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The reality of climate change and biodiversity collapse is irrefutable in the 21st century, with urgent action required not only to conserve threatened species but also to protect human life and wellbeing. This existential threat forces us to recognise that our existence is completely dependent upon well-functioning ecosystems that sustain the diversity of life on our planet, including that required for human health. By synthesising data on the ecology, epidemiology and evolutionary biology of various pathogens, we are gaining a better understanding of factors that underlie disease emergence and spread. However, our knowledge remains rudimentary with limited insight into the complex feedback loops that underlie ecological stability, which are at risk of rapidly unravelling once certain tipping points are breached. In this paper, we consider the impact of climate change and biodiversity collapse on the ever-present risk of infectious disease emergence and spread. We review historical and contemporaneous infectious diseases that have been influenced by human environmental manipulation, including zoonoses and vector- and water-borne diseases, alongside an evaluation of the impact of migration, urbanisation and human density on transmissible diseases. The current lack of urgency in political commitment to address climate change warrants enhanced understanding and action from paediatricians - to ensure that we safeguard the health and wellbeing of children in our care today, as well as those of future generations.

Blueberries have been extensively studied for the health benefits associated with their high phenolic content. The positive impact of blueberry consumption on human health is associated in part with modulation of proinflammatory molecular pathways and oxidative stress. Here, we review in vitro studies examining the anti-inflammatory and antioxidant effects of blueberry phytochemicals, discuss the results in terms of relevance to disease and health, and consider how different blueberry components modulate cellular mechanisms. The dampening effects of blueberry-derived molecules on inflammation and oxidative stress in cell models have been demonstrated through downregulation of the NF-κB pathway and reduction of reactive oxygen species (ROS) and lipid peroxidation. The modulatory effects of blueberry phytochemicals on the mitogen-activated protein kinase (MAPK) pathway and antioxidant system are not as well described, with inconsistent observations reported on immune cells and between models of endothelial, dermal, and ocular inflammation. Although anthocyanins are often reported as being the main bioactive compound in blueberries, no individual phytochemical has emerged as the primary compound when different fractions are compared; rather, an effect of whole blueberry extracts or synergy between different phenolic and nonphenolic extracts seems apparent. The major molecular mechanisms of blueberry phytochemicals are increasingly defined in cell models, but their relevance in more complex human systems needs further investigation using well-controlled clinical trials, in which systemic exposures to blueberry-associated molecules are measured concurrently with physiologic indices of inflammation and oxidative stress.

This study investigated pretreatment variables associated with depression severity in adolescents following maintenance treatment for major depressive disorder (MDD). Data was derived from the Treatment for Adolescents with Depression Study (TADS). Participants received one of three treatments: cognitive behavioral therapy (CBT), fluoxetine (FLX), or combined CBT and fluoxetine (COMB). Participants received 12 weeks of acute treatment, 6 weeks of consolidation treatment, and 18 weeks of maintenance treatment (N = 327, M age = 14.62 yrs). Outcome was measured by the Children’s Depression Rating Scale-Revised. Results showed adolescents with shorter depressive episodes, better global functioning, less suicidal ideation, better health/social functioning, and greater expectancy of positive treatment response were more likely to have lower depression severity following 36 weeks of treatment, regardless of modality. Adolescents with lower initial depression demonstrated lower depression severity if treated with CBT. FLX was more effective in reducing depression severity in adolescents with severe baseline depression than for those with mild or moderate depression. Adolescents with higher family incomes were more likely to have lower depression severity if they received CBT only. In conclusion, adolescents with shorter depressive episodes, better health, social, and global functioning, less suicidal ideation, and greater expectancy for treatment at baseline respond equally well to CBT, fluoxetine, and combined treatment. Adolescents who are more severely depressed at baseline may have a better treatment response if they are treated with FLX; whereas adolescents of higher income are more likely to have a better response if they receive CBT only.

Purpose To quantify the amount of strain across an anterior cruciate ligament reconstruction (ACLR) before and after a lateral meniscus (LM) posterior root complex tear and determine whether a meniscal root repair effectively protects the ACLR against excessive strain. Methods Fresh-frozen cadaveric knees were tested with an 88-N anterior drawer force and an internal and external torque of 5-Nm applied at 0°, 15°, 30°, 60°, and 90° of flexion. A simulated pivot shift was also applied at 0, 15, and 30° of flexion. Rotation and translation of the tibia, and strain across the ACL graft were recorded. Testing was repeated for the following four conditions: ACL-intact, ACLR with intact LM, ACLR with LM posterior root complex tear, and ACLR with root repair. Results The kinematic data from 12 fresh frozen cadaveric knees underwent analysis. Only 11 specimens had usable strain data. Sectioning the meniscofemoral ligaments and the LM posterior root increased rotational and translational laxity at 30° of knee flexion. ACLR graft strain significantly increased when an anterior load and internal torque were applied. Repair of the LM posterior root reduced strain when the knee was internally rotated but was unable to normalize strain when an anterior force was applied. Conclusions This cadaveric biomechanical study suggests injury to the LM posterior root complex increases rotational and anterior laxity of the knee and places increased strain across reconstructed ACL grafts. Subsequent root repair did not result in a statistically significant reduction in strain. Clinical Relevance This study provides quantitative data on the implications of a LM posterior root injury in the setting of an ACL reconstruction to help guide clinical decision-making.

