Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Improving medical students' written communication skills: design and evaluation of an educational curriculum.

BACKGROUND AND OBJECTIVES: Written and verbal communication skills are important skills for all physicians. While verbal skills are taught and assessed in medical school, medical students report limited instruction in written communication skills. This study examined the impact of a curriculum delivered during a 6-week clinical rotation in Internal Medicine on the objective assessment of medical students' written communication skills. METHODS: The curriculum consisted of two educational programmes: a medical student communication tutorial and a resident feedback workshop. The study was conducted from March 2012 to January 2013 at McMaster University in Hamilton, Ontario, Canada. The study featured three arms: (1) control, (2) medical student communication tutorial alone and (3) student tutorial and resident feedback workshop. Data were collected on 126 students during 6-week Internal Medicine clerkship rotations. Students' written consultation notes were collected prior to the educational programmes and at 6 weeks. Blinded faculty assessors used an independently validated Assessment Checklist to evaluate consultation notes. RESULTS: Consultation note scores improved from week 1 to week 6 across all study arms. However, the change was statistically significant only in arm 3, featuring both the medical student tutorial and the resident feedback workshop, with mean scores improving from 4.75 (SD=1.496) to 5.56 (SD=0.984) out of 7. The mean difference between week 1 and week 6 was significantly different (0.806, p=0.002, 95% CI 0.306 to 1.058). CONCLUSIONS: The combination of a resident feedback workshop with medical student written communication tutorial improves objective evaluations of consultation note scores over student tutorial alone.

Young women with polycystic ovary syndrome have raised levels of circulating annexin V-positive platelet microparticles.

STUDY QUESTION: Are circulating microparticles (MPs) altered in young women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS have elevated concentrations of circulating platelet-derived MPs, which exhibit increased annexin V binding and altered microRNA (miR) profiles compared with healthy volunteers. WHAT IS KNOWN ALREADY: Some studies have shown that cardiovascular risk is increased in young women with PCOS but the mechanisms by which this occurs are uncertain. Circulating MPs are elevated in patients with cardiovascular disease but the characteristics of MPs in patients with PCOS are unclear. STUDY DESIGN, SIZE, DURATION: Case-control study comprising 17 women with PCOS (mean ± SD; age 31 ± 7 years, BMI 29 ± 6 kg/m(2)) and 18 healthy volunteers (age 31 ± 6 years, BMI 30 ± 6 kg/m(2)). PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a University hospital. Nanoparticle tracking analysis (NTA) and flow cytometry (CD41 platelet, CD11b monocyte, CD144 endothelial) were used to determine MP size, concentration, cellular origin and annexin V positivity (reflecting phosphatidylserine exposure). Fatty acid analysis was performed by gas chromatography and MP miR expression profiles were compared by microarray. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS subjects showed increased MP concentrations compared with healthy volunteers (mean ± SD; 11.5 ± 5 × 10(12)/ml versus 10.0 ± 4 × 10(12)/ml, respectively; P = 0.03), which correlated with the homeostasis model of insulin resistance (r = 0.53, P = 0.03). This difference was predominantly seen in MPs whose size was in the small exosomal range (<150 nm in diameter, P< 0.05). PCOS patients showed a greater percentage of annexin V(+) MPs compared with healthy volunteers (84 ± 18 versus 74 ± 24%, respectively, P = 0.05) but the cellular origin of MPs, which were predominantly platelet-derived (PCOS: 99 ± 0.9%; controls: 99 ± 2.5%), did not differ. MP fatty acid concentration and composition was similar between groups but 16 miRs were differentially expressed (P < 0.05). LIMITATIONS, REASON FOR CAUTION: Patients with PCOS were classified by the Rotterdam criteria, which describes a less severe metabolic phenotype than other definitions of the syndrome. Our findings may thus not be generalizable to all patients with PCOS. MicroRNA expression analysis was only undertaken in an exploratory subset of the overall study population hence, validation of our findings in a larger cohort is mandatory. Furthermore, miR levels were unaltered for the highly expressed miRs and it is unclear whether differences in the lowly expressed miRs carries pathological relevance. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that women with PCOS have an altered MP profile but further studies are needed to confirm this, to explore the mechanisms by which these alterations develop and to establish whether therapies that improve insulin sensitivity are able to reduce circulating MP concentrations. STUDY FUNDING/COMPETING INTERESTS: The study was funded by grants from the Wales Heart Research Institute and Mrs John Nixon Scholarship. The authors have no conflicts of interest to declare.

Observation of electron neutrino appearance in a muon neutrino beam.

