Understanding Research Methods: Up-and-down Designs for Dose-finding.

SUMMARY: For the task of estimating a target benchmark dose such as the ED50 (the dose that would be effective for half the population), an adaptive dose-finding design is more effective than the standard approach of treating equal numbers of patients at a set of equally spaced doses. Up-and-down is the most popular family of dose-finding designs and is in common use in anesthesiology. Despite its widespread use, many aspects of up-and-down are not well known, implementation is often misguided, and standard, up-to-date reference material about the design is very limited. This article provides an overview of up-and-down properties, recent methodologic developments, and practical recommendations, illustrated with the help of simulated examples. Additional reference material is offered in the Supplemental Digital Content.

Covasim: An agent-based model of COVID-19 dynamics and interventions.

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.

Feasibility of Family-Assisted Severity of Illness Monitoring for Hospitalized Children in Low-Income Settings.

OBJECTIVES: To determine the feasibility of having caregivers assist in recognition of clinical deterioration in children hospitalized with febrile illness in a resource-limited setting. DESIGN: Single-center, prospective, interventional pilot study. SETTING: General pediatric wards at Kenyatta National Hospital, Nairobi, Kenya's largest public tertiary-care hospital. PATIENTS: Children hospitalized with acute febrile illness, accompanied by caregivers available at the bedside for 24 hours soon after hospital admission. INTERVENTIONS: Caregivers were trained to recognize signs of critical illness using the Family-Assisted Severe Febrile Illness Therapy tool, which quantifies patients' work of breathing, mental status, and perfusion, producing color-coded flags to signal illness severity. Caregivers' Family-Assisted Severe Febrile Illness Therapy assessments were compared with healthcare professional assessments and to established Pediatric Early Warning Scores (PEWS). An initial study stage was followed by refinement of training and a larger second stage with intervention/control arms. MEASUREMENTS AND MAIN RESULTS: A total of 107 patient/caregiver pairs were enrolled in the interventional arm; 106 caregivers underwent Family-Assisted Severe Febrile Illness Therapy training and were included in the analysis. Patient characteristics included median age 1.1 years (0.2-10 yr), 55 (52%) female, and diagnoses: pneumonia (64 [60%]), meningitis (38 [36%]), gastroenteritis (24 [23%]), and malaria (21 [20%]). Most caregivers had primary (34 [32%]) or secondary (53 [50%]) school education. Fourteen of 106 patients (13%) died during their stay, six within 2 days. Across all severity levels, caregiver Family-Assisted Severe Febrile Illness Therapy assessments matched professionals in 87% and 94% for stages 1 and 2, respectively. Caregiver Family-Assisted Severe Febrile Illness Therapy assessments had a moderate to strong correlation with coinciding Pediatric Early Warning Scores and were sensitive to life-threatening deterioration: for all six patients who died within 2 days of admission, caregiver assessment reached the highest alert level. CONCLUSIONS: Caregiver involvement in recognition of critical illness in hospitalized children in low-resource settings may be feasible. This may facilitate earlier detection of clinical deterioration where staffing is severely limited by constrained resources. Further validation of the Family-Assisted Severe Febrile Illness Therapy tool is warranted, followed by its application in a larger multisite patient population to assess provider response and associated clinical outcomes.

Patterns of child mortality in rural area of Burkina Faso: evidence from the Nanoro health and demographic surveillance system (HDSS).

BACKGROUND: Half of global child deaths occur in sub-Saharan Africa. Understanding child mortality patterns and risk factors will help inform interventions to reduce this heavy toll. The Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso was described previously, but patterns and potential drivers of heterogeneity in child mortality in the district had not been studied. Similar studies in other districts indicated proximity to health facilities as a risk factor, usually without distinction between facility types. METHODS: Using Nanoro HDSS data from 2009 to 2013, we estimated the association between under-5 mortality and proximity to inpatient and outpatient health facilities, seasonality of death, age group, and standard demographic risk factors. RESULTS: Living in homes 40-60 min and > 60 min travel time from an inpatient facility was associated with 1.52 (95% CI: 1.13-2.06) and 1.74 (95% CI: 1.27-2.40) greater hazard of under-5 mortality, respectively, than living in homes < 20 min from an inpatient facility. No such association was found for outpatient facilities. The wet season (July-November) was associated with 1.28 (95% CI: 1.07, 1.53) higher under-5 mortality than the dry season (December-June), likely reflecting the malaria season. CONCLUSIONS: Our results emphasize the importance of geographical proximity to health care, distinguish between inpatient and outpatient facilities, and also show a seasonal effect, probably driven by malaria.