1. John Scheuer, BA* 2. Alice Lehman, MD* 3. Cynthia Howard, MD† 4. Emily Greengard, MD‡ 5. Alexander A. Boucher, MD‡ 1. *Department of Pediatrics, 2. †Department of Pediatrics, Division of Global Pediatrics, and 3. ‡Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Minnesota Medical School, Minneapolis, MN An 11-year-old boy is transferred from a community emergency department to a university hospital with multifocal bone pain and fevers for 2 weeks. The pain sites include his clavicles, forearms, right leg, and chest, and he has been “crying all night” despite daily use of ice and ibuprofen. He also endorses difficulty walking, fatigue, and anorexia. On physical examination he has a temperature of 100°F (37.8°C) and is tachycardic (heart rate, 118 beats/min) but normotensive. He appears ill and distressed. He has mild scleral icterus and nontender mild hepatomegaly. He has palpable tenderness over his reported pain sites. A 1 × 1-cm warm, soft mass is noted over the mid-shaft of his left clavicle. His laboratory results, shown in Table 1, demonstrate leukocytosis (white blood cell count, 17,700/μL [17.7×109/L]), microcytosis (mean corpuscular volume, 75 µm3 [75 fL]), and reticulocytosis (absolute reticulocyte count, 143×103/µL [143×109/L]), along with an elevated C-reactive protein level (106 mg/dL [1,060 mg/L]) and erythrocyte sedimentation rate (36 mm/h). View this table: Table 1. Laboratory Findings in the Patient and Normal Values The patient is admitted to the hospital for further diagnosis and management with fluids, morphine, and empirical ceftriaxone and vancomycin. Blood cultures from admission are negative, but an interferon-gamma release assay is positive. Point-of-care ultrasonography shows a small area of echogenicity overlying the left clavicle. A chest radiograph demonstrates no nodules or opacities in the lungs and no apparent clavicular abnormality. Magnetic resonance imaging (MRI) of the left clavicle confirms the irregularity detected on ultrasonography, described as a 2.3 × 0.6 × 1.7-cm fluid collection anterior to the …

Current declines in terrestrial insect biomass and abundance have raised global concern for the fate of insects and the ecosystem services they provide. However, the ecological and economic contributions of many insects have yet to be quantified. Carrion-specializing invertebrates are important mediators of carrion decomposition; however, the role of their reproductive activities in facilitating this nutrient pulse into ecosystems is poorly understood. Here, we investigate whether insects that sequester carrion belowground for reproduction alter soil biotic and abiotic properties in North American temperate forests. We conducted a field experiment that measured soil conditions in control, surface carrion alone, and beetle-utilized carrion treatments. Our data demonstrate that Nicrophorus beetle reproduction and development results in changes in soil characteristics which are consistent with those observed in surface carrion decomposition alone. Carrion addition treatments increase soil labile C, DON and DOC, while soil pH and microbial C:N ratios decrease. This study demonstrates that the decomposition of carrion drives soil changes but suggests that the behaviors of insect scavengers play an important role in the release of carrion nutrients directly into the soil by sequestering carrion resources in the ecosystem where they were deposited.

Background The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success. Methods FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial. Results The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres. Conclusions FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community. Trial registration ISRCTN Registry ISRCTN01844152. Registered on August 08, 2014

Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

1. Ashley R.B. Bjorklund, MD*,† 2. Tina M. Slusher, MD*,† 3. Abigail Faulman, MD‡ 4. Cynthia R. Howard, MD† 5. Beatrice Odongkara, MBChB§ 1. *Hennepin Healthcare, Minneapolis, MN 2. †University of Minnesota, Minneapolis, MN 3. ‡Children’s Minnesota, Minneapolis, MN 4. §Gulu University/Gulu Regional Referral Hospital, Gulu, Uganda A 12-year-old boy with a history of sickle cell disease (SCD) presents to a government regional referral hospital in Northern Uganda with complaints of feeling ill with fever and a painful lump on his forehead. He also notes pain and swelling of his left upper arm. The fever, forehead lump, and painful swelling of the left arm had been present for at least 2 months. He denies any trauma. On presentation to the hospital he is febrile, tachycardic, and ill appearing. Initial physical examination is remarkable for frontal bossing with multiple tender, fluctuant, round (2- to 3-cm-diameter) lesions over his forehead and scalp; respiratory distress; a prominent systolic murmur; thin limbs; a tender, indurated lesion (approximately 5 × 3 cm) draining purulent fluid on his left upper arm; and no noted focal neurologic deficits. In the emergency department, incision and drainage of the forehead lesion yields scant drainage despite what appears to be a visibly purulent and fluctuant swelling. The fluid obtained is serous and bloody, without overt purulence. There is concern that the lesions may involve more than the subcutaneous tissues, with possible extension to the bone. Laboratory tests show leukocytosis with a neutrophil predominance (white blood cell count, 23,360/μL [23.36×109/L]; neutrophils, 77.5%), thrombocytosis, and anemia (hemoglobin level, 7.7 g/dL [4.78 mmol/L]). Rapid diagnostic testing for malaria is negative. Urine is remarkable for dark coloration without red blood cells on microscopic examination. Cultures from the wound are sent to the laboratory. Radiographs of the cranium (Fig 1) and humerus (Fig 2) are obtained. Figures 1. Radiograph demonstrating lytic lesions of the frontal and parietal bones. Figure 2. Radiograph demonstrating …

The COVID‐19 pandemic provides a pertinent reminder of the imperative to generate timely reliable clinical evidence. Delivery of optimal paediatric care is predicated on the availability of comprehensive, high quality, clinical evidence in a relevant population. However, over 80% of current clinical guidelines and bedside decisions are not based on direct high‐level evidence. Integration of research activities into routine clinical care is paramount to address this shortfall. Active engagement of patients, families and hospital administrations is required to reframe integrated clinical trials as a tenet of quality health‐care delivery. Current research funding in health care is 1–2 orders of magnitude below that of other industries. At an institutional level, investment in research should be prioritised with enhanced funding and supportive policies. Thoughtful integration of trials into routine bedside care will enable pragmatic research outcomes, tangible returns on financial investments and improved decision‐making for patients in the medium‐ to long‐term.

