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Byline: Payal. Shah, Mahesh. Palanivelu Medulloepithelioma is a rare nonhereditary tumor seen most often in children, usually in the first decade. In this paper, we present a case of extensive [...]

Byline: Payal. Shah, Mahesh. Shanmugam, Ushma. Vora, Surbhi. Agrawal, Indrani. Sirivella, Shwetha. Suryakanth, Ramya. Jayasingh Purpose: To assess and analyze the visual outcomes of patients with retinal vein occlusions in [...]

Byline: Payal. Shah, Divyansh. Mishra, Mahesh. Shanmugam, M. Vighnesh, Hariprasad. Jayaraj Purpose: A deep learning system (DLS) using artificial intelligence (AI) is emerging as a very promising technology in the [...]

Byline: Mahesh. Shanmugam, Payal. Shah, Pradeep. Sagar, Rajesh. Ramanjulu, Divyansh. Mishra Purpose: Coats' disease is associated with poor outcomes, and there are limited studies on long-term outcomes of Coats' disease. [...]

IMPORTANCE: Agents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with PD-L1–positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined. OBJECTIVE: To evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021. INTERVENTIONS: Patients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up. MAIN OUTCOME AND MEASURES: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers. RESULTS: All 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio [HR], 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1–positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03206203

Byline: Kaushik. Murali, Viswesh. Krishna, Vrishab. Krishna, B. Kumari, Sowmya. Raveendra Murthy, C. Vidhya, Payal. Shah Purpose: Amblyopia is a significant public health problem. Photoscreeners have been shown to have [...]

Introduction: The incidence of post vitrectomy endophthalmitis (PVE) is reported to be between 0.02 and 0.84%. Resterilization of single use instruments is a common practice amidst developing countries to make it more affordable to the patients by reducing the cost of the surgery and also reduce the environmental hazard. The aim of our study is to evaluate the incidence of PVE amidst existing sterilization practices of reused instruments in multiple vitreoretinal centres in India. Methodology: Centres with an endophthalmitis tracking system were invited to participate in a survey. Twenty-five centres were sent a questionnaire via email. The questionnaire included details about the institution, number of vitrectomies performed in a year, sterilization practices followed pre-operatively, intraoperatively and postoperatively, incidence of endophthalmitis and instrument reuse policies. Results: A total of 29 cases of endophthalmitis were reported out of the 47,612 vitrectomies performed across various centres. The mean incidence of endophthalmitis was 0.06%. There was no difference in the rates of endophthalmitis based on various pre-operative, intraoperative or postoperative prophylactic measures. Nearly 80% of the centres change most of the instruments after every case, while the rest reused. The mean number of times a cutter was being reused until discarded was 4.7. Nearly 76% followed a performance-based protocol, and the remaining 24% had a fixed protocol for the number of times an instrument can be reused before discarding it. Conclusion: PVE rates are not significantly different in India despite the multiuse of single use instruments. The purpose of this paper is not to suggest an alternate protocol but to creating one in the future with these results in mind, to rationalise the use of single use instruments, make VR surgery more affordable and also have a positive impact on the carbon footprint of consumables in surgery.

Byline: Payal. Shah, Divyansh. Mishra, Mahesh. Shanmugam, Bindiya. Doshi, Hariprasad. Jayaraj, Rajesh. Ramanjulu Purpose: Deep learning is a newer and advanced subfield in artificial intelligence (AI). The aim of our [...]

Byline: Mahesh. Shanmugam, Payal. Shah, R. Rajesh, Divyansh. Mishra, Pradeep. Sagar, Abhishek. Sheemar A 34-year-old gentleman met with road traffic accident 3 months ago with multiple fractures and ocular trauma. [...]

With adolescents and youth constituting a quarter of the global population-for a total of 1.8 billion people--it has never been more critical that their human rights be fully recognised and [...]

Climate change is transforming the decision-making landscape for many conservation organizations. Conservation planning and implementation under climate change are challenging due to uncertainties about climate impacts and the effectiveness of adaptation options. Strategically building flexibility into conservation plans so they can be adjusted over time in response to unforeseen events, or new information, is one solution to this challenge. Yet, there are a wide range of mechanisms to choose from to enhance flexibility and so there is a need for a more structured approach to inform building flexibility into conservation plans. To achieve this, we conceptualize flexible strategies as three types, procedural flexibility, resource flexibility, and action flexibility, and explicitly link these to climate risks and steps in conservation decision-making processes. We discuss how this framework can guide choices of flexible strategies, including identifying the costs and benefits, and illustrate this using examples. This provides a new conceptual tool for conservation organizations to make strategic choices about flexibility for climate adaptation.

