Success of the US Veterans Health Administration's Hepatitis C Virus Care Continuum in the Direct-acting Antiviral Era.

BACKGROUND: Estimated hepatitis C prevalence within the Veterans Health Administration is higher than the general population and is a risk factor for advanced liver disease and subsequent complications. We describe the hepatitis C care continuum within the Veterans Health Administration 1 January 2014 to 31 December 2022. METHODS: We included individuals in Veterans Health Administration care 2021-2022 who were eligible for direct-acting antiviral treatment 1 January 2014 to 31 December 2022. We evaluated the proportion of Veterans who progressed through each step of the hepatitis C care continuum, and identified factors associated with initiating direct-acting antivirals, achieving sustained virologic response, and repeat hepatitis C viremia. RESULTS: We identified 133 732 Veterans with hepatitis C viremia. Hepatitis C treatment was initiated in 107 134 (80.1%), with sustained virologic response achieved in 98 136 (91.6%). In those who achieved sustained virologic response, 1097 (1.1%) had repeat viremia and 579 (52.8%) were retreated for hepatitis C. Veterans of younger ages were less likely to initiate treatment and achieve sustained virologic response, and more likely to have repeat viremia. Stimulant use and unstable housing were negatively associated with each step of the hepatitis C care continuum. CONCLUSIONS: The Veterans Health Administration has treated 80% of Veterans with hepatitis C in care 2021-2022 and achieved sustained virologic response in more than 90% of those treated. Repeat viremia is rare and is associated with younger age, unstable housing, opioid use, and stimulant use. Ongoing efforts are needed to reach younger Veterans, and Veterans with unstable housing or substance use disorders.

Feasibility and Acceptability of Home-Delivered Medically Tailored Meals for Treatment of Diabetes in Pregnancy.

BACKGROUND: Diabetes complicates ≤7% of pregnancies in the United States. Although medical nutrition therapy is the mainstay of diabetes treatment, many barriers exist to the successful implementation of dietary modifications. Home-delivered medically tailored meals (MTMs) are promising to overcome such barriers. OBJECTIVE: The objective of this study was to evaluate the feasibility and acceptability of home-delivered MTM in pregnant patients with diabetes. METHODS: We performed a prospective cohort study of home-delivered MTM for pregnant patients with diabetes using a mixed-methods approach. Participants <35 wk of gestation at the time of enrollment received weekly home delivery of diabetes-specific meals. Qualitative semistructured interviews were conducted to gain insight into participants' experience. Diabetes self-efficacy was assessed pre- and postintervention using the Diabetes Self-Efficacy Scale and 2-Item Diabetes Distress Screening Scale. The difference in mean scores was compared using t-tests with P value of <0.05 considered significant. Feasibility and acceptability were evaluated through participants' attitude toward MTM in qualitative interviews and indirectly evaluated through diabetes self-efficacy surveys. RESULTS: Twenty pregnant people with diabetes who received home-delivered MTM during pregnancy were interviewed postpartum. Participants found this program convenient for various reasons, including reduced time for grocery shopping and preparing meals. Participants were satisfied with meals, citing a positive impact on diabetes management, accessibility of healthy foods, reduced stress with meal planning, and greater perceived control of blood glucose. Most participants shared meals with their families or received specific meals for their dependents, which was positively received. Reduced financial and mental stress was also widely reported. Diabetes self-efficacy was significantly improved postintervention with MTM. CONCLUSION: Home-delivered MTM is feasible and acceptable in pregnant patients with diabetes and may improve diabetes self-efficacy. Individual experiences offered insight into various barriers overcome by using this service. Home-delivered MTM may help ensure an accessible, healthy diet for pregnant patients with diabetes.

Strengthening rural community water safety planning in Pacific Island countries: evidence and lessons from Solomon Islands, Vanuatu, and Fiji.