1. Jessica Hane, MD* 2. Cynthia Howard, MD, MPHTM* 3. Kelly Dietz, MD† 4. Stacene R. Maroushek, MD, PhD, MPH‡ 1. *Division of Pediatric Hospital Medicine and 2. †Department of Radiology, Pediatrics Division, and 3. ‡Division of Pediatric Infectious Disease, Hennepin Healthcare and University of Minnesota School of Medicine, Minneapolis, MN An 8-year-old boy presents to the adoption clinic for behavioral concerns and poor growth. The patient was adopted from Ethiopia 2 years before presentation. His medical history is significant for physical abuse and multiple housing transitions, including time spent in an orphanage. The patient does not have any immunization records but was noted to have a borderline Mantoux tuberculin skin test (TST) on arrival in the United States at an outside clinic. His parents are concerned that he has not grown taller since arriving in the United States. The patient has a good appetite and denies any fever, cough, or weight loss. He enjoys competitive running and has won multiple 5-km races. In the clinic, the patient’s weight is 48.7 lb (22.1 kg) (8th percentile on the Centers for Disease Control and Prevention [CDC] growth chart), height is 47.2 in (119.8 cm) (third percentile on the CDC growth chart), BMI is 15.4 (37th percentile on the CDC growth chart), and occipital frontal circumference is 21.3 in (54 cm) (75th percentile on the CDC growth chart). The physical examination reveals a small-for-age but otherwise well-appearing child. His lung fields are clear bilaterally, and no lymphadenopathy is appreciated. His complete blood cell count is normal except for a mildly elevated absolute eosinophil count of 600/μL (0.6 × 109/L). His thyrotropin level is normal (1.61 mIU/L), free thyroxine level is normal (1.23 ng/dL \[15.83 pmol/L]), insulinlike growth factor binding protein 3 level is normal (2,100 ng/mL [275 nmol/L]), insulinlike growth factor 1 level is low normal (63 ng/mL [8.25 nmol/L\] (reference range, 62–349 ng/mL [8.12–45.72 nmol/L]), and 25-hydroxyvitamin D level is low normal (23 ng/mL [57.41 nmol/L]). Results of human immunodeficiency virus 1 and 2 antibody, hepatitis B surface antibody and antigen, hepatitis C antibody, and Treponema pallidum antibody tests are all negative. …

Purpose: A T1D diagnosis can have a profound psychosocial impact on families, and adaptation post diagnosis is critical for long term well-being. This study sought to assess the psychosocial experiences of families during the first year following T1D diagnosis. Method: Focus groups and interviews with children diagnosed with T1D between 8-12 years of age within the past two years (n=10) and parents (n=16) were conducted to explore the feelings, challenges, and experiences of that first year. Transcripts were analyzed using thematic analysis and deductive coding. Results: Children reported fear of needles and concerns about their relationships with peers, family and teachers changing once people knew of their diagnosis. They expressed annoyance with the number of questions asked of them and the intrusion of diabetes tasks in activities. Children and parents experienced feelings of distress, isolation, and sadness during the first year and were overwhelmed by the amount of information they were required to master. Parents expressed distress over keeping their child safe while also managing the emotional burden of diagnosis. Parents reported frustration with their inability to recall the content of their diabetes education and the calculations necessary to maintain “ideal” blood sugars. After receiving formal education, families reported fear and anxiety around managing food and insulin, concern about hyper- and hypoglycemia, feeling overwhelmed by the practical demands, like supply management, and a general lack of support. Most parents felt the need for their child maintain perfect blood sugars and a sense of hopelessness in trying to do so. Conclusions: Prior research has shown that individuals who are overwhelmed, worried, or sleep-deprived find it more difficult to learn new content. Our results suggest the need for an alternate approach to education at diagnosis that provides families with increased psychosocial support in a way that assists families during this first year, a time of learning and change. Disclosure K. P. Garza: None. K. R. Howard: None. N. W. Smith: None. J. Weissberg-benchell: None. M. Feldman: None. Funding JDRF (2-SRA-2020-985-S-B)

Background Childhood trauma is associated with the development of depression during adolescence. Prior research suggests that traumatic experiences may result in differential acute treatment outcomes for depressed adolescents. However, the long-term effects of trauma on treatment response remain unclear. Method Participants (N = 318) with a primary diagnosis of major depressive disorder were randomly assigned to 1 of 3 treatment groups: cognitive-behavioral therapy (CBT), fluoxetine (FLX), or their combination (COMB). All participants received 36 weeks of active treatment followed by 1 year of open follow-up. We hypothesized that (a) adolescents without a trauma history would have greater symptom reduction over the course of treatment compared to those with a trauma history and (b) there would be an interaction between trauma history, treatment arm, and time such that adolescents without trauma histories in combination treatment would improve the most rapidly. Linear mixed effects modeling, factorial ANOVAs, and log-linear analyses were used to test these hypotheses. Results The linear mixed effect model revealed a significant 3-way interaction of time, trauma, and treatment type. In the CBT and COMB groups, adolescents without trauma histories improved more rapidly than traumatized adolescents. In the single-time-point analyses, there were no significant differences between adolescents with trauma histories and those without trauma histories. Conclusions Whereas all treatment groups experienced significant reductions in depression regardless of trauma history, adolescents without trauma histories receiving psychotherapy demonstrated more rapid improvements in depression symptom severity. Treatment response did not differ between traumatized and nontraumatized youth at long-term follow-up. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Because of a focus on science, technology, engineering, and mathematics (STEM), elementary school systems are implementing material that is more complex in nature. However, children with learning d...

