Purpose
Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well ...understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including
GSTT1, GSTM1
and
GSTP1,
encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN. This study aimed to investigate four markers in these genes for an association in a mixed cancer cohort in relation to CIPN (
n
= 172).
Methods
CIPN was measured using the neuropathy item from the Patient Reported Outcome Common Terminology Criteria for Adverse Event (PRO-CTCAE) assessment. Genotyping for all samples was performed using PCR for the
GSTM1
and
GSTT1
null variants and restriction fragment length polymorphisms for the
GSTP1
and
GSTM1
polymorphisms.
Results
No associations were found for the GST gene markers in relation to CIPN within our study, or CIPN severity. Longitudinal stratification of the CIPN phenotypes to examine links for neuropathy, identified nominally significant protective associations with the
GSTM*
null allele (
p
-value = 0.038, OR = 0.55) and the presence of pain at month 2 of treatment, as well as a risk factor for pain related month 2 of treatment for individuals with the
GSTT1*
null allele (
p
-value = 0.030, OR = 1.64). Higher severity of pain in patients with CIPN persisted at each time-point compared to those without CIPN.
Conclusion
No significant results for an association between CIPN with polymorphisms in GSTM1, GSTT1 and GSTP1 were identified. However, associations for the GSTM1¬-null and GSTT1-null polymorphisms with pain at month 2 following chemotherapy were identified.
Summary Background Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of ...adjunctive vitamin D on sputum culture conversion are absent. Methods We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for Taq I and Fok I polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D3 . This trial is registered with ClinicalTrials.gov number NCT00419068. Findings 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14). Taq I genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (pinteraction =0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36–48·01; p=0·02). Fok I genotype did not modify the effect of vitamin D supplementation (pinteraction =0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p<0·0001). Interpretation Administration of four doses of 2·5 mg vitamin D3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. Funding British Lung Foundation.
Summary Background Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of ...end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. Methods We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov , NCT00299260. Findings 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients. Interpretation Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. Funding National Institute of Allergy and Infectious Diseases , Grant R01AI051355 and Wellcome Trust , Grant 078332 . Sponsor: University College London (UCL).
We performed flow cytometry and AgNOR counts on 117 serous and mucinous ovarian tumours, comprising 56 cystadenomas, 21 borderline tumours, and 40 cystadenocarcinomas. DNA aneuploidy was present in ...one cystadenoma and in 11% of mucinous and 46% of serous cystadenocarcinomas. All borderline tumours were DNA diploid. Major and minor FIGO stages and flow cytometrically determined DNA ploidy and DNA index were prognostically significant. Age, histological type (serous versus mucinous), flow cytometric proliferative index, and AgNOR counts were not predictive of survival. Cystadenomas and borderline tumours had lower rates of proliferation than cystadenocarcinomas. AgNORs correlated with DNA ploidy and proliferative index. Borderline tumours showed elevated