Pacific Island Countries (PICs) collectively have the lowest rates of access to safely managed or basic drinking water and sanitation globally. They are also the least urbanised, have dynamic socioeconomic and increasing climate-linked challenges. Community-based water managers need to respond to variability in water availability and quality caused by a range of hazards. Water Safety Planning (WSP), a widely adopted approach to assessing water supply, offers a risk-based approach to mitigating both existing and future hazards. WSP is adaptable, and making modifications to prescribed WSP to adapt it to the local context is common practice. Within the Pacific Community Water Management Plus research project, we used formative research and co-development processes to understand existing local modifications, whether further modifications are required, and, to develop additional modifications to WSP in Fiji, Vanuatu and Solomon Islands. The types of additional local modifications we recommend reflect the unique context of PICs, including adjusting for community management of water supplies and required collective action, community governance systems, levels of social cohesion in communities, and preferred adult-learning pedagogies. Incorporating modifications that address these factors into future WSP will improve the likelihood of sustained and safe community water services in Pacific and similar contexts.

The Association between Psychosocial Stressors and Gestational Weight Gain: Analysis of the National Pregnancy Risk Assessment Monitoring System (PRAMS) Results from 2012 to 2015.

OBJECTIVE: Both psychosocial stress and gestational weight gain are independently associated with adverse maternal and fetal outcomes. Studies of the association between psychosocial stress and gestational weight gain (GWG) have yielded mixed results. The objective of this study was to evaluate the association between psychosocial stress and GWG in a large population-based cohort. METHODS: Data from the nationally representative Pregnancy Risk Assessment Monitoring System (PRAMS) Phase 7 questionnaire 2012-2015 was utilized. Maternal psychosocial stress was assessed through response to questions designed to examine four domains of psychosocial stress (i.e., traumatic, financial, emotional, partner-related) three months prior to or during pregnancy. GWG was categorized using pre-pregnancy BMI and total GWG into inadequate, adequate, or excessive according to the Institute of Medicine's GWG guidelines. Multinomial logistic regression was used to evaluate the association between psychosocial stressors and adequacy of GWG. Analyses took into account complex survey design. RESULTS: All respondents who delivered ≥ 37 weeks gestation with GWG information available were included in the analysis (n = 119,183). After adjusting for confounders, patients who reported financial stress were more likely to experience excessive versus adequate GWG (RRR 1.09 [95%CI: 1.02-1.17]). Exposure to any of the stressor groups did not significantly increase the risk of inadequate GWG. CONCLUSIONS: This large, population-based study revealed that among pregnant people in the US, exposure to financial stress is associated with higher risk of excessive GWG. Understanding the role stress plays in GWG will help to inform initiatives targeting this important aspect of prenatal care.

Effects of Implementing a Routine Postpartum Fasting Blood Glucose on the Completion of the Gold Standard 2-Hour Oral Glucose Tolerance Test in Gestational Diabetics.

OBJECTIVE: Rates of completion of the gold standard 2-hour oral glucose tolerance test (OGTT) for impaired glucose intolerance postpartum in patients with gestational diabetes mellitus (GDM) are consistently less than 50%. Screening tests performed prior to hospital discharge, including fasting blood glucose (FBG) to detect persistent hyperglycemia, have been investigated. We lack evidence, however, on whether implementation of routine postpartum FBG impacts the likelihood of obtaining the routine 2-hour OGTT. We sought to retrospectively compare the rates of completion of the 2-hour OGTT pre- and postimplementation of a routine FBG screen. STUDY DESIGN: We performed a single-center retrospective cohort study comparing the completion of the 2-hour OGTT pre- and postimplementation of a routine FBG screen. Our primary outcome was the completion of the postpartum OGTT. Bivariate analyses assessed associations between demographic and preinduction clinical characteristics by pre- and post-implementation groups, as well as OGTT completion. Multivariable logistic regression was used to control for possible confounders. A sensitivity analysis was performed to account for the overlap with the coronavirus disease 2019pandemic. RESULTS: In total, 468 patients met the inclusion and exclusion criteria. In our post-intervention group, 64% of patients completed a postpartum FBG. For our primary outcome, completion of the 2-hour OGTT significantly decreased in our postintervention group from 37.1 to 25.9% (p = 0.009), adjusted odds ratio (aOR): 0.62, confidence interval (CI): 0.41-0.92. This difference was no longer statistically significant when excluding patients during the pandemic, from 40.3 to 33.1% (p = 0.228), aOR: 0.76, CI: 0.455-1.27. CONCLUSION: Implementation of a routine FBG was associated with a negative impact on patients completing a 2-hour OGTT. The difference was no longer significant when excluding patients who would have obtained the OGTT during the pandemic, which may have been due to the smaller cohort. Future work should investigate patient perceptions of the FBG and its impact on their decision-making around the OGTT. KEY POINTS: · Screening for postpartum glucose intolerance is imperative for gestational diabetics.. · A fasting blood glucose is recommended as a postpartum screen for hyperglycemia in GDM patients.. · Implementation of an FBG was associated with a decrease in completion of the gold standard OGTT..