This single-blind, pragmatic, cluster randomised controlled trial aims to investigate uptake of children's weight management services in response to enhanced National Child Measurement Programme (NCMP) letters providing weight status feedback to parents in three English counties in 2015. Parents of 2642 overweight or very overweight (obese) children aged 10-11 years received an intervention or control letter informing them of their child's weight status. Intervention letters included (i) a visual tool to help weight status recognition, (ii) a social norms statement, and for very overweight children, (iii) a prepopulated booking form for weight management services. The primary outcome was weight management service enrolment. Additional outcome measures included attendance at and contact made with weight management services, and a number of self-report variables. A small effect was observed, with intervention parents being significantly more likely to enrol their children in weight management services (4.33% of Intervention group) than control parents (2.19% of Control group) in both unadjusted (OR = 2.08, p = .008) and adjusted analyses (AOR = 2.48, p = .001). A similar picture emerged for contact with services (4.80% Intervention vs. 2.41% Control; OR = 2.10, p = .003; AOR = 2.46, p .001) and attendance at services, although group differences in the latter measure were not significant after corrections for multiple comparisons (1.89% Intervention vs. 1.02% Control; AOR = 2.11, p = .047). No effects were found on self-report variables. Theoretically informed weight status feedback letters appear to be an effective strategy to improve enrolment in paediatric weight management services.

1. Rachel Cafferty, MD† 2. Cynthia Howard, MD, MPHTM† 3. Rahul Kaila, MD‡ 1. †Department of Pediatrics, and 2. ‡Department of Pediatric Emergency Medicine, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN After Match Day this month, some senior medical students will be heading off for global health rotations. Some residents and practicing physicians are finalizing plans for summer service-learning trips in countries far from home. Meanwhile, pediatric offices in North America are increasingly seeing recent immigrants who might carry conditions that seem uncommon. To help prepare all readers in all parts of the world, Index of Suspicion highlights cases this month that are particularly relevant to readers interested in global health. Philip R. Fischer, MD Associate Editor, Index of Suspicion A 16-year-old previously healthy girl with recent international emigration with refugee status from Tanzania presents via emergency medical services (EMS) with new-onset seizurelike activity. She had spent the 48 hours immediately before presentation traveling from Tanzania to the United States via Switzerland, with minimal sleep. The EMS was called to the home after the family found the girl lying on the floor covered in vomit with shaking movements of her extremities and eyes rolled back. She is without seizure activity and is not postictal in appearance when EMS arrives. She is noted to have a history of malaria several years earlier (treated and without recurrence), but no other medical problems. She has no personal or family history of seizure disorders, she is not taking medications, and there is no concern for illicit substance abuse, medication ingestion, or precipitating trauma. She has had no recent fever, headache, abdominal pain, vomiting, diarrhea, or other concerns. During transport to the emergency department (ED) she receives a dose of ondansetron. On arrival, her temperature is 98.4°F (36.9°C), respirations are 16 breaths/min, heart rate is …

We report, to our knowledge, the first Australian case of multisystem inflammatory syndrome in adults, a rare but severe systemic inflammatory syndrome occurring 4-6 weeks after COVID-19 infection. Clinicians should be aware of this syndrome in children or adults with shock, mucocutaneous and/or gastrointestinal features, even without prior symptomatic COVID-19 infection.

Background: Hamstring tendons are commonly harvested as autograft for ulnar collateral ligament reconstruction. There is no consensus in the literature whether the hamstring tendon should be harvested from the ipsilateral (drive) leg or contralateral (landing) leg of baseball pitchers undergoing ulnar collateral ligament reconstruction. Hamstring injuries commonly occur in baseball players, but there are no reports on their incidence specifically among Major League Baseball (MLB) pitchers, nor are there reports on whether they occur more commonly in the drive leg or the landing leg. Hypothesis: Hamstring injuries occur more commonly in the landing legs of MLB pitchers. Study Design: Descriptive epidemiology study. Methods: MLB pitchers who sustained hamstring injuries requiring time spent on the disabled list were identified from publicly available sources over 10 seasons. Demographics of the pitchers and injury and return-to-sport data were collected. Hamstring injuries to the drive leg were compared with injuries to the landing leg. Results: Sixty-five pitchers had 78 disabled list stints due to hamstring injuries over 10 seasons. The landing leg was injured in 67.9% of cases, and the most common mechanism of injury was pitching. There were no significant differences in demographics between pitchers who sustained drive leg and landing leg injuries. There was no significant difference in mechanism of injury or time to return to sport between pitchers who sustained drive leg and landing leg injuries. Conclusion: The landing leg is more commonly injured than the drive leg among MLB pitchers who sustain hamstring injuries. There is no difference in time to return to sport between pitchers who sustain drive leg and landing leg injuries. More research is required to determine whether there is a difference in performance or future injury between hamstring tendons harvested from the drive leg and the landing leg for ulnar collateral ligament reconstruction among pitchers.

