Citations

While resistance to older antimalarials is increasingly common, newer antimalarials are still not widely available or affordable in much of Africa. Older antimalarials used in combination might be adequately effective in treating uncomplicated malaria. The objective of this study was to determine whether the combination of sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is superior to SP alone in the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian patients. We recruited subjects with malaria, defined as the presence of fever and parasitemia > 2,000/μL, from the outpatient department of a Nigerian teaching hospital. We alternately assigned 280 subjects to receive SP with or without CQ. We assessed clinical and parasitologic responses on days 1, 2, 3, 7, and 14. A total of 114 in the SP + CQ group and 116 in the SP group completed the study. By day 3, 97 (75%) in the SP + CQ group and 52 (42%) in the SP group had cleared their parasitemia (P < 0.001); by day 14, 112 (98%) and 67 (58%), respectively, had cleared their parasitemia (P < 0.001). By day 3, 82 (63%) in the SP + CQ group and 20 (16%) in the SP group were symptom free (P < 0.001). When a modified World Health Organization clinical classification system was used, adequate clinical response occurred in 99 (87%) and 61 (53%) of those in the SP + CQ and SP groups, respectively. RI, RII, and RIII resistance to SP + CQ was 7.9%, 3.5%, and 1.8%, respectively, whereas resistance to SP was 23%, 17%, and 5%, respectively. Combined SP + CQ is superior to SP alone for treatment of uncomplicated malaria in Nigerian patients and may prolong the usefulness of these readily available and affordable drugs.

Summary All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long‐term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well‐designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare‐related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

Abstract This Consensus Document is the first of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The first document appraises the role of intracoronary imaging to guide percutaneous coronary interventions (PCIs) in clinical practice. Current evidence regarding the impact of intracoronary imaging guidance on cardiovascular outcomes is summarized, and patients or lesions most likely to derive clinical benefit from an imaging-guided intervention are identified. The relevance of the use of IVUS or OCT prior to PCI for optimizing stent sizing (stent length and diameter) and planning the procedural strategy is discussed. Regarding post-implantation imaging, the consensus group recommends key parameters that characterize an optimal PCI result and provides cut-offs to guide corrective measures and optimize the stenting result. Moreover, routine performance of intracoronary imaging in patients with stent failure (restenosis or stent thrombosis) is recommended. Finally, strengths and limitations of IVUS and OCT for guiding PCI and assessing stent failures and areas that warrant further research are critically discussed.

Improved methods are needed to risk stratify and predict outcomes in patients with primary sclerosing cholangitis (PSC). Therefore, we sought to derive and validate a prediction model and compare its performance to existing surrogate markers. The model was derived using 509 subjects from a multicenter North American cohort and validated in an international multicenter cohort (n = 278). Gradient boosting, a machine‐based learning technique, was used to create the model. The endpoint was hepatic decompensation (ascites, variceal hemorrhage, or encephalopathy). Subjects with advanced PSC or cholangiocarcinoma (CCA) at baseline were excluded. The PSC risk estimate tool (PREsTo) consists of nine variables: bilirubin, albumin, serum alkaline phosphatase (SAP) times the upper limit of normal (ULN), platelets, aspartate aminotransferase (AST), hemoglobin, sodium, patient age, and number of years since PSC was diagnosed. Validation in an independent cohort confirms that PREsTo accurately predicts decompensation (C‐statistic, 0.90; 95% confidence interval [CI], 0.84‐0.95) and performed well compared to Model for End‐Stage Liver Disease (MELD) score (C‐statistic, 0.72; 95% CI, 0.57‐0.84), Mayo PSC risk score (C‐statistic, 0.85; 95% CI, 0.77‐0.92), and SAP <1.5 × ULN (C‐statistic, 0.65; 95% CI, 0.55‐0.73). PREsTo continued to be accurate among individuals with a bilirubin <2.0 mg/dL (C‐statistic, 0.90; 95% CI, 0.82‐0.96) and when the score was reapplied at a later course in the disease (C‐statistic, 0.82; 95% CI, 0.64‐0.95). Conclusion: PREsTo accurately predicts hepatic decompensation (HD) in PSC and exceeds the performance among other widely available, noninvasive prognostic scoring systems.

AbstractAtopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

Background: The American Academy of Pediatrics and the National Academy of Medicine recommend vitamin D supplementation for breastfeeding infants. However, compliance with this recommendation is poor. Maternal supplementation with vitamin D is a safe and effective alternative to achieving vitamin D sufficiency in breastfeeding infants, and mothers have indicated a preference for self-supplementation over infant supplementation. Research aim: We sought to explore Family Medicine clinicians’ knowledge, attitudes, and practices regarding vitamin D supplementation recommendations for breastfeeding dyads. Methods: Fifty-six Family Medicine clinicians (including faculty physicians, resident physicians, and nurse practitioners/physician assistants) completed an online, anonymous survey regarding their knowledge and practices concerning vitamin D supplementation for breastfeeding infants. Results: The vast majority of clinicians (92.9%) correctly identified the American Academy of Pediatrics’ 2008 recommended dose for vitamin D supplementation in breastfeeding infants and estimated recommending vitamin D supplementation of exclusively breastfeeding infants 70.1% of the time. If all options were equivalent, clinicians would prefer to offer maternal or infant supplementation (50%) or maternal supplementation (37.5%) over infant supplementation (12.5%). Most (69.6%) preferred daily over monthly supplementation regimens. Conclusion: Family Medicine clinicians are knowledgeable regarding current recommendations for vitamin D supplementation in breastfeeding infants. They are also open to recommending maternal supplementation or offering parents a choice of maternal or infant vitamin supplementation.

Objective: 1) Characterize corrective saccades (CS) in normal controls, and 2) examine the sensitivity of the video head impulse test (vHIT) for identifying vestibular loss using both gain and CS. Study Design: Prospective combined with retrospective review. Setting: Tertiary referral center. Patients: Seventy subjects with normal vestibular function served as controls (mean age, 44.1 yr; range, 10–78) and data from 49 patients with unilateral and bilateral vestibular loss was retrospectively reviewed (mean age, 50; range, 7–81). Intervention: vHIT; individual horizontal head impulses were then analyzed in MATLAB. Main Outcome Measures: Horizontal vHIT gain, CS peak velocity, frequency, and latency. Results: There was not an age effect for CS velocity or latency, and only a weak relationship between CS frequency and age in the control group. Gain and CS latency were the only parameters affected by impulse side, demonstrating higher gain and longer latency on the right. The group with vestibular loss had significantly lower mean vHIT gain, higher mean CS frequency, higher mean CS velocity, earlier CS latency, and smaller mean CS standard deviations of the latency compared with the control group. When all factors were analyzed separately by logistic regression, vHIT gain provided the best classification (83.8%), closely followed by CS frequency (83.1%). Using a two variable approach (both gain and CS frequency) yielded the best diagnostic accuracy (overall classification = 84.6%). Conclusions: Along with gain, incorporating CS frequency in interpreting vHIT improves diagnostic accuracy. A repeatable CS (>81.89%) and/or low gain (<0.78) indicate vestibular loss.

Motilin is a potent agonist for gastrointestinal smooth muscle contraction and has been proposed to regulate the onset of phase III of the migrating motor complex in dogs and humans. The effects of motilin and OHM-11526, a motilin antagonist in rabbit smooth muscle strips, were examined in isolated canine and human jejunal circular smooth muscle cells using whole cell patch-clamp techniques with Ba2+ as the charge carrier. Effects of both drugs on inward current through L-type Ca2+ channels (ICaL) in both canine and human cells were first observed at 10(-3) M. At 10(-6) M, motilin increased ICaL in canine and human jejunal circular smooth muscle cells by 43 +/- 20 and 45 +/- 11%, respectively, and OHM-11526 increased ICaL by 54 +/- 8 and 54 +/- 14%, respectively. The increase in inward current was blocked by nifedipine and by guanosine 5'-O-(2-thiodiphosphate) but not by pertussis toxin. Washout of both drugs resulted in a further increase in ICaL. These data suggest that both motilin and OHM-11526 activate and ICaL in human and canine jejunal circular smooth muscle cells through a G protein-coupled mechanism.

We evaluated a method of baroreflex testing involving sequential intravenous bolus injections of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside in 18 healthy men and women, and we drew inferences regarding human sympathetic and vagal baroreflex mechanisms. We recorded the electrocardiogram, photoplethysmographic finger arterial pressure, and peroneal nerve muscle sympathetic activity. We then contrasted least squares linear regression slopes derived from the depressor (nitroprusside) and pressor (phenylephrine) phases with 1) slopes derived from spontaneous fluctuations of systolic arterial pressures and R-R intervals, and 2) baroreflex gain derived from cross-spectral analyses of systolic pressures and R-R intervals. We calculated sympathetic baroreflex gain from integrated muscle sympathetic nerve activity and diastolic pressures. We found that vagal baroreflex slopes are less when arterial pressures are falling than when they are rising and that this hysteresis exists over pressure ranges both below and above baseline levels. Although pharmacological and spontaneous vagal baroreflex responses correlate closely, pharmacological baroreflex slopes tend to be lower than those derived from spontaneous fluctuations. Sympathetic baroreflex slopes are similar when arterial pressure is falling and rising; however, small pressure elevations above baseline silence sympathetic motoneurons. Vagal, but not sympathetic baroreflex gains vary inversely with subjects’ ages and their baseline arterial pressures. There is no correlation between sympathetic and vagal baroreflex gains. We recommend repeated sequential nitroprusside followed by phenylephrine doses as a simple, efficientmeans to provoke and characterize human vagal and sympathetic baroreflex responses.