Caring for Africa's sickle cell children: will we rise to the challenge?

BACKGROUND: Most of the world's sickle cell disease (SCD) burden is in Africa, where it is a major contributor to child morbidity and mortality. Despite the low cost of many preventive SCD interventions, insufficient resources have been allocated, and progress in alleviating the SCD burden has lagged behind other public-health efforts in Africa. The recent announcement of massive new funding for research into curative SCD therapies is encouraging in the long term, but over the next few decades, it is unlikely to help Africa's SCD children substantially. MAIN DISCUSSION: A major barrier to progress has been the absence of large-scale early-life screening. Most SCD deaths in Africa probably occur before cases are even diagnosed. In the last few years, novel inexpensive SCD point-of-care test kits have become widely available and have been deployed successfully in African field settings. These kits could potentially enable universal early SCD screening. Other recent developments are the expansion of the pneumococcal conjugate vaccine towards near-universal coverage, and the demonstrated safety, efficacy, and increasing availability and affordability of hydroxyurea across the continent. Most elements of standard healthcare for SCD children that are already proven to work in the West, could and should now be implemented at scale in Africa. National and continental SCD research and care networks in Africa have also made substantial progress, assembling care guidelines and enabling the deployment and scale-up of SCD public-health systems. Substantial logistical, cultural, and awareness barriers remain, but with sufficient financial and political will, similar barriers have already been overcome in efforts to control other diseases in Africa. CONCLUSION AND RECOMMENDATIONS: Despite remaining challenges, several high-SCD-burden African countries have the political will and infrastructure for the rapid implementation and scale-up of comprehensive SCD childcare programs. A globally funded effort starting with these countries and expanding elsewhere in Africa and to other high-burden countries, including India, could transform the lives of SCD children worldwide and help countries to attain their Sustainable Development Goals. This endeavor would also require ongoing research focused on the unique needs and challenges of SCD patients, and children in particular, in regions of high prevalence.

Factors Associated with Health-Related Quality of Life in Children with Intestinal Failure.

OBJECTIVE: To evaluate disease-specific and age-related factors contributing to health-related quality of life (HRQOL). in children with intestinal failure. STUDY DESIGN: A prospective study of HRQOL was performed in a regional intestinal rehabilitation program. Parent-proxy Pediatric Quality of Life Inventory surveys were administered annually to families of 91 children with intestinal failure over a 6-year period. Survey data was stratified by age and compared with pediatric HRQOL data in healthy and chronically ill populations. Linear mixed-effect models using multivariable regression were constructed to identify associations with HRQOL. RESULTS: A total of 180 surveys were completed by 91 children and their families. HRQOL scores were lowest for children ages 5-7 years (P < .001) and 8-12 years (P < .01), and these changes were primarily related to school dimension scores. In multivariable regression, age of 5 years and older and developmental delay were independently associated with lower HRQOL scores. The trend toward lower HRQOL scores parallels reference data from healthy and chronically ill children, although patients with intestinal failure scored lower than both populations at school age. CONCLUSIONS: Children with intestinal failure experience lower parent-proxy HRQOL scores in the 5-7 and 8-12 year age groups primarily related to school dimension scores. Multicenter data to validate these findings and identify interventions to improve QOL for children with intestinal failure are needed.

Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults.

Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 106 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease-negative (MRD-) remission rate for this phase 1 study was 89%. The MRD- remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.

Attitudes Surrounding the Management of Neonates with Severe Necrotizing Enterocolitis.