While acquired chemoresistance is recognized as a key challenge to treating many types of cancer, the dynamics with which drug sensitivity changes after exposure are poorly characterized. Most chemotherapeutic regimens call for repeated dosing at regular intervals, and if drug sensitivity changes on a similar time scale then the treatment interval could be optimized to improve treatment performance. Theoretical work suggests that such optimal schedules exist, but experimental confirmation has been obstructed by the difficulty of deconvolving the simultaneous processes of death, adaptation, and regrowth taking place in cancer cell populations. Here we present a method of optimizing drug schedules in vitro through iterative application of experimentally calibrated models, and demonstrate its ability to characterize dynamic changes in sensitivity to the chemotherapeutic doxorubicin in three breast cancer cell lines subjected to treatment schedules varying in concentration, interval between pulse treatments, and number of sequential pulse treatments. Cell populations are monitored longitudinally through automated imaging for 600–800 hours, and this data is used to calibrate a family of cancer growth models, each consisting of a system of ordinary differential equations, derived from the bi-exponential model which characterizes resistant and sensitive subpopulations. We identify a model incorporating both a period of growth arrest in surviving cells and a delay in the death of chemosensitive cells which outperforms the original bi-exponential growth model in Akaike Information Criterion based model selection, and use the calibrated model to quantify the performance of each drug schedule. We find that the inter-treatment interval is a key variable in determining the performance of sequential dosing schedules and identify an optimal retreatment time for each cell line which extends regrowth time by 40%-239%, demonstrating that the time scale of changes in chemosensitivity following doxorubicin exposure allows optimization of drug scheduling by varying this inter-treatment interval.

1. Judith Kim Eckerle, MD*,† 2. Megan Marie Bresnahan, OTR/L† 3. Maria Kroupina, PhD, LP*,† 4. Dana Ernest Johnson, MD, PhD*,† 5. Cynthia Ruth Howard, MD, MPHTM*,† 1. *Department of Pediatrics, University of Minnesota, Minneapolis, MN 2. †MHealth Fairview University of Minnesota Masonic Children’s Hospital, Minneapolis, MN * Abbreviations: Ab : : antibody ACE : : adverse childhood experience CDC : : Centers for Disease Control and Prevention CXR : : chest radiography IA : : international adoptee TB : : tuberculosis 1. Key information for accurate assessment of the preadoption referral. 2. Determining immunization status and planning catch-up strategy. 3. Updated screening protocol for and treatment of latent tuberculosis infection. 4. Evaluation of developmental delays in the context of international adoption. 5. Screening for risk factors indicating the need for referral to child mental health and developmental specialists. After completing this article, readers should be able to: 1. Review the basic components of an adoption referral file and know when to consult an international adoption medicine expert. 2. Perform the initial medical assessment of a newly arrived international adoptee, including evaluation of the efficacy of previous immunizations and planning of catch-up immunization based on new recommendations. 3. Screen for tuberculosis and treat latent tuberculosis infection based on recent Centers for Disease Control and Prevention (CDC) guidelines. 4. Understand the multiple areas of a developmental baseline of adopted children and assess for catch-up needs. 5. Identify the child with multiple risk factors and/or parental or family stressors who needs a referral to an adoption-competent mental health specialist. Although interest in intercountry adoption continues to be high, the numbers of international adoptions have changed dramatically since the peak in 2004 when 45,483 international adoptees (IAs) were placed in families worldwide. By 2017, the number dropped 79% to 9,387. In the United …

Honey bees exhibit remarkable visual learning capacities, which can be studied using virtual reality (VR) landscapes in laboratory conditions. Existing VR environments for bees are imperfect as they provide either open-loop conditions or 2D displays. Here we achieved a true 3D environment in which walking bees learned to discriminate a rewarded from a punished virtual stimulus based on color differences. We included ventral or frontal background cues, which were also subjected to 3D updating based on the bee movements. We thus studied if and how the presence of such motion cues affected visual discrimination in our VR landscape. Our results showed that the presence of frontal, and to a lesser extent, of ventral background motion cues impaired the bees’ performance. Whenever these cues were suppressed, color discrimination learning became possible. We analyzed the specific contribution of foreground and background cues and discussed the role of attentional interference and differences in stimulus salience in the VR environment to account for these results. Overall, we show how background and target cues may interact at the perceptual level and influence associative learning in bees. In addition, we identify issues that may affect decision-making in VR landscapes, which require specific control by experimenters.

The global disruption of the COVID-19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and treatment of COVID-19 in children, summarising the most up-to-date data including recent developments regarding variants of concern. The acute infection with SARS-CoV-2 is generally mild in children, whilst the post-infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and 'long COVID' in children, are more complex. Given that most research on COVID-19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID-19 in children needs to be prioritised.

