Importance
Improving the representation of indigenous ophthalmologists in New Zealand.
Background
Māori, indigenous to New Zealand/Aotearoa and Pacific Peoples indigenous to Pacific Island Nations ...living in New Zealand, experience poorer health outcomes across several ophthalmic conditions. The Royal Australian and New Zealand College of Ophthalmologists have identified indigenous workforce development as a priority.
Design
Mixed‐methods study, utilizing retrospective analysis of Medical Schools Outcomes Database and Longitudinal Tracking Project responses, and prospective interviews with Māori/Pasifika medical graduates.
Participants
This study involved 64 medical graduates from the University of Auckland (UoA) and the University of Otago, and six Māori/Pasifika medical postgraduates in New Zealand.
Methods
Retrospective analysis of medical graduate responses who ranked ophthalmology among their top‐three preferred specialties in the Medical Schools Outcomes Database and Longitudinal Tracking Project. Prospective semi‐structured interviews with Māori/Pasifika medical postgraduates.
Main Outcome Measures
Specialty training influencing factors and prevocational ophthalmology experience.
Results
A total of 64 (6.7%) out of 954 medical graduates from the UoA and University of Otago ranked ophthalmology among their top‐three preferred training specialties (2012‐2017). Of the 64 graduates, six (9.3%) identified as Māori/Pasifika. No significant difference in influencing factors between Māori/Pasifika and non‐Māori/Pasifika students was identified. Both groups ranked intellectual content, procedural skills, specialty exposure and mentorship as highly influential. Qualitative interviews with Māori/Pasifika graduates highlighted positive experiences in ophthalmology but limited exposure overall. Negative anecdotes and unclear training pathways discouraged Māori/Pasifika interest in Ophthalmology training.
Conclusions and Relevance
Māori/Pasifika graduate interest in ophthalmology training was relatively low. Valuable insights include enhancing specialty exposure, mentor development, promoting Māori/Pasifika connections and clarifying training pathways for future graduates.
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together ...with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10
), 3p22.1 (rs67311347, P=2.5 × 10
), 3q26.2 (rs10936602, P=8.8 × 10
), 8p21.3 (rs2241261, P=5.8 × 10
), 10q24.33-q25.1 (rs11813268, P=3.9 × 10
), 11q22.3 (rs74911261, P=2.1 × 10
) and 14q24.2 (rs4903064, P=2.2 × 10
). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to ...immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.
Groundwater can have a critical role in sustaining the functioning of natural ecosystems during droughts, especially in dry and seasonally dry climates. However, the response to droughts of ...ecosystems embedded in urban areas is not well known. This study investigates how different scenarios of groundwater availability control the water balance and vegetation productivity of two urban reserves hosting native vegetation in the Melbourne metropolitan area, Australia. Using a mechanistic ecohydrological model supported by field observations, long‐term simulations were run to explore the impact of groundwater flow on water, carbon, and energy fluxes under present climatic conditions, including the Millennium Drought (2001–2009), and in response to perturbations in key environmental variables (air temperature, atmospheric CO2 concentrations, and rainfall). It was found that the presence of a water table and its capillary fringe within the root depths supports ecosystem transpiration and vegetation productivity. The effects of declining groundwater were found to be more severe in predominantly sandy soils because of the lower water holding capacity, identifying that the water status of vegetation differs significantly depending on soil type. Differences in rooting strategies and groundwater availability also had a pivotal role in helping plants soften the impacts of increased air temperature (Ta) and make use of higher atmospheric CO2 concentrations. Increased Ta strongly affected evapotranspiration, enhancing the competition for water between different vegetation types. These results provide quantitative insights of how vegetation responds to groundwater depletion and climate variability, highlighting the essential role of groundwater resources in urban ecosystems characterized by seasonally dry climates.