The T2K experiment has observed electron neutrino appearance in a muon neutrino beam produced 295 km from the Super-Kamiokande detector with a peak energy of 0.6 GeV. A total of 28 electron neutrino events were detected with an energy distribution consistent with an appearance signal, corresponding to a significance of 7.3σ when compared to 4.92±0.55 expected background events. In the Pontecorvo-Maki-Nakagawa-Sakata mixing model, the electron neutrino appearance signal depends on several parameters including three mixing angles θ12, θ23, θ13, a mass difference Δm(32)(2) and a CP violating phase δ(CP). In this neutrino oscillation scenario, assuming |Δm(32)(2)|=2.4×10(-3) eV(2), sin(2)θ(23)=0.5, and Δm322>0 (Δm(32)(2)<0), a best-fit value of sin(2)2θ(13)=0.140(-0.032)(+0.038) (0.170(-0.037)(+0.045)) is obtained at δ(CP)=0. When combining the result with the current best knowledge of oscillation parameters including the world average value of θ(13) from reactor experiments, some values of δ(CP) are disfavored at the 90% C.L.

Precise measurement of the neutrino mixing parameter θ23 from muon neutrino disappearance in an off-axis beam.

New data from the T2K neutrino oscillation experiment produce the most precise measurement of the neutrino mixing parameter θ23. Using an off-axis neutrino beam with a peak energy of 0.6 GeV and a data set corresponding to 6.57×10(20) protons on target, T2K has fit the energy-dependent νµ oscillation probability to determine oscillation parameters. The 68% confidence limit on sin(2)(θ23) is 0.514(-0.056)(+0.055) (0.511±0.055), assuming normal (inverted) mass hierarchy. The best-fit mass-squared splitting for normal hierarchy is Δm32(2)=(2.51±0.10)×10(-3) eV(2)/c(4) (inverted hierarchy: Δm13(2)=(2.48±0.10)×10(-3) eV(2)/c(4)). Adding a model of multinucleon interactions that affect neutrino energy reconstruction is found to produce only small biases in neutrino oscillation parameter extraction at current levels of statistical uncertainty.

Measurement of the inclusive electron neutrino charged current cross section on carbon with the T2K near detector.

The T2K off-axis near detector ND280 is used to make the first differential cross-section measurements of electron neutrino charged current interactions at energies ∼1 GeV as a function of electron momentum, electron scattering angle, and four-momentum transfer of the interaction. The total flux-averaged ν(e) charged current cross section on carbon is measured to be ⟨σ⟩(ϕ)=1.11±0.10(stat)±0.18(syst)×10⁻³8 cm²/nucleon. The differential and total cross-section measurements agree with the predictions of two leading neutrino interaction generators, NEUT and GENIE. The NEUT prediction is 1.23×10⁻³8 cm²/nucleon and the GENIE prediction is 1.08×10⁻³8 cm²/nucleon. The total ν(e) charged current cross-section result is also in agreement with data from the Gargamelle experiment.

Who are the PDCO?

In January 2007, the Paediatric Regulation entered into force and established the Paediatric Committee (PDCO) within the European Medicines Agency. The goal of the PDCO is to improve the health of the children of Europe by increasing high-quality research for medicinal products and promoting the development and authorization of such medicines at the EU level. A major function of the PDCO is to formulate and authorize Paediatric Investigation Plans and Paediatric Use Marketing Authorisations. The EU's Seventh Framework Programme for Research has facilitated the establishment of consortia whose ultimate goal is to answer important clinical questions involving medicines commonly used "off-label", in children. The benefits of these consortia include enhanced collaboration amongst paediatricians, scientists and small to medium enterprises whose ultimate goal is to obtain an authorization for a new indication or formulation for use in the paediatric population. It will be interesting in a number of years time to measure the success of this very important European initiative.

Anticancer activity of combination targeted therapy using cetuximab plus vemurafenib for refractory BRAF (V600E)-mutant metastatic colorectal carcinoma.

Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wild-type colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf- and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.

Measurement of neutrino oscillation parameters from muon neutrino disappearance with an off-axis beam.

The T2K Collaboration reports a precision measurement of muon neutrino disappearance with an off-axis neutrino beam with a peak energy of 0.6 GeV. Near detector measurements are used to constrain the neutrino flux and cross section parameters. The Super-Kamiokande far detector, which is 295 km downstream of the neutrino production target, collected data corresponding to 3.01×10(20) protons on target. In the absence of neutrino oscillations, 205±17 (syst) events are expected to be detected while only 58 muon neutrino event candidates are observed. A fit to the neutrino rate and energy spectrum, assuming three neutrino flavors and normal mass hierarchy yields a best-fit mixing angle sin2(θ23)=0.514±0.082 and mass splitting |Δm(32)(2)|=2.44(-0.15)(+0.17)×10(-3) eV2/c4. Our result corresponds to the maximal oscillation disappearance probability.