There and back again: An evolutionary perspective on long-distance coordination of plant growth and development.

Vascular plants, unlike bryophytes, have a strong root-shoot dichotomy in which the tissue systems are mutually interdependent; roots are completely dependent on shoots for photosynthetic sugars, and shoots are completely dependent on roots for water and mineral nutrients. Long-distance communication between shoot and root is therefore critical for the growth, development and survival of vascular plants, especially with regard to variable environmental conditions. However, this long-distance signalling does not appear an ancestral feature of land plants, and has likely arisen in vascular plants to service the radical alterations in body-plan seen in this taxon. In this review, we examine the defined hormonal root-to-shoot and shoot-to-root signalling pathways that coordinate the growth of vascular plants, with a particular view to understanding how these pathways may have evolved. We highlight the completely divergent roles of isopentenyl-adenine and trans-zeatin cytokinin species in long-distance signalling, and ask whether cytokinin can really be considered as a single class of hormones in the light of recent research. We also discuss the puzzlingly sparse evidence for auxin as a shoot-to-root signal, the evolutionary re-purposing of strigolactones and gibberellins as hormonal signals, and speculate on the possible role of sugars as long-distance signals. We conclude by discussing the 'design principles' of long-distance signalling in vascular plants.

Contemporary Obstetric and Neonatal Outcomes in Sickle Cell Disease: A Retrospective Cohort Study.

OBJECTIVE: Sickle cell disease is associated with adverse perinatal outcomes. Aspects of sickle cell disease in pregnancy, such as health care utilization and neonatal abstinence syndrome, are understudied. We aimed to describe contemporary sickle cell disease outcomes in a U.S. hospital system to improve perinatal counseling. STUDY DESIGN: We conducted a retrospective cohort study of patients with sickle cell disease who delivered at >20 weeks' gestation at two sites within the University of Pennsylvania Health System from May 1, 2017 to August 30, 2020. Descriptive statistics were utilized. RESULTS: Over the study period, 48 patients with sickle cell disease had 52 deliveries of 53 neonates. Sickle cell disease-related morbidity was prevalent prior to pregnancy; 27% had a history of avascular necrosis, and 58% had experienced acute chest syndrome. In the year prior to pregnancy, 52% used daily opioids. During pregnancy, more than half of patients were admitted at least once for sickle cell disease-related complications, spending a median 3 days admitted interquartile range (0-23); >10% spent >70 days of pregnancy admitted. New daily opioids were prescribed during pregnancy for 10% to manage pain crises. Acute chest syndrome was experienced by 23% of patients during pregnancy, and 8% required placement of long-term intravenous access. Preterm delivery <37 weeks occurred in 48%. The primary cesarean rate in nulliparas was 43%. Additionally, 50% experienced a hypertensive disorder of pregnancy, 35% underwent transfusion during delivery admission, and 10% had a perinatal venous thromboembolism. Finally, 53% of neonates were admitted to the intensive care unit. Low birth weight was noted in 34%, severe respiratory distress in 15% of infants, and neonatal abstinence syndrome in 21%. CONCLUSION: Sickle cell disease remains associated with significant perinatal morbidity and need for hospitalization. These data provide contemporary outcomes to target improvements in the care of patients with sickle cell disease. KEY POINTS: · SCD was associated with significant perinatal morbidity and healthcare utilization.. · Most patients with SCD required hospitalization during pregnancy.. · Neonates of patients with SCD experienced preterm birth, NICU admission, and neonatal abstinence syndrome..