We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1and BRCA2pathogenic variant carriers.

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P= .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P= .042). They had faster vasoconstriction than the controls (P= .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P= .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Nonmedical descriptors, adjectives that are not related to a medical condition, such as “cute,” are often used in presentations in pediatrics. We hypothesize that patterns of their use may reflect obesity bias. Descriptors used by pediatric residents presenting cases of children <9 years in an outpatient clinic during the 2018–2019 and 2019–2020 academic years were recorded. The primary outcome was the association of the use of positive nonmedical descriptors with children's obesity status using logistic regression. Positive descriptors were used in 14% of 994 presentations. Most addressed the appearance of the child with variations of “cute” and “adorable.” There was no variation in use of positive descriptors by obesity status. On multivariate logistic regression, the odds of using positive descriptors were higher among female residents, and positive descriptor use declined with patient age. Negative descriptors were rare and often focused on weight.

Introduction:Sudden and unpredictable onset of pain is one of the biggest contributors to the morbidity of sickle cell disease (SCD), thought to occur due to obstruction of microvascular blood flow by rigid sickle-shaped red blood cells. Autonomic mediated vasoconstriction in the peripheral vasculature, with resulting decrease in tissue perfusion, is likely a triggering mechanism for the onset of vaso-occlusive pain, while the autonomic nervous system is also implicated in the pathogenesis of chronic neuropathic pain. Our analysis of 212 polysomnograms in SCD subjects showed that greater magnitude of nocturnal vasoconstriction (Mvasoc) is predictive of increased frequency of hospitalizations for vaso-occlusive pain crises (VOC) in the subsequent years (Chalacheva et al., Am J Hematol, 2020). In order to further develop this finding into a biomarker of more imminent pain, we monitored nocturnal photoplethysmography (PPG) at home with a wearable wristband device to measure vasoconstriction activity and heart rate variability, along with a daily electronic pain survey.

The heterogeneity and dynamic of IoT-systems pose new challenges for their simulation, which can be met by a modular co-simulation. Therefore several existing co-simulation approaches are presented and evaluated. A new concept for a dynamic co-simulation of IoT-systems utilizing a multi-agent-system is presented, wherein each IoT-component is simulated in a separate simulation tool. Each separate simulation is represented by an agent, and therefore able to enter a running co-simulation dynamically during runtime, which allows for a “Plug-and-Simulate” behavior. The connection between agents and simulation tools is realized by an interface concept. The presented concept is evaluated by a prototypical implementation.

ABSTRACT:Recent work uses Markowitz’s mean-variance framework to identify efficient allocations of conservation activity across subregions of a planning landscape to minimize climate change–induced uncertainty in future conservation benefits. We replace variance with a downside measure of uncertainty and compare the resulting portfolios of conservation activity and uncertainty–expected value results against those generated by the mean-variance approach. Results illustrate that conservation agents can manage climate changed–induced uncertainty in future conservation outcomes more efficiently using our framework when they are particularly averse to downside uncertainty and when predicted future conservation outcomes within subregions across their planning horizon exhibit skewed distributions.

Quetiapine fumarate (QF) is an atypical antipsychotic, undergoing extensive first pass metabolism and hence shows lower bioavailability orally. Solid Lipid Nanoparticles (SLNs) of QF were developed using lipid dynasan 114 and surfactant poloxamer 188 and 407 by double microemulsion-solvent evaporation technique. The aim of this study was to develop and evaluate SLNs of QF for enhancement of bioavailability via oral route. A Box-Behnken design has been applied to study the effect of independent variables i.e. lipid concentration, surfactant concentration and homogenization time on dependent variables i.e. particle size and entrapment efficiency. Optimized SLNs were evaluated for morphological characteristics using scanning electron microscopy, and were further evaluated for entrapment efficiency, drug content, fourier transform infrared spectroscopy, differential scanning calorimetry and In vitro drug release study. The formulation was also subjected to In vivo pharmacokinetic study using a rat model for determination of bioavailability. In vivo study suggested increase in bioavailability of QF SLNs (up to 10 fold increase in Area under curve) as compared to pure drug suspension following oral administration. The enhanced relative bioavailability by the SLNs formulation might be attributed to avoidance of first-pass hepatic metabolism by intestinal lymphatic transport, direct uptake of nanoparticles through the GI tract, increased permeability by surfactants, and decreased degradation of drug. The results suggest that QF SLNs can be used as an approach for enhancement of bioavailability of QF via oral route.