OBJECTIVES: To assess providers' recommendations as to comfort care versus medical and surgical management in clinical scenarios of newborns with severe bowel loss and to assess how a variety of factors influence providers' decision making. STUDY DESIGN: We conducted a survey of pediatric surgeons and neonatologists via the American Pediatric Surgical Association and American Academy of Pediatrics Section of Neonatal-Perinatal Medicine. We examined how respondents' recommendations were affected by a variety of patient and provider factors. RESULTS: There were 288 neonatologists and 316 pediatric surgeons who responded. Irrespective of remaining bowel length, comfort care was recommended by 73% of providers for a premature infant with necrotizing enterocolitis and 54% for a full-term infant with midgut volvulus. The presence of comorbidities and earlier gestational age increased the proportion of providers recommending comfort care. Neonatologists were more likely to recommend comfort care than surgeons across all scenarios (OR, 1.45-2.00; P < .05), and this difference was more pronounced with infants born closer to term. In making these recommendations, neonatologists placed more importance on neurodevelopmental outcomes (P < .001), and surgeons emphasized experience with long-term quality of life (P < .001). CONCLUSION: Despite a contemporary survival of >90% in infants with intestinal failure, a majority of providers still recommend comfort care in infants with massive bowel loss. Significant differences were identified in clinical decision making between surgeons and neonatologists. These data reinforce the need for targeted education on long-term outcomes in intestinal failure to neonatal and surgical providers.

Comparison of Aberrant Behavior Checklist profiles across Prader-Willi syndrome, Down syndrome, and autism spectrum disorder.

Prader-Willi syndrome (PWS, OMIM # 176270) and Down syndrome (DS, OMIM #190685) are neurodevelopmental genetic disorders with higher rates of autism spectrum disorder (ASD). The Aberrant Behavior Checklist (ABC) is a caregiver rating scale that assesses maladaptive behaviors. Overlapping symptoms exist between PWS, DS, and ASD, including maladaptive behaviors. We aimed to evaluate ABC profiles between PWS, DS, and ASD alone (without known genetic syndrome). In addition, we hypothesized PWS and DS with a comorbid ASD positive screen or diagnosis would have similar ABC profiles to ASD alone. ABC data from the following cohorts were analyzed: PWS (Seattle Children's Hospital, n = 28, mean age = 12.8 ± 4.9 years; University of Florida, n = 35, mean age = 9.3 ± 7.1 years), DS (Johns Hopkins, n = 406, mean age = 8.1 ± 2.4 years), and ASD (University of Florida, n = 102, mean age = 10.8 ± 3.5 years). ASD alone had significantly higher ABC scores. Subgroups of PWS and DS with a comorbid ASD positive screen or diagnosis had similarities in scores with the ASD only group, with subscale patterns unique to each syndrome. The ABC indicated worse maladaptive behaviors in children with ASD, including those with genetic syndromes. Although more studies are needed to evaluate the utility and the accuracy of the ABC as a tool to screen for ASD in special populations, it may be a useful adjunct in screening those children with PWS or DS who need more in depth ASD evaluation.

Association of ambient pollution with inhaler use among patients with COPD: a panel study.

BACKGROUND: Studies have linked ambient air pollution to chronic obstructive pulmonary disease (COPD) healthcare encounters. However, the association between air quality and rescue medication use is unknown. OBJECTIVES: We assessed the role of air pollution exposure for increased short-acting beta-2-agonist (SABA) use in patients with COPD through use of remote monitoring technology. METHODS: Participants received a portable electronic inhaler sensor to record the date, time and location for SABA use over a 3-month period. Ambient air pollution data and meteorological data were collected from a centrally located federal monitoring station. Mixed-effects Poisson regression was used to examine the association of daily inhaler use with pollutant levels. Four criteria pollutants (PM2.5, PM10, O3 and NO2), two particulate matter species (elemental carbon (EC) and organic carbon), estimated coarse fraction of PM10 (PM10-2.5) and four multipollutant air quality measures were each examined separately, adjusting for covariates that passed a false discovery rate (FDR) screening. RESULTS: We enrolled 35 patients with COPD (94.3% male and mean age: 66.5±8.5) with a mean forced expiratory volume in 1 s (FEV1) % predicted of 44.9+17.2. Participants had a median of 92 observation days (range 52-109). Participants' average SABA inhaler use ranged from 0.4 to 13.1 puffs/day (median 2.8). Controlling for supplemental oxygen use, long-acting anticholinergic use, modified Medical Research Council Dyspnoea Scale and influenza season, an IQR increase in PM10 concentration (8.0 µg/m3) was associated with a 6.6% increase in daily puffs (95% CI 3.5% to 9.9%; FDR <0.001). NO2 and EC concentration were also significantly associated with inhaler use (3.9% and 2.9% per IQR increase, respectively). CONCLUSIONS: Exposure to increased ambient air pollution were associated with a significant increase in SABA use for patients with COPD residing in a low-pollution area.