Background: Most populations affected by conflict still lack adequate reproductive health (RH) care. This study examined the association between conflict and modern contraceptive use, unmet need, and provision in 30 sub-Saharan African (SSA) countries. Objectives were to compare outcomes in conflict-affected, post-conflict and non-affected countries, and quantify the effect of conflict status on where women sourced their contraception. Methods: We used Demographic and Health Survey datasets to estimate our primary outcome of contraceptive use, within which we examined unmet need and type of contraceptive used. To examine where women accessed care, we categorised health services into public and non-public sectors. We classified countries as non-conflict, conflict-affected, or post-conflict using Uppsala criteria. Bivariate and multivariable logistic regression models were used to examine the association between outcomes and conflict. Findings: Among 344,394 women, unmet need was 53∙9%, 64∙3% and 66∙0% in non-, conflict-affected, and post-conflict settings, respectively. Use of modern contraceptives was 15∙1% overall, highest in non-conflict (21∙3%) and lowest in conflict-affected countries (10∙5%). Women in conflict-affected countries had 2∙35 times higher adjusted odds (95%CI 2∙10-2∙62) of seeking contraceptive services in the non-public sector than women in non-conflict affected countries. Interpretation: Contraceptive prevalence in conflict-affected SSA countries was low with a skew toward short-acting methods in conflict-affected countries. Women in conflict areas were more likely to seek services in the non-public sector. MCPR could potentially be increased through engagement with non-public sector entities, as women are already accessing contraceptive services there. Funding Information: Funding for this work came from MSD, through MSD for Mothers. Declaration of Interests: None declared. Ethics Approval Statement: Informed consent and ethical approval is obtained in every country the DHS is conducted. Ethical approval for this analysis was obtained from the London School of Hygiene and Tropical Medicine ethics committee.

Purpose/objectives During the global pandemic of Covid-19, the hospital setting transitional care management was challenged by the complexities of the rapidly changing health care environment, requiring the implementation of an innovative approach to hospital discharge planning. The purpose of this article is to review the experiences of an integrated urban health system, exploring the strategic tactics to ensure effective communication between team members, patient and family engagement in discharge planning, establishing and maintaining trust, connecting patients to appropriate next level of care services, and providing transitional care management support. Primary practice settings The Covid-19 pandemic response stimulated the rapid transformation of the acute care management model amidst the tremendous challenge of meeting the discharge planning needs of the hospitalized population in one large, urban, integrated health care system. Findings/conclusions Patients transitioning to the community setting following discharge are vulnerable and at risk for adverse sequelae, and transitional care management that does not end when the patient leaves the hospital setting is integral to promoting positive patient outcomes (Naylor, Aiken, Kurtzman, Olds, & Hirschman, 2011). The care management approach during the pandemic in one health care system precipitously shifted to an entirely virtual, remote model, and the team continued to provide transitional care support for hospitalized patients to avoid the common pitfalls that are associated with unfavorable outcomes. Implications for case management practice The insights gleaned from one health system's experiences during the pandemic are transferable to other facets of care management in routine circumstances, with emphasis on the avoidance of the common care management snares that lead to less than optimal patient outcomes. The development and implementation of multifaceted interventions, with the goals of supporting health-promoting behavior changes and self-care capacity for at risk populations, are relevant in the current health care environment.

Objectives In this study, we examined the indirect effects of anxiety on glycated hemoglobin (A1C) via automatic negative thinking and diabetes distress among adolescents with type 1 diabetes (T1D) during the follow-up interval of a randomized controlled trial of an intervention targeting resilience promotion/depression prevention. Methods Adolescents (N=264) participating in the Supporting Teen Problem Solving clinical trial were included and assessed at 8, 12, 16 and 28 months postbaseline. A serial, double-mediation model was used to examine path effects from anxiety to A1C through automatic negative thinking, through diabetes distress and through both automatic negative thinking and diabetes distress. Relevant demographic and clinical covariates were included. Results Anxiety significantly predicted increases in both automatic negative thinking and diabetes distress. Automatic negative thinking was not found to mediate the association between anxiety and A1C, but diabetes distress did mediate the association. The double-mediation path through automatic negative thinking and diabetes distress together was significant. The indirect effect of anxiety on A1C through diabetes distress was significant and greater than the indirect effect of the double-mediator path. Anxiety did not predict A1C independent of its effects on automatic negative thinking and diabetes distress. Inclusion of demographic covariates did not substantively change the results. Conclusions Analyses suggest that automatic negative thinking and diabetes distress mediate the relationship between anxiety and A1C among adolescents with T1D. Diabetes distress appears to be a robust factor linking anxiety to A1C. Diabetes distress should be further examined as a mediator of glycemic variability in anxious youth with T1D.

Background: The safety of higher dose vitamin D (vitD) supplementation in women who change from exclusive or full breastfeeding to combination feeding or who continue supplementation after cessation of breastfeeding is unknown. Objective: Compare vitD supplementation safety of 6,400 to 400 IU/day and 2,400 IU/day using specific laboratory parameters in postpartum women and their infants through 7 months postpartum by feeding type. Design: In this randomized controlled trial, mothers (exclusively breastfeeding or formula-feeding) were randomized at 4–6 weeks' postpartum to 400, 2,400, or 6,400 IU vitD(3) (cholecalciferol)/day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitD(3)/day; infants in 2,400 and 6,400 IU groups received placebo. Maternal safety parameters (serum vitD, 25-hydroxy-vitamin D [25(OH)D; calcidiol], calcium, phosphorus, intact PTH; urinary calcium/creatinine ratios; and feeding type/changes) were measured monthly; infant parameters were measured at months 1, 4, and 7. Sufficiency was defined as 25(OH)D >50 nmol/L. Feeding type was defined as exclusive/full, combination, or formula-feeding. Data were analyzed using SAS 9.4. Results: Four hundred nineteen mother-infant pairs were randomized into the three treatment groups and followed: 346 breastfeeding and 73 formula-feeding pairs. A dose of 6400 IU/day safely and significantly increased maternal vitD and 25(OH)D from baseline in all mothers regardless of feeding type (p