Oroxylum indicumis traditional herbal medicine in India, China and Japan used for its anti-diarrhoeal/anti-dysenteric activity, also found to be active against experimentally induced (DNBS induced) inflammatory bowel disease in rats with potential reduction in diarrhoea. It promotes us to evaluate effects of Oroxylum indicumon intestinal motility, both in vitro and in vivo, in rodents. Flavonoids rich fraction of O. indicumwas obtained and the effect of extract on contraction of acetylcholine, barium chloride and electrical field stimulation was studied on isolated rabbit ileum. Anti-diarrhoeal activities were investigated using castor oil and magnesium sulphate-induced diarrhoeal models in mice. Effect on intestinal motility was studied using gastrointestinal motility and antienteropooling assay methods. Antimicrobial activity of extract was evaluated using disc diffusion assay method. Extract inhibited the contractions induced by acetylcholine, barium chloride and electrical field stimulation. Verapamil potentiates inhibitory effect of extract. Extract showed significant and dose-dependent anti-diarrhoeal effect devoid of altering gastrointestinal motility in normal animals. It also inhibited the microbial growth in disc diffusion assay method. Extract normalized intestinal motility altered by inflammatory stimulus and possesses antidiarrhoeal activity. Alteration of intestinal motility may involve modification in L-type Ca2+channels.Oroxylum indicumis traditional herbal medicine in India, China and Japan used for its anti-diarrhoeal/anti-dysenteric activity, also found to be active against experimentally induced (DNBS induced) inflammatory bowel disease in rats with potential reduction in diarrhoea. It promotes us to evaluate effects of Oroxylum indicumon intestinal motility, both in vitro and in vivo, in rodents. Flavonoids rich fraction of O. indicumwas obtained and the effect of extract on contraction of acetylcholine, barium chloride and electrical field stimulation was studied on isolated rabbit ileum. Anti-diarrhoeal activities were investigated using castor oil and magnesium sulphate-induced diarrhoeal models in mice. Effect on intestinal motility was studied using gastrointestinal motility and antienteropooling assay methods. Antimicrobial activity of extract was evaluated using disc diffusion assay method. Extract inhibited the contractions induced by acetylcholine, barium chloride and electrical field stimulation. Verapamil potentiates inhibitory effect of extract. Extract showed significant and dose-dependent anti-diarrhoeal effect devoid of altering gastrointestinal motility in normal animals. It also inhibited the microbial growth in disc diffusion assay method. Extract normalized intestinal motility altered by inflammatory stimulus and possesses antidiarrhoeal activity. Alteration of intestinal motility may involve modification in L-type Ca2+channels.

Background: Hospitalized patients who develop febrile neutropenia (FN) are treated empirically with antibiotics due to a high risk of developing septic shock. Currently, there is no method to predict which patients are at greatest risk. This study was designed to determine whether serum lactate, measured at the time of FN, is associated with the development of septic shock in hospitalized hematologic malignancy (HM) patients. Methods:Vital signs and lactate were measured during episodes of FN. The primary endpoint was the development of septic shock.  Using a prospective, nested, case-control design, controls were matched on length of stay at the time of septic shock to achieve 80% power to detect an OR of ≥ 2.5. Using logistic regression, we evaluated the association of vital signs and lactate with the subsequent development of septic shock. Results:Of the 547 patients enrolled, 46 (8.4%; 95% CI 6.2-10.9) developed septic shock. Baseline characteristics were similar between the groups. In univariate analysis, tachypnea (OR 5.9; 95% CI: 2.0-16.9, p =.001) and lactate (OR 18.4; 95% CI: 4.1-81.6, p

Background: The systemic inflammatory response syndrome (SIRS) criteria have not been validated in patients with hematologic malignancies (HM). Objective: To determine whether daily assessment of SIRS criteria allows early identification of HM patients who will develop septic shock (SS). Design: Observational, single-center, nested case-control study. Setting: Oncology unit of a tertiary care center. Patients: 547 consecutive, hospitalized, HM subject were enrolled. Using incidence-density sampling, 184 controls were matched to 46 SS cases. Measurements: The study exposure was the SIRS score. The study outcome was the development of SS during the hospitalization. Main Results: 8.4% of subjects developed SS. SIRS scores measured 24 hours prior to SS were significantly higher in cases than in controls (2.1 vs. 1.4, p