Using dynamic treatment regimes to understand erythropoietin-stimulating agent hyporesponsiveness.

BACKGROUND: Erythropoietin-stimulating agent hyporesponsiveness (ESAH) is associated with increased cardiovascular mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Dynamic treatment regimes (DTR), a clinical decision support (CDS) tool that guides the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic illnesses that require frequent monitoring and therapy changes. Our objective is to explore the role of utilizing a DTR to reduce ESAH in pediatric hemodialysis patients. METHODS: Retrospective analysis of ESRD patients on hemodialysis who received ESAs. Dosing was adjusted using a locally developed protocol designed to target a hemoglobin between 10 and 12 g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hyporesponse index (ESA dose/hemoglobin value) changed due to varying levels of adherence. RESULTS: Eighteen patients met study criteria. Median hemoglobin was 11.4 g/dl (range 6.1-15.4), and median weekly ESA dose (darbepoetin-equivalent) was 0.4 mcg/kg/dose (range 0-2.1). Full adherence to the DTR was identified in 266 (71%) of the 4-week periods, with a median average adherence score of 0.80 (range 0.63-0.91). As adherence to the DTR improved, ESAH decreased. During the last 12 weeks, 13 out of 18 patients had lower average ESA/hemoglobin ratio than the first 12 weeks. CONCLUSIONS: A DTR appears to be well-suited to the treatment of anemia in ESRD and reduces ESAH. Our work shows the potential of DTRs to drive the development and evaluation of clinical practice guidelines.

Comparison of Transplant Waitlist Outcomes for Pediatric Candidates Supported by Ventricular Assist Devices Versus Medical Therapy.

OBJECTIVES: Ventricular assist devices have gained popularity in the management of refractory heart failure in children listed for heart transplantation. Our primary aim was to compare the composite endpoint of all-cause pretransplant mortality and loss of transplant eligibility in children who were treated with a ventricular assist device versus a medically managed cohort. DESIGN: This was a retrospective cohort analysis. SETTINGS: Data were obtained from the Scientific Registry of Transplant Recipients. PATIENTS: The at-risk population (n = 1,380) was less than 18 years old, either on a ventricular assist device (605 cases) or an equivalent-severity, intensively medically treated group (referred to as MED, 775 cases). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The impact of ventricular assist devices was estimated via Cox proportional hazards regression (hazard ratio), dichotomizing 1-year outcomes to "poor" (22%: 193 deaths, 114 too sick) versus all others (940 successful transplants, 41 too healthy, 90 censored), while adjusting for conventional risk factors. Among children 0-12 months old, ventricular assist device was associated with a higher risk of poor outcomes (hazard ratio, 2.1; 95% CI, 1.5-3.0; p < 0.001). By contrast, ventricular assist device was associated with improved outcomes for ages 12-18 (hazard ratio, 0.3; 95% CI, 0.1-0.7; p = 0.003). For candidates 1-5 and 6-11 years old, there were no differences in outcomes between the ventricular assist device and MED groups (hazard ratio, 0.8 and 1.0, p = 0.43 and 0.9). The interaction between ventricular assist devices and age group was strongly significant (p < 0.001). CONCLUSIONS: This is a comparative study of ventricular assist devices versus medical therapy in children. Age is a significant modulator of waitlist outcomes for children with end-stage heart failure supported by ventricular assist device, with the impact of ventricular assist devices being more beneficial in adolescents.

Precision, Sensitivity and Patient Preference of Non-Invasive Thermometers in a Pediatric Surgical Acute Care Setting.