Light-sheet microscopy of cleared tissues with isotropic, subcellular resolution.

We present cleared-tissue axially swept light-sheet microscopy (ctASLM), which enables isotropic, subcellular resolution imaging with high optical sectioning capability and a large field of view over a broad range of immersion media. ctASLM can image live, expanded, and both aqueous and non-aqueous chemically cleared tissue preparations. Depending on the optical configuration, ctASLM provides up to 260 nm of axial resolution, a three to tenfold improvement over confocal and other reported cleared-tissue light-sheet microscopes. We imaged millimeter-scale cleared tissues with subcellular three-dimensional resolution, which enabled automated detection of multicellular tissue architectures, individual cells, synaptic spines and rare cell-cell interactions.

Integrated dominance mechanisms regulate reproductive architecture in Arabidopsis thaliana and Brassica napus.

The production of seed in flowering plants is complicated by the need to first invest in reproductive shoots, inflorescences, flowers, and fruit. Furthermore, in many species, it will be months between plants generating flowers and setting seed. How can plants therefore produce an optimal seed-set relative to environmental resources when the "reproductive architecture" that supports seed-set needs to be elaborated so far in advance? Here, we address this question by investigating the spatio-temporal control of reproductive architecture in Arabidopsis (Arabidopsis thaliana) and Brassica napus. We show that resource and resource-related signals such as substrate volume play a key role in determining the scale of reproductive effort, and that this is reflected in the earliest events in reproductive development, which broadly predict the subsequent reproductive effort. We show that a series of negative feedbacks both within and between developmental stages prevent plants from over-committing to early stages of development. These feedbacks create a highly plastic, homeostatic system in which additional organs can be produced in the case of reproductive failure elsewhere in the system. We propose that these feedbacks represent an "integrated dominance" mechanism that allows resource use to be correctly sequenced between developmental stages to optimize seed set.

Reproductive tradeoffs govern sexually dimorphic tubular lysosome induction in Caenorhabditis elegans.

Sex-specific differences in animal behavior commonly reflect unique reproductive interests. In the nematode Caenorhabditis elegans, hermaphrodites can reproduce without a mate and thus prioritize feeding to satisfy the high energetic costs of reproduction. However, males, which must mate to reproduce, sacrifice feeding to prioritize mate-searching behavior. Here, we demonstrate that these behavioral differences influence sexual dimorphism at the organelle level; young males raised on a rich food source show constitutive induction of gut tubular lysosomes, a non-canonical lysosome morphology that forms in the gut of hermaphrodites when food is limited or as animals age. We found that constitutive induction of gut tubular lysosomes in males results from self-imposed dietary restriction through DAF-7/TGFß, which promotes exploratory behavior. In contrast, age-dependent induction of gut tubular lysosomes in hermaphrodites is stimulated by self-fertilization activity. Thus, separate reproductive tradeoffs influence tubular lysosome induction in each sex, potentially supporting different requirements for reproductive success.

The challenge of antibiotic selection in prosthetic joint infections due to Corynebacterium striatum: a case report.