Summary As the SARS-CoV-2 pandemic unfolds across the globe, consistent themes are emerging with regard to aspects of SARS-CoV-2 infection and its associated disease entities in children. Overall, children appear to be less frequently infected by, and affected by, SARS-CoV-2 virus and the clinical disease COVID-19. Large epidemiological studies have revealed children represent less than 2% of the total confirmed COVID-19 cases, of whom the majority experience minimal or mild disease that do not require hospitalisation. Children do not appear to be major drivers of SARS-CoV-2 transmission, with minimal secondary virus transmission demonstrated within families, schools and community settings. There are several postulated theories regarding the relatively low SARS-CoV-2 morbidity and mortality seen in children, which largely relate to differences in immune responses compared to adults, as well as differences in angiotensin converting enzyme 2 distribution that potentially limits viral entry and subsequent inflammation, hypoxia and tissue injury. The recent emergence of a multisystem inflammatory syndrome bearing temporal and serological plausibility for an immune-mediated SARS-CoV-2-related disease entity is currently under investigation. This article summarises the current available data regarding SARS-CoV-2 and the paediatric population, including the spectrum of disease in children, the role of children in virus transmission, and host-virus factors that underpin the unique aspects of SARS-CoV-2 pathogenicity in children.

Berries are a rich source of phytochemicals, especially phenolics well known for protective activity against many chronic diseases. Berries also contain a complex mixture of volatile compounds that are responsible for the unique aromas of berries. However, there is very limited information on the composition and potential health benefits of berry volatiles. In this study, we isolated phenolic and volatile fractions from six common berries and characterized them by HPLC/HPLC-MS and GC/GC-MS, respectively. Berry phenolic and volatile fractions were evaluated for an anti-inflammatory effect using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells by measuring levels of pro-inflammatory cytokines and the nuclear factor-kappa B (NF-&kappa, B) signaling pathway. Results showed that LPS-induced excessive production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and tumor necrosis factor-&alpha, (TNF-&alpha, ), which were inhibited by berry phenolic and volatile extracts. Moreover, berry phenolic and volatile extracts reduced the nuclear translocation of NF-&kappa, B by blocking the phosphorylation of p65 and degradation of I&kappa, B&alpha, These findings showed that berry volatiles from six berries had comparable anti-inflammatory effects to berry phenolics through the suppression of pro-inflammatory mediators and cytokines expression via NF-&kappa, B down-regulation, despite being present in the fruit at a lower concentration.

In the early to mid-twentieth-century United States, prenatal care helped reshape pregnancy by extending medical directives into the everyday life of pregnant women. What began with minimal strategies for a few women at high risk grew into a “lifestyle” for all expecting babies. Maternity manuals helped popularize this process. Studying revisions of a widely circulated and publicly funded manual, Prenatal Care, from the U.S. Children’s Bureau between 1913 and 1983, shows that prenatal-care standards offered women healthy pregnancies on condition that they abandon older ways of understanding pregnancy and become maternity patients. Prenatal Care taught women to take positive steps to enhance outcomes, but a woman’s active role in her own pregnancy was complicated by the fact that the guides made obedience to her doctor her primary responsibility.

Purpose Anatomical agenesis within a population is not well understood, with variations including but not limited to complete absence, unilateral presence, or bilateral presence. Agenesis of human vestigial muscles including the palmaris longus (PL), fibularis tertius (FT), and psoas minor (PM) has been studied; however, the relationship between their presence and absence has not been examined. The purpose of this study is to analyze the prevalence of the PL, FT, and PM muscles, investigate any relationship of prevalence based on sex or race, and investigate any correlation between the presence or absence of each muscle within individual donors. Methods Twenty-three willed body donors were comprehensively dissected by medical students, and the presence or absence of the PL, FT, and PM muscles was recorded. Results The PL was present bilaterally in 87% of donors and absent bilaterally in 13%. The FT was present bilaterally in 96% of donors, and present unilaterally in 4% of donors. There was no evidence of total agenesis of the FT within our sample. The PM was present bilaterally in 39% of donors, and absent bilaterally in 61% of donors. No statistically significant relationship was indicated between muscle presence and the sex or race of the donors. No correlation between the presence or absence of each of the muscles was found. Conclusion In this sample of willed body donors, there was no relationship between muscular agenesis of the vestigial muscles. This suggests that muscle agenesis is a local genetic developmental event at each muscle, and that there is not a single developmental event that leads to agenesis of multiple vestigial muscles. Further understanding of the agenesis of vestigial structures within populations and subpopulations can aid in physician diagnosis and understanding of the anatomical makeup of individuals.

Awareness of the human health benefits of blueberries is underpinned by a growing body of positive scientific evidence from human observational and clinical research, plus mechanistic research using animal and in vitro models. Blueberries contain a large number of phytochemicals, including abundant anthocyanin pigments. Of their various phytochemicals, anthocyanins probably make the greatest impact on blueberry health functionality. Epidemiological studies associate regular, moderate intake of blueberries and/or anthocyanins with reduced risk of cardiovascular disease, death, and type 2 diabetes, and with improved weight maintenance and neuroprotection. These findings are supported by biomarker-based evidence from human clinical studies. Among the more important healthful aspects of blueberries are their anti-inflammatory and antioxidant actions and their beneficial effects on vascular and glucoregulatory function. Blueberry phytochemicals may affect gastrointestinal microflora and contribute to host health. These aspects have implications in degenerative diseases and conditions as well as the aging process. More evidence, and particularly human clinical evidence, is needed to better understand the potential for anthocyanin-rich blueberries to benefit public health. However, it is widely agreed that the regular consumption of tasty, ripe blueberries can be unconditionally recommended.