PURPOSE: The purpose of the project was to compare the temporal artery thermometer (TAT) to the digital probe thermometer readings at axillary or oral sites, to determine the relative precision and sensitivity of the three methods of thermometry, to compare their readings to core temperature when feasible, and to survey patient and family thermometer preferences. DESIGN & METHODS: A randomized crossover design in a 70-bed surgical unit over eight months. Two sets of temperature measurements were obtained for each patient: TAT, axillary, oral (depending on patient ability) and a bladder temperature representing core body temperature (when available). Each method was used twice on each patient, to examine within-method precision. Following measurement, patients or caregivers provided their thermometer preference. For younger/nonverbal patients, a professional observer recorded a disruption score. N=298 patients were enrolled RESULTS: TAT was more precise than oral and axillary thermometers (p<0.001 vs. axillary, p=0.001 vs. oral). TAT measurements were higher on average than axillary and oral, by 0.7°C and 0.6°C respectively (p<0.001). TAT's disruption score for younger patients was 0.6 points lower on average than axillary (p<0.001). 84% of patients and families who indicated a clear thermometry preference chose TAT. Only 3 patients had bladder-temperature devices, and therefore accuracy could not be analyzed. CONCLUSIONS: TAT is more precise, more fever sensitive, less disruptive to younger children, and more preferred by patients and families. PRACTICE IMPLICATIONS: TAT is an acceptable temperature measure that could be substituted for oral or axillary temperature in acute care pediatric settings.

Neurodevelopmental and Cognitive Outcomes in Children With Intestinal Failure.

OBJECTIVES: Recent advances in medical and surgical management have led to improved long-term survival in children with intestinal failure. Yet, limited data exist on their neurodevelopmental and cognitive outcomes. The aim of the present study was to measure neurodevelopmental outcomes in children with intestinal failure. METHODS: Children enrolled in a regional intestinal failure program underwent prospective neurodevelopmental and psychometric evaluation using a validated scoring tool. Cognitive impairment was defined as a mental developmental index <70. Neurodevelopmental impairment was defined as cerebral palsy, visual or hearing impairment, or cognitive impairment. Univariate analyses were performed using the Wilcoxon rank-sum test. Data are presented as median (range). RESULTS: Fifteen children with a remnant bowel length of 18 (5-85) cm were studied at age 17 (12-67) months. Thirteen patients remained dependent on parenteral nutrition. Twelve (80%) subjects scored within the normal range on cognitive testing. Each child with cognitive impairment was noted to have additional risk factors independent of intestinal failure including cardiac arrest and extreme prematurity. On univariate analysis, cognitive impairment was associated with longer inpatient hospital stays, increased number of surgical procedures, and prematurity (P < 0.02). In total, 4 (27%) children demonstrated findings consistent with neurodevelopmental impairment. CONCLUSIONS: A majority of children with intestinal failure demonstrated normal neurodevelopmental and cognitive outcomes on psychometric testing. These data suggest that children with intestinal failure without significant comorbidity may be at low risk for long-term neurodevelopmental impairment.

Neighborhood-Scale Spatial Models of Diesel Exhaust Concentration Profile Using 1-Nitropyrene and Other Nitroarenes.

With emerging evidence that diesel exhaust exposure poses distinct risks to human health, the need for fine-scale models of diesel exhaust pollutants is growing. We modeled the spatial distribution of several nitrated polycyclic aromatic hydrocarbons (NPAHs) to identify fine-scale gradients in diesel exhaust pollution in two Seattle, WA neighborhoods. Our modeling approach fused land-use regression, meteorological dispersion modeling, and pollutant monitoring from both fixed and mobile platforms. We applied these modeling techniques to concentrations of 1-nitropyrene (1-NP), a highly specific diesel exhaust marker, at the neighborhood scale. We developed models of two additional nitroarenes present in secondary organic aerosol: 2-nitropyrene and 2-nitrofluoranthene. Summer predictors of 1-NP, including distance to railroad, truck emissions, and mobile black carbon measurements, showed a greater specificity to diesel sources than predictors of other NPAHs. Winter sampling results did not yield stable models, likely due to regional mixing of pollutants in turbulent weather conditions. The model of summer 1-NP had an R(2) of 0.87 and cross-validated R(2) of 0.73. The synthesis of high-density sampling and hybrid modeling was successful in predicting diesel exhaust pollution at a very fine scale and identifying clear gradients in NPAH concentrations within urban neighborhoods.