Introduction

Methods for measuring rates of DNA synthesis, and thus cell proliferation, in humans had not been available until recently. We (D. C. Macallan, C. A. Fullerton, R. A. Neese, K. Haddock, S. S. Park, and M. K. Hellerstein, 1998, Proc. Natl. Acad. Sci. USA 95, 708–713) recently developed a stable isotope–mass spectrometric technique for measuring DNA synthesis by labeling the deoxyribose (dR) moiety of purine deoxyribonucleotides through the de novo nucleotide synthesis pathway. The original analytic approach had limitations, however. Here, we describe technical improvements that increase yield, stability, sensitivity, and reproducibility of the method. The purine deoxyribonucleoside, deoxyadenosine (dA), is directly isolated from hydrolysates of DNA by using an LC18 SPE column. Two derivatives were developed for analyzing the dR moiety of dA alone (without the base), an aldonitrile-triacetate derivative, and a reduced pentose-tetraacetate (PTA) derivative. The PTA derivative in particular exhibited greater stability (no degradation after several weeks), greater GC/MS signal, and much less abundance sensitivity of isotope ratios (i.e., less dependence of mass isotopomer abundances on the amount of material injected into the mass spectrometer source), compared to previous derivatives of dA. The need for complex, multidimensional abundance corrected standard curves was thereby avoided. Using the PTA derivative, dR enrichments from DNA of fully turned over cells of rodents with ²H₂O enrichments in body water of 2.2–2.8% were 9.0–9.5%, and less than 1.0 μg DNA (ca. 2 × 10⁵ cells) was required for reproducible analyses. In summary, these methodologic advances allow measurement of stable isotope incorporation into DNA and calculation of cell proliferation and death rates in vivo in humans and experimental animals, with fewer cells, greater reproducibility, and less labor. Many applications of this approach can be envisioned. Copyright 2001 Academic Press.

A diagnosis of late stage melanoma is associated with significant mortality. From a public health perspective, knowledge of geographic disparities in late-stage diagnoses can inform efforts to facilitate the diagnosis of earlier stage, highly curable melanomas. We conducted a county-level analysis of melanoma in New York State to identify communities that may benefit from pilot health interventions to reduce the burden of late stage melanoma. From 1995 to 2016, late-stage melanoma incidence increased from 1.5 to 2.8 cases/100,000 in NY State. We found statistically significant associations between decreased county-level health system access (including physician density and resident educational status), and increased county incidence and proportion of late-stage disease among diagnosed cases (p<0.001 for both). Increased county-level socioeconomic status (SES), (including measures of resident wealth and medical insurance status), was positively associated with greater late-stage incidence (p<0.001). However, decreased county-level SES was positively associated with a greater proportion of late-stage disease among cases at diagnosis (p=0.009). Counties with reduced access to physician services and lower SES may be suitable for pilot interventions promoting recognition and diagnosis of early stage melanomas to reduce late stage diagnoses and associated mortality.

Introduction:Arginase competes with nitric oxide synthase by converting Arginine (Arg) to ornithine, thereby decreasing Arg and nitric oxide bioavailability. Both enzymes are modulated by shear stress. Single ventricle (1V) physiology after Fontan palliation creates chronically low shear stress in the pulmonary arterial (PA) tree.Hypothesis:We hypothesize that a gradient exists in plasma arginase concentration (conc) & activity (act) from the right atrium(RA) to the pulmonary capillary bed (PCW) in patients with biventricular circulation (2V) & is altered in 1V physiology following Fontan palliation.Methods:A prospective cohort study in patients undergoing cardiac catheterization for ASD or PDA closure & Fontan surveillance. Blood samples were obtained in 18 1V & 11 2V patients from 4 sites: RA/Fontan, PA, PCW & systemic artery. Plasma arginase conc & act were measured & compared to 11 controls. Hemodynamic data was recorded. Repeated measures was used after rank transformation due to non-parametric distribution.Results:Median age in years for 1V was 13.5[11.1-15.2], 61% male, 11.6[9.2-14], 27% male for 2V & 9.9[4.5-12.6], 50% male for controls. Arginase conc, act & act:conc were similar in 1V/2V patients vs control. There was a rise in conc from the Fontan to PCW in 1V not 2V subjects (p=0.02). Act & act:conc were similar throughout the vasculature in 1V and 2V. PA pressure, PCW pressure, Qp & Qs were higher in 2V vs 1V, but oxygen delivery was similar. Conc in the Fontan was associated with pleural effusion post Fontan (p=0.014) & larger RPA diameter (r=0.77, p=0.001). Act in PA is inversely proportional to Qp (R2=0.42, p=0.02).Conclusions:Arginase conc increases across the lung in Fontan but not biventricular circulation. Arginase conc in the Fontan circuit is associated with effusions post Fontan & larger RPA diameter; activity predicts lower Qp. Arginase from the hepatic/lower body may be an important determinant in Fontan physiology.