Berries of Vaccinium meridionale Swartz contain a variety of phytochemicals, which are believed to account for their bioactive properties. The potential of Vaccinium meridionale Swartz pomace as a source of bioactive compounds was investigated. The dietary fiber (DF) content was assessed by the AOAC method, phenolic compounds were characterized and quantified via HPLC-PDA and UPLC-QTOF-MS. The in vitro antibacterial activity was tested against Gram-positive and Gram-negative bacteria. The antioxidant properties were assessed by the ORAC and the ABTS assays. The DF content was 52.4 ± 3.7%, phenolic compounds comprised anthocyanins (ACNs) (747.6 ± 167.5 mg cyanidin-3-glucoside/100 g FW), hydroxycinammic acids (HCAs) (229.2 ± 68.4 mg chlorogenic acid equivalents/100 g FW), flavonols (335.0 ± 139.5 rutin equivalents/100 g FW), and procyanidins (PACs) (140.9 ± 33.3 mg cocoa procyanidin equivalents/100 g FW). Staphylococcus aureus was more sensitive than E. coli. The ORAC value was 250.0 ± 32.0 μmol TE/g fresh weight (FW). Results suggest that the residue from V. meridionale S. can be utilized to obtain valuable nutraceuticals for the development of functional foods., Food science, Food analysis, Phenolic profile, Vaccinium meridionale swartz, Pomace, Phenolics, Procyanidins, Antimicrobial, ORAC, ABTS.

The novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic unprecedented in modern times. Understanding the key features that have enabled this virus to propagate so widely in the global community is critical to current and future clinical and public health efforts. High proportions of mild disease and peak viral loads at, and likely prior to, symptom onset have hindered efforts to identify and isolate infected persons effectively, facilitating undetected spread of the virus. In countries with limited diagnostic and/or contact tracing capabilities, population-wide transmission escalated beyond a critical threshold, challenging even well-developed healthcare systems. This ‘perfect storm’ for transmissibility has led to widespread outbreaks and deaths in many regions around the world. Extensive testing and contact tracing, together with Australia’s geographic advantage, tightening of international travel restrictions, physical distancing and public health messaging measures, have contributed to limiting the extent of coronavirus disease 2019 (COVID-19) spread in the country, but recent case escalation in Victoria highlights the country’s vulnerability to future outbreaks due to low population immunity.

Tart cherries have been reported to exert potential health benefits attributed to their specific and abundant polyphenol content. However, there is a need to study the impact and fate of tart cherries polyphenols in the gut microbiota. Here, tart cherries, pure polyphenols (and apricots) were submitted to in vitro bacterial fermentation assays and assessed through 16S rRNA gene sequence sequencing and metabolomics. A short-term (5 days, 8 oz. daily) human dietary intervention study was also conducted for microbiota analyses. Tart cherry concentrate juices were found to contain expected abundances of anthocyanins (cyanidin-glycosylrutinoside) and flavonoids (quercetin-rutinoside) and high amounts of chlorogenic and neochlorogenic acids. Targeted metabolomics confirmed that gut microbes were able to degrade those polyphenols mainly to 4-hydroxyphenylpropionic acids and to lower amounts of epicatechin and 4-hydroxybenzoic acids. Tart cherries were found to induce a large increase of Bacteroides in vitro, likely due to the input of polysaccharides, but prebiotic effect was also suggested by Bifidobacterium increase from chlorogenic acid. In the human study, two distinct and inverse responses to tart cherry consumption were associated with initial levels of Bacteroides. High-Bacteroides individuals responded with a decrease in Bacteroides and Bifidobacterium, and an increase of Lachnospiraceae, Ruminococcus and Collinsella. Low-Bacteroides individuals responded with an increase in Bacteroides or Prevotella and Bifidobacterium, and a decrease of Lachnospiraceae, Ruminococcus and Collinsella. These data confirm that gut microbiota metabolism, in particular the potential existence of different metabotypes, needs to be considered in studies attempting to link tart cherries consumption and health.

IKZF1 (IKAROS) is essential for normal lymphopoiesis in both humans and mice. Previous Ikzf1 mouse models have demonstrated the dual role for IKZF1 in both B and T cell development and have indicated differential requirements of each zinc finger. Furthermore, mutations in IKZF1 are known to cause common variable immunodeficiency in patients characterized by a loss of B cells and reduced Ab production. Through N-ethyl-N-nitrosourea mutagenesis, we have discovered a novel Ikzf1 mutant mouse with a missense mutation (L132P) in zinc finger 1 (ZF1) located in the DNA binding domain. Unlike other previously reported murine Ikzf1 mutations, this L132P point mutation (Ikzf1L132P) conserves overall protein expression and has a B cell–specific phenotype with no effect on T cell development, indicating that ZF1 is not required for T cells. Mice have reduced Ab responses to immunization and show a progressive loss of serum Igs compared with wild-type littermates. IKZF1L132P overexpressed in NIH3T3 or HEK293T cells failed to localize to pericentromeric heterochromatin and bind target DNA sequences. Coexpression of wild-type and mutant IKZF1, however, allows for localization to pericentromeric heterochromatin and binding to DNA indicating a haploinsufficient mechanism of action for IKZF1L132P. Furthermore, Ikzf1+/L132P mice have late onset defective Ig production, similar to what is observed in common variable immunodeficiency patients. RNA sequencing revealed a total loss of Hsf1 expression in follicular B cells, suggesting a possible functional link for the humoral immune response defects observed in Ikzf1L132P/L132P mice.