Pediatric infection and intestinal carriage due to extended-spectrum-cephalosporin-resistant Enterobacteriaceae.

The objective of this study is to describe the epidemiology of intestinal carriage with extended-spectrum-cephalosporin-resistant Enterobacteriaceae in children with index infections with these organisms. Patients with resistant Escherichia coli or Klebsiella bacteria isolated from the urine or a normally sterile site between January 2006 and December 2010 were included in this study. Available infection and stool isolates underwent phenotypic and molecular characterization. Clinical data relevant to the infections were collected and analyzed. Overall, 105 patients were identified with 106 extended-spectrum-cephalosporin-resistant E. coli (n = 92) or Klebsiella (n = 14) strains isolated from urine or a sterile site. Among the 27 patients who also had stool screening for resistant Enterobacteriaceae, 17 (63%) had intestinal carriage lasting a median of 199 days (range, 62 to 1,576). There were no significant differences in demographic, clinical, and microbiological variables between those with and those without intestinal carriage. Eighteen (17%) patients had 37 subsequent resistant Enterobacteriaceae infections identified: 31 urine and 6 blood. In a multivariable analysis, antibiotic intake in the 91 days prior to subsequent urine culture was significantly associated with subsequent urinary tract infection with a resistant organism (hazard ratio, 14.3; 95% confidence interval [CI], 1.6 to 130.6). Intestinal carriage and reinfection were most commonly due to bacterial strains of the same sequence type and with the same resistance determinants as the index extended-spectrum-cephalosporin-resistant Enterobacteriaceae, but carriage and reinfection with different resistant Enterobacteriaceae strains also occurred.

Small-sample behavior of novel phase I cancer trial designs.

BACKGROUND: Novel dose-finding designs for Phase I cancer clinical trials, using estimation to assign the best estimated Maximum Tolerated Dose (MTD) at each point in the experiment, most prominently via Bayesian techniques, have been widely discussed and promoted since 1990. PURPOSE: To examine the small-sample behavior of these 'Bayesian Phase I' designs, and also of non-Bayesian designs sharing the same main 'Long-Memory' traits of using likelihood estimation and assigning the estimated MTD to the next patient. METHODS: Data from several recently published experiments are presented and discussed, and Long-Memory designs' operating principles are explained. Simulation studies compare the small-sample behavior of Long-Memory designs with short-memory 'Up-and-Down' designs. RESULTS: In simulation, Long-Memory and Up-and-Down designs achieved similar success rates in finding the MTD. However, for all Long-Memory designs examined, the number n (*) of cohorts treated at the true MTD was highly variable between simulated experiments drawn from the same toxicity-threshold distribution. Further investigation using the same set of thresholds in permuted order indicates that this Long-Memory behavior is driven by sensitivity to the order in which participants enter the experiment. This sensitivity is related to Long-Memory designs' 'winner-takes-all' dose-assignment rule, which grants the early cohorts a disproportionately large influence, and causes many experiments to settle early on a specific dose. Additionally for the Bayesian Long-Memory designs, the prior-predictive distribution over the dose levels has a substantial impact upon MTD-finding performance, long into the experiment. LIMITATIONS: While the numerical evidence for Long-Memory designs' order sensitivity is broad, and plausible explanations for it are provided, we do not present a theoretical proof of the phenomenon. CONCLUSIONS: Method developers, analysts, and practitioners should be aware of Long-Memory designs' order sensitivity and related phenomena. In particular, they should be informed that settling on a single dose does not guarantee that this dose is the MTD. Presently, Up-and-Down designs offer a simpler and more robust alternative for the sample sizes of 10-40 patients used in most Phase I trials. Future designs might benefit from combining the two approaches. We also suggest that the field's paradigm change from dose-selection to dose-estimation.

Effect of reduced two-dose (1+1) schedule of 10 and 13-valent pneumococcal conjugate vaccines (SynflorixTM and Prevenar13TM)) on nasopharyngeal carriage and serotype-specific immune response in the first two years of life: Results from an open-labelled randomized controlled trial in Indian children.