Coates: ApoPharma: Consultancy, Honoraria; Celgene Corp.: Consultancy; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria.

Coates: Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria; Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria.

Coates: ApoPharma: Consultancy, Honoraria; Sangamo: Consultancy, Honoraria; Vifor Pharma: Consultancy; Celgene Corp.: Consultancy.

Introduction:Sickle cell disease (SCD) is characterized by microvascular occlusion from sickled red blood cells that can develop into full-blown vaso-occlusive crisis. We hypothesize that abnormal autonomic function plays a role in promoting microvascular occlusion in SCD. Head-up tilt (HUT) evokes a strong sympathetic response to the transient drop in blood pressure resulting from blood pooling in the lower extremities. Baroreflex regulation leads to heart rate (HR) increase and peripheral vasoconstriction. In this study, we subjected control and SCD subjects to the HUT test to assess their autonomic response.

Sickle Cell Disease (SCD) is a genetic disorder in which sudden onset of painful vaso-occlusive crises (VOC) can occur due to the obstruction of the microvasculature by the rigid sickled red blood cells. We have previously shown that pain itself could be a trigger for VOC by causing significant neural mediated vasoconstriction in the microvasculature and thereby promoting obstruction and eventual progression to VOC. Many scientific models and experimental studies have shown that increased attention to painful stimuli influences subjective pain measures such as pain sensitivity and tolerance and can alter acute pain outcomes. In this study, we explored the role of pain attention in modulating the objective vasoconstriction response to thermal pain in SCD and controls.

Background:Painful vaso-occlusive crises (VOC) are a frequent and debilitating complication of sickle cell disease (SCD). The exact mechanism of transition from steady state to VOC is not well understood although it is thought to occur due to progressive blockage of the microvasculature with rigid sickle shaped red blood cells. Thus, any trigger that decreases the microvascular blood flow increases the red blood cell transit time and can promote entrapment of sickled cells in the microvasculature and progression to VOC. Environmental factors such as exposure to cold wind and changes in weather are common triggers of VOC and have been shown to be associated with increased frequency of hospitalizations for pain in patients with SCD. There is limited experimental data in literature on the physiologic effects of these factors on peripheral perfusion in SCD.

Wood: Celgene: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; World Care Clinical: Consultancy; World Care Clinical: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy.

Introduction:Sickle cell disease (SCD), an inherited blood disorder, is characterized by episodes of painful vaso-occlusive crises (VOC). Peripheral vasoconstriction may contribute to VOC by prolonging the transit time of red blood cells through the microvasculature. We recently demonstrated that heat-induced pain produces stronger vasoconstriction in SCD subjects versus controls, suggesting abnormal autonomic regulation of regional blood flow in SCD. Thus, although pain is generally thought to be a consequence of VOC, it is possible that pain itself may trigger a cascade of events that leads to large-scale VOC by promoting regional peripheral vasoconstriction.

No relevant conflicts of interest to declare.

The article offers a narrative of a road trip to Bagan, Myanmar and includes recommendations for dining, shopping, and accommodations.

Sequential hypothesis testing in pest management applications are usually carried out using Wald’s procedure or Iwao’s procedure. Both of these procedures are applicable for one-parameter pest count models. The current practice for handling nuisance parameters when using the Wald procedure is to assume they are equal to specified values based on historical experience, and in the case of Iwao’s procedure to assume a known mean–variance relationship such as Taylor’s power law. In this article, we discuss the weaknesses of these practices, and advocate the use of Bartlett’s sequential procedure as a better way to handle nuisance parameters. We also show how Bartlett’s procedure can be implemented within three-hypothesis testing scenarios, where differentiation between three levels of infestation is desired.