BACKGROUND: Corynebacterium striatum is a gram-positive facultative anaerobe found in the environment and human flora that has historically been considered a contaminant. More recently, Corynebacterium striatum has been implicated in human infections, including respiratory infections, endocarditis, and bone and joint infections, particularly those involving hardware or implanted devices. CASE PRESENTATION: A 65-year-old man presented for washout of his left total knee arthroplasty following a revision 20 days prior. The patient underwent debridement of his left total knee and revision of the left total femur arthroplasty. Daptomycin was initiated empirically due to a previous rash from vancomycin. Operative tissue cultures grew Staphylococcus haemolyticus, Staphylococcus epidermidis and Corynebacterium striatum. Given concern for daptomycin resistance and the reliability of vancomycin susceptibility, daptomycin was discontinued and vancomycin initiated following a graded challenge. Within a few days, the patient developed a diffuse, blanching, erythematous, maculopapular rash and daptomycin was restarted. Over the next 72 h, his rash progressed and he met criteria for drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Daptomycin was stopped and oral linezolid initiated; rash improved. C. striatum returned with susceptibility to gentamicin, linezolid, vancomycin and daptomycin. Due to concern for adverse effects on long-term linezolid, daptomycin was restarted and was tolerated for 20 days, at which point purulent drainage from incision increased. The patient underwent another arthroplasty revision and washout. Operative cultures from this surgery were again positive for C. striatum. Repeat C. striatum susceptibilities revealed resistance to daptomycin but retained susceptibility to linezolid. Daptomycin was again changed to linezolid. He completed six weeks of linezolid followed by linezolid 600 mg daily for suppression and ultimately opted for disarticulation. CONCLUSIONS: C. striatum has historically been regarded as a contaminant, particularly when grown in tissue culture in the setting of prosthetic joint infection. Based on the available literature and susceptibility patterns, the most appropriate first-line therapy is vancomycin or linezolid. Treatment with daptomycin should be avoided, even when isolates appear susceptible, due to the risk of development of high-level resistance (MIC > 256 µg/mL) and clinical failure.

Early intervention for very young children with or at high likelihood for autism spectrum disorder: An overview of reviews.

AIM: To identify which interventions are supported by evidence and the quality of that evidence in very young children with or at high likelihood for autism spectrum disorder (ASD) to improve child outcomes. METHOD: We conducted an overview of reviews to synthesize early intervention literature for very young children with or at high likelihood for ASD. Cochrane guidance on how to perform overviews of reviews was followed. Comprehensive searches of databases were conducted for systematic reviews and meta-analyses between January 2009 and December 2020. Review data were extracted and summarized and methodological quality was assessed. Primary randomized controlled trial evidence was summarized and risk of bias assessed. This overview of reviews was not registered. RESULTS: From 762 records, 78 full texts were reviewed and seven systematic reviews and meta-analyses with 63 unique studies were identified. Several interventional approaches (naturalistic developmental behavioral intervention, and developmental and behavioral interventions) improved child developmental outcomes. Heterogeneity in design, intervention and control group, dose, delivery agent, and measurement approach was noted. Inconsistent methodological quality and potential biases were identified. INTERPRETATION: While many early interventional approaches have an impact on child outcomes, study heterogeneity and quality had an impact on our ability to draw firm conclusions regarding which treatments are most effective. Advances in trial methodology and design, and increasing attention to mitigating measurement bias, will advance the quality of the ASD early intervention evidence base. WHAT THIS PAPER ADDS: Naturalistic developmental behavioral interventions, as well as developmental and behavioral interventions, improve child outcomes in autism spectrum disorder (ASD). If only randomized controlled trials are considered, guidelines for early intensive behavioral intervention in younger children should be revisited. The greatest intervention impacts were on proximal, intervention-specific outcomes. Inadequacies in the quality of the early ASD intervention evidence base were observed.

A Call for Development of Point-of-Care Ultrasound Training Recommendations in Obstetrics and Gynecology Residency.

Point-of-care ultrasound (POCUS) skillsets are now taught throughout training levels from medical school through fellowship given the broad utility in assisting with bedside procedures and triaging clinical presentations for expedited workup. This is reflected in training curricula for emergency medicine, internal medicine, and general surgery residencies. However, these skillsets are not formally taught or required in obstetrics and gynecology residency. We present the opinion that these skillsets and curricula should be developed for obstetrics and gynecology trainees given their exposure to patients with similar clinical presentations in which the clinical management would be aided by POCUS.