Key Points
Groundwater access is pivotal in supporting urban ecosystems functioning during prolonged droughts
Soil water holding capacity strongly affects ecosystem response to groundwater depletion
Groundwater access buffers the impacts of climate variability on ecosystem mass/energy fluxes
The semileptonic decay channel B→Dτν is sensitive to the presence of a scalar current, such as that mediated by a charged-Higgs boson. Recently, the BABAR experiment reported the first observation of ...the exclusive semileptonic decay B→Dτ(-)ν, finding an approximately 2σ disagreement with the standard-model prediction for the ratio R(D)=BR(B→Dτν)/BR(B→Dℓν), where ℓ = e,μ. We compute this ratio of branching fractions using hadronic form factors computed in unquenched lattice QCD and obtain R(D)=0.316(12)(7), where the errors are statistical and total systematic, respectively. This result is the first standard-model calculation of R(D) from ab initio full QCD. Its error is smaller than that of previous estimates, primarily due to the reduced uncertainty in the scalar form factor f(0)(q(2)). Our determination of R(D) is approximately 1σ higher than previous estimates and, thus, reduces the tension with experiment. We also compute R(D) in models with electrically charged scalar exchange, such as the type-II two-Higgs-doublet model. Once again, our result is consistent with, but approximately 1σ higher than, previous estimates for phenomenologically relevant values of the scalar coupling in the type-II model. As a by-product of our calculation, we also present the standard-model prediction for the longitudinal-polarization ratio P(L)(D)=0.325(4)(3).
At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term.
We conducted an open-label randomized controlled ...trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34(+0) and 37(+0) wk of gestation. Participants were randomly allocated in a 1:1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate. From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk RR 0.64; 95% confidence interval CI 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported. Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM.
In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM.
Current Controlled Trials ISRCTN29313500
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new ...treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6–180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42–120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.
Display omitted
Post-kala-azar dermal leishmaniasis (PKDL) is a chronic parasitic disease with limited treatment options. Here, Musa and colleagues report on a phase IIa therapeutic trial of the adenoviral-vectored leishmaniasis vaccine ChAd63-KH. Single-dose vaccination with ChAd63-KH was safe and induced innate and T cell responses in Sudanese patients with PKDL.
Objective
The aim of this study was to evaluate changes in speech characteristics and self-perceived quality of speech in tooth wear patients, after occlusal rehabilitation.
Materials and methods
...Patients with tooth wear were included in this study after informed consent. The amount of tooth wear was scored with Tooth Wear Evaluation System (TWES). To assess the perspective of the patient, the Dutch Speech Handicap Index was used (SHI). Acoustic analysis was performed to evaluate changes with the use of voice recordings. These were made before treatment,
T
0
; directly after treatment,
T
1
; 1 month after treatment,
T
2
. With the use of PRAAT software, the spectral characteristic centre of gravity (COG) was evaluated for the sounds /s/, /f/, /v/, /d/, /t/, /m/.
Results
Recordings of 17 patients (14 men, 3 women, mean age 41.2 ± 10.4 years) were included. SHI scores did not change significantly between
T
0
and
T
2
(
p
= 0.054). A multiple regression model showed that for all sounds the intercept was negative, but statistically significant only for /s/ and /f/ between
T
0
and
T
1
. The effect of the initial change (between
T
0
and
T
1
) on the change between
T
1
and
T
2
was clearly negative for all sounds (
p
< 0.001), showing a rebound effect ranging between 29 and 68% of the initial change.
Conclusion
Tooth wear patients perceive improvement in speech function after treatment.
Clinical significance
Clinicians may explain to patients that speech is likely to alter for a short period due to treatment but that there will be a good adaption to the new situation.
Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic ...susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (OR
) = 0.83 95% CI = 0.78-0.89, P
= 1.71 × 10
compared with female odds ratio (OR
) = 0.98 95% CI = 0.90-1.07, P
= 0.68) and 12q23.3 (intergenic, OR
= 0.75 95% CI = 0.68-0.83, P
= 1.59 × 10
compared with OR
= 0.93 95% CI = 0.82-1.06, P
= 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
PDF