INTRODUCTION: This study aimed to assess the effect of a reduced dose regime (1 + 1) of PCV10 and PCV13 along with 3-dose regimes on pneumococcal vaccine-type (VT) carriage and immunogenicity in the first two years of life in PCV-naïve Indian children. METHODS: A total of 805 healthy infants aged 6-8 weeks were randomised to 7 groups (n = 115). Six groups received SynflorixTM(PCV10) or Prevenar13TM(PCV13) in the following schedules: 3 + 0 (three primary at 6, 10, and 14 weeks); 2 + 1 (two primary 6 and 14 weeks with booster at 9 months; 1 + 1 (one primary at 14 weeks with booster at 9 months). The 7th group was a PCV-naïve control group. Nasopharyngeal swabs were collected at 6, 18 weeks, 9, 10, 15, and 18 months of age. Venous blood samples were collected at 18 weeks, 9, 10, and 18 months of age for assessment of sero-specific IgG antibodies. Additionally, functional activity using a serotype specific opsonophagocytic assay (OPA) was assessed at 10 and 18 months of age in a subset (20%) of participants. RESULTS: All schedules of PCV13 showed significant 13VT carriage reduction in the second year of life as compared to control. At 15 months of age, PCV13 (1 + 1) showed 45 % reduction in 13VT-carriage compared to the control [OR = 0.55 (95% CI; 0.31-0.97), p= 0.038]. None of the PCV10 schedules showed significant reduction in 10VT carriage in the second year. Although not powered for these outcomes, at 18 months of age, 1 + 1 and 2 + 1 schedules of both vaccines demonstrated higher sero-responders for all serotypes, higher geometric mean concentrations (GMC) for all serotypes except 23F [with both vaccines], higher percent OPA responders and OPA geometric mean titres (GMT) compared to the 3 + 0 schedules for all serotypes. CONCLUSION: The reduced dose schedule (1 + 1) of PCV13 results in significant VT-carriage reduction in the second year of life. Immune protection provided by 1 + 1 schedules of PCV10 and PCV13 in the second year of life is comparable to WHO-recommended 3-dose schedules.

Effect of adolescent pregnancy on child mortality in 46 countries.

INTRODUCTION: Adolescent pregnancy is a known health risk to mother and child. Statements and reports of health outcomes typically group mothers under 20 years old together. Few studies examined this risk at a finer age resolution, none of them comprehensively, and with differing results. METHODS: We analysed Demographic and Health Surveys data from 2004 to 2018 in sub-Saharan Africa (SSA) and South Asia, on firstborn children of mothers 25 years old or younger. We examined the association between maternal age and stillbirths, and neonatal mortality rate (NNMR), infant mortality rate (IMR) and under-5 mortality rate (U5MR), using mixed-effects logistic regression adjusting for major demographic variables and exploring the impact of maternal health-seeking. RESULTS: In both regions and across all endpoints, mortality rates of children born to mothers aged <16 years, 16-17 years and 18-19 years at first birth were about 2-4 times, 1.5-2 times and 1.2-1.5 times higher, respectively, than among firstborn children of mothers aged 23-25. Absolute mortality rates declined over time, but the age gradient remained similar across time periods and regions. Adjusting for rural/urban residence and maternal education, in SSA in 2014-2018 having a <16-year-old mother was associated with ORs of 3.71 (95% CI: 2.50 to 5.51) for stillbirth, 1.92 (1.60-2.30) for NNMR, 2.13 (1.85-2.46) for IMR and 2.39 (2.13-2.68) for U5MR, compared with having a mother aged 23-25. In South Asia, in 2014-2018 ORs were 5.12 (2.85-9.20) for stillbirth, 2.46 (2.03-2.97) for NNMR, 2.62 (2.22-3.08) for IMR and 2.59 (2.22-3.03) for U5MR. Part of the effect on NNMR and IMR may be mediated by a lower maternal health-seeking rate. CONCLUSIONS: Adolescent pregnancy is associated with dramatically worse child survival and mitigated by health-seeking behaviour, likely reflecting a combination of biological and social factors. Refining maternal age reporting will avoid masking the increased risk to children born to very young adolescent mothers. Collection of additional biological and social data may better reveal mediators of this relationship. Targeted intervention strategies to reduce unintended pregnancy at earlier ages may also improve child survival.