Persistent bacteremia and psoas abscess caused by a lethal toxin-deficient Paeniclostridiumsordellii.

We present a case of persistent bacteremia and psoas abscess from Paeniclostridium sordellii without severe symptoms or the classically associated toxic shock syndrome. Further laboratory evaluation demonstrated that the Paeniclostridium sordellii isolate lacked the lethal toxin gene and there was no cytotoxicity to exposed Vero cells.

Wheat plants sense substrate volume and root density to proactively modulate shoot growth.

Plants must carefully coordinate their growth and development with respect to prevailing environmental conditions. To do this, plants can use a range of nutritional and non-nutritional information that allows them to proactively modulate their growth to avoid resource limitations. As is well-known to gardeners and horticulturists alike, substrate volume strongly influences plant growth, and maybe a key source of non-nutritional information for plants. However, the mechanisms by which these substrate volume effects occur remain unclear. Here, we show that wheat plants proactively modulate their shoot growth with respect to substrate volume, independent of nutrient availability. We show that these effects occur in two phases; in the first phase, the dilution of a mobile 'substrate volume-sensing signal' (SVS) allows plants to match their shoot (but not root) growth to the total size of the substrate, irrespective of how much of this they can occupy with their roots. In the second phase, the dilution of a less mobile 'root density-sensing signal' (RDS) allows plants to match root growth to actual rooting volume, with corresponding effects on shoot growth. We show that the effects of soil volume and plant density are largely interchangeable and that plants may use both SVS and RDS to detect their neighbours and to integrate growth responses to both volume and the presence of neighbours. Our work demonstrates the remarkable ability of plants to make proactive decisions about their growth, and has implications for mitigating the effects of dense sowing of crops in agricultural practice.

Long-Term Safety of Rituximab (Risks of Viral and Opportunistic Infections).

PURPOSE OF REVIEW: We reviewed the current data on infections associated with rituximab use published over the last 5 years. RECENT FINDINGS: New literature was available on rates of serious infections, Hepatitis B reactivation and screening, and infection with Severe Acute Respiratory Syndrome Coronavirus 2. Rates of infection varied by study and population, however, higher risk of infection in patients with underlying rheumatologic diseases was seen in those who required a therapy switch, had a smoking history, and those undergoing retreatment who had a serious infection with their first course of therapy. With regards to HBV, the proportion of patients screened continues to be inadequate. Despite the upfront cost, HBV screening and prophylaxis were found to be cost effective. There is still limited data regarding COVID-19 severity in the setting of rituximab, however, rituximab, especially in combination with steroids, may lead to more severe disease and higher mortality.

Risk of Cesarean Delivery for Women with Obesity Using a Standardized Labor Induction Protocol.

OBJECTIVE: We aimed to determine the risk of cesarean among women with obesity undergoing labor induction within a prospective trial that utilized a standardized labor protocol. STUDY DESIGN: This was a secondary analysis of a randomized trial of induction methods. Term (≥37 weeks) women with intact membranes undergoing induction with an unfavorable cervix (Bishop's score ≤6 and dilation ≤2 cm) were included. The trial utilized a labor protocol that standardized induction and active labor management, with recommendations for interventions at particular time points. Only women with a recorded body mass index (BMI) at prenatal care start were included in this analysis. The primary outcome was cesarean delivery compared between obese (≥30 kg/m2) and nonobese (<30 kg/m2) women. Indication for cesarean was also evaluated. RESULTS: A total of 465 women were included: 207 (44.5%) obese and 258 (55.5%) nonobese. Women with obesity had a higher risk of cesarean compared with women without obesity (33.3 vs. 23.3%, p = 0.02), even when adjusting for parity, weight change over pregnancy, and indication for induction (adjusted relative risk [aRR] = 1.79, 95% confidence interval [CI]: [1.34-2.39]). Compared with women without obesity, women with obesity had a higher risk of failed induction (47.8 vs. 26.7%, p = 0.01) without a difference in arrest of active phase (p = 0.39), arrest of descent (p = 0.95) or fetal indication (p = 0.32), despite adherence to a standardized labor protocol. CONCLUSION: Compared with women without obesity, women with obesity undergoing an induction are at increased risk of cesarean, in particular a failed induction, even within the context of standardized induction management. As standardized practices limit provider variation in labor management, this study may support physiologic differences in labor processes secondary to obesity. KEY POINTS: · Even with a standardized induction protocol, women with obesity are at higher risk of cesarean.. · In particular, women with obesity are at increased risk of cesarean for failed induction.. · These findings support a possible biologic relationship between obesity and failed induction..