Impact of the collaborative care model on medical spending.

OBJECTIVES: The collaborative care model integrates mental health care into primary care. In 2017, CMS created new billing codes to reimburse collaborative care. We measured the impact of a program supported by these codes on medical spending. STUDY DESIGN: Quasi-experimental. METHODS: We identified a commercially insured and managed Medicare sample of 825 patients who received collaborative care services in 8 primary care practices. We used propensity score matching to match treated patients to potential controls, resulting in 569 patients per group. We performed a difference-in-differences regression analysis to evaluate the impact of collaborative care on total medical spending, including medical, psychiatric, and pharmaceutical claims. RESULTS: Collaborative care patients' mean total medical cost began to fall after a patient's third month in the program and fell below the mean cost of control patients at month 7. Difference-in-differences regressions indicate a nonsignificant savings in total medical cost of $29.35 per member per month for patients in collaborative care compared with matched controls (95% CI, -$226.52 to $167.82). Treated members incurred $34.11 (95% CI, $31.95-$36.27) higher primary care costs that were directly attributed to collaborative care, $19.91 (95% CI, $4.84-$34.98) higher costs for other mental or behavioral health care, and a nonsignificant reduction of $91.34 (95% CI, -$319.32 to $136.63) in inpatient costs. CONCLUSIONS: Modest spending on collaborative care services to address the behavioral health needs of patients did not increase overall health care costs. This is the first economic study of a collaborative care program supported by the new billing codes.

Commercial beef farms excelling in terminal and maternal genetic merit generate more gross profit.

Validation of beef total merit breeding indexes for improving performance and profitability has previously been undertaken at the individual animal level; however, no herd-level validation of beef genetic merit and profit has been previously investigated. The objective of the present study was to quantify the relationship between herd profitability and both herd-average terminal and maternal genetic merit across 1,311 commercial Irish beef herds. Herd-level physical and financial performance data were available from a financial benchmarking tool used by Irish farmers and their extension advisors. Animal genetic merit data originated from the Irish Cattle Breeding Federation who undertake the national beef and dairy genetic evaluations. Herd-average genetic merit variables included the terminal index of young animals, the maternal index of dams, and the terminal index of service sires. The herds represented three production systems: 1) cow-calf to beef, 2) cow-calf to weanling/yearling, and 3) weanling/yearling to beef. Associations between herd financial performance metrics and herd average genetic merit variables were quantified using a series of linear mixed models with year, production system, herd size, stocking rate, concentrate input, and the two-way interactions between production system and herd size, stocking rate, and concentrate input included as nuisance factors. Herd nested within the county of Ireland (n = 26) was included as a repeated effect. Herds with young cattle excelling in terminal index enjoyed greater gross and net profit per hectare (ha), per livestock unit (LU), and per kg net live-weight output. The change in gross profit per LU per unit change in the terminal index of young animals was €1.41 (SE = 0.23), while the respective regression coefficient for net profit per LU was €1.37 (SE = 0.30); the standard deviation of the terminal index is €37. Herd-average dam maternal index and sire terminal index were both independently positively associated with gross profit per ha and gross profit per LU. Each one unit increase in dam maternal index (standard deviation of €38) was associated with a €1.40 (SE = 0.48) and €0.76 (SE = 0.29) greater gross profit per ha and per LU, respectively. Results from the present study at the herd-level concur with previous validation studies at the individual animal level thus instilling further confidence among stakeholders as to the expected improvement in herd profitability with improving genetic merit.

Kikuchi disease in a child.

Kikuchi disease, also called histocytic necrotizing lymphadenitis or focal histiocytic lymphadenitis, is a rare, idiopathic and generally self limited cause of lymphadenitis. It was first described in 1972 in Japan. The most common clinical manifestation is cervical lymphadenopathy with or without systemic symptoms & signs. It almost always runs a benign course and resolves in several weeks to months.

Orf: contagious pustular dermatitis.

Orf is a common viral infection in sheep. It spreads to humans by direct contact. It is self-limiting, treatment having no beneficial effect. Misdiagnosis by those unfamiliar with its characteristic features is common, and may result in unnecessary treatment with antibiotics or surgery. We present a series of five cases of Orf in children of farmers in the west of Ireland, seen over a 10 year period.

Phenocopies of pigmentary and behavioral effects of the yellow mutant in Drosophila induced by alpha-dimethyltyrosine.

alpha-Dimethyltyrosine induces a phenocopy of the body color mutant yellow when fed to larvae of Drosophila melanogaster. The compound also induces changes in male courtship behavior which are similar to the effects of the mutant gene.

Functional requirement of a site-specific ribose methylation in ribosomal RNA.

