviors and health outcomes in both adolescents and adults.

Relationship between distance of referring facilities and haemoglobin change in children in Malawi.

BACKGROUND: Anaemia is a significant cause of mortality in children in sub-Saharan Africa where blood transfusion is often available only at referral hospitals. Understanding the pattern of referrals by health facilities is essential to identify the delays that affect child survival. AIM: To determine if there was a correlation between change in haemoglobin (Hb) level and distance from referring facilities to Kamuzu Central Hospital (KCH) in Malawi, and whether distance affected mortality rates. METHODS: This was a retrospective cohort study of 2259 children referred to KCH whose Hb was measured at the referring facility or at KCH. Maps were created using ArcGIS® software. The relationship between distance from KCH and change in Hb was assessed by χ2 analysis and multiple linear regression with SAS© software. RESULTS: The majority of children were referred by health facilities in the Lilongwe District. When categorised as Hb <4, 4-6 or >6 g/dL, 87.0% of children remained in the same category during transfer. There was no significant relationship between Hb drop and distance from KCH. Distance from KCH was not a significant predictor of Hb level at KCH or Hb change. However, mortality rates were significantly higher in facilities that were 10-50 km from KCH than in those which were <10 km away. CONCLUSIONS: Using distance as a proxy for time, this suggests that referring facilities are transferring children sufficiently quickly to avert significant reductions in Hb. Despite this, there is a need to identify the factors that influence the decision to transfer anaemic children.

The sequence of the Mycoplasma arthritidis superantigen, MAM: identification of functional domains and comparison with microbial superantigens and plant lectin mitogens.

Mycoplasma arthritidis, an agent of chronic proliferative arthritis of rodents, secretes a potent soluble superantigen, MAM, that is active for both murine and human T and B lymphocytes. We now report the complete nucleotide and amino acid sequence of MAM and show it to be distinct from other proteins and not closely related phylogenetically to other superantigens. Two functional domains on MAM are identified based on the ability of peptides encompassing these regions to inhibit lymphocyte proliferation by the intact MAM molecule. One of these domains shares short sequences or epitopes with other microbial superantigens. The second domain contains the consensus legume lectin motif-beta, which is important for T cell activation by concanavalin (Con) A. MAM and Con A peptides containing this motif are functionally cross reactive, suggesting a novel secondary pathway for T cell activation by MAM.