Adolescent and parent perspectives on the acceptability of financial incentives to promote self-care in adolescents with type 1 diabetes.

BACKGROUND: An understanding of acceptability among potential intervention participants is critical to the design of successful real-world financial incentive (FI) programs. The purpose of this qualitative study was to explore adolescent and parent perspectives on the acceptability of using FI to promote engagement in diabetes self-care in adolescents with type 1 diabetes (T1D). METHODS: Focus groups with 46 adolescents with T1D (12-17 years old) and 39 parents of adolescents with T1D were conducted in the Seattle metropolitan area. Semistructured questions addressed participants' current use of incentives to promote change in diabetes self-care and receptivity to a theoretical incentive program administered by a third-party. Qualitative data were analyzed and emergent themes identified. RESULTS: Three thematic categories informed participant views about the acceptability of FI programs: (a) the extent to which using FIs in the context of diabetes management fit comfortably into a family's value system, (b) the perceived effectiveness for FIs to promote improved diabetes self-care, and (c) the urgent need for improved self-care due to the threat of diabetes-related health complications. These factors together led most parents and adolescents to be open to FI program participation. CONCLUSIONS: The results from this qualitative study suggest that well-designed FI programs to support diabetes management are acceptable to families with adolescents with T1D. Additionally, the use of FIs may have the potential to support adolescents with T1D in developing strong self-care habits and ease the often-turbulent transition to independent self-care.

Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model.

High-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the therapeutic model, intratumorally inhibiting tumor-derived HMGB1 (causing downstream loss of TSLP production) attenuated Treg activation, unleashed tumor-specific CD8 T cell responses, and elicited CD8α+/CD103+DC- and T cell-dependent antitumor activity. These results suggest a new pathway for the activation of Treg involving in tumor-derived HMGB1 and TSLP, and have important implications for incorporating HMGB1 inhibitors into cancer immunotherapy.

Folic Acid Supplementation to Prevent Recurrent Neural Tube Defects: 4 Milligrams Is Too Much.

Some medical practices have been ingrained in custom for decades, long after "proof" that they were effective was established. It is necessary to periodically reevaluate these practices, as newer theories and research may challenge the evidence upon which they were based. An example is the decades' old practice of recommending a 4-mg (4,000-µg) supplement of folic acid to women who are at risk for recurrent neural tube defect (NTD) during pregnancy. This recommendation was based on findings from a randomized clinical trial in 1991. Since then, multiple studies have confirmed the utility of 400-800 µg of folic acid in lowering both primary and recurrent risks of NTDs, but no studies have established any further reduction in risk with doses over 1 mg. Current understanding of folic acid metabolism during pregnancy suggests that at higher doses, above ∼1 mg, there is not increased absorption. Recent evidence suggests that 4 mg folic acid supplementation may not be any more effective than lower doses for the prevention of recurrent NTDs. Thus, we recommend that it is time for clinicians to reexamine their reliance on this outdated recommendation and consider using current recommendations of 400-800 µg per day for all patients in conjunction with assessment of maternal folate status.