The product of the PET56 nuclear gene of Saccharomyces cerevisiae was shown to be required for ribose methylation at a universally conserved nucleotide in the peptidyl transferase center of the mitochondrial large ribosomal RNA (21S rRNA). Cells reduced in this activity were deficient in formation of functional large subunits of the mitochondrial ribosome. The purified Pet56 protein catalyzed the site-specific formation of 2'-O-methylguanosine on in vitro transcripts of both mitochondrial 21S rRNA and Escherichia coli 23S rRNA. These results provide evidence for an essential modified nucleotide in rRNA.

Psychiatric consultation of patients with hyperemesis gravidarum.

The request for a psychiatric examination of patients with hyperemesis gravidarum (HG) is a unique challenge for the psychiatric consultant. Unfortunately, there are little data in the psychosomatic medicine literature to guide diagnostic evaluations and treatment of patients with HG. In this article, we summarize the existing literature and propose a practical approach to such patients based on the literature and our clinical experience.

Analysis techniques for congruence of the patellofemoral joint.

Quantifying joint congruence may help to understand the relationship between joint function and health. In previous studies, a congruence index (CI) has been used to define subject-specific joint congruence. However, the sensitivity of the CI algorithm to surface representation was unknown. The purpose of this study was to assess the effects of applying five modifications (M1-M5) to the CI algorithm to determine whether the magnitude and variability of the patellofemoral CI is dependent on the surface representation used. The five modifications focused on calculating the CI based on the principal curvature (M1) at the centroid of the contact region, (M2) using an root mean square value for the contact region, (M3) using a mean value for the contact region, (M4) using all digitized points of the patellar surface, and (M5) using all digitized points in contact. The CI found using the contact area (M1, M2, M3, and M5) provides a local measure for congruence, which was shown to increase (decreasing CI) with increasing joint angle. In ten healthy subjects measured with magnetic resonance (MR) images, the patellofemoral joint became significantly more congruent as the knee angle increased from 15 deg to 45 deg using method M5. The magnitude and variability of the patellofemoral CI was dependent on the surface representation used, suggesting that standardization of the surface representation is important to provide a consistent measure. Specifically, M5 provides a local measure of joint congruence, which can account for joint position and orientation. M5 balances the ability to detect differences in congruence between knee angles without introducing high variability.

Extracellular Vesicles in the Synovial Joint: Is there a Role in the Pathophysiology of Osteoarthritis?

The role of extracellular vesicles (EV) in osteoarthritis has become the focus of much research. These vesicles were isolated from several cell types found in synovial joint including chondrocytes and synovium. As articular cartilage is an avascular tissue surrounded by synovial fluid, it is believed that EV might play a crucial role in the homeostasis of cartilage and also could hold key information in the pathogenesis of osteoarthritis. This is thought to be due to activation of pro-inflammatory factors leading to a catabolic state and degradation of cartilage. In addition, due to the nature of articular cartilage lacking neuronal innervation, knowledge of EV can contribute to identification of novel biomarkers in this debilitating condition. This can be either directly isolated from aspirate of synovial fluid or from peripheral blood. Finally, EVs are known to shuttle important signalling molecules which can be utilised as unique modality in transferring therapeutic compounds in a cell free manner.

Decreased immunosuppression associated with antitumor activity of 5-deoxy-5-fluorouridine compared to 5-fluorouracil and 5-fluorouridine.

5-Fluorouracil (5-FUra), 5-deoxy-5-fluorouridine (5'dFUrd), and 5-fluorouridine were compared for their relative antitumor activity, their capacity to inhibit leukocyte exudation and macrophage (macrophage) killing of tumor cells in vivo and in vitro, and their ability to induce leukopenia and monocytopenia. 5'dFUrd was less toxic than 5-FUra and exhibited anti-Ehrlich ascites activity over a wider range of drug doses. Inflammatory exudates induced by thioglycollate or pyran were inhibited up to 91% by prior 5-FUra injection but were inhibited not more than 62% by 5'dFUrd. Pyran-induced macrophage inhibition of Ehrlich ascites proliferation in vivo was diminished up to 5-fold by 5-FUra but was never diminished more than 2-fold by 5'dFUrd, while neither agent suppressed in vitro macrophage cytotoxicity of in vivo pyran-activated macrophage. At high doses, 5-FUra reduced white blood cell counts 73%, in contrast to the 8% reduction caused by 5'dFUrd, while at their optimal anti-Ehrlich ascites doses, 5-FUra and 5'dFUrd both lowered white blood cell counts by only 20%. However, 5-FUra caused a severe monocytopenia not seen in animals given injections of comparable doses of 5'dFUrd. Therefore, 5-FUra appeared to inhibit the inflammatory response and antitumor activity by inhibiting the influx of immature macrophage into the peritoneal cavity, not by inhibiting the function of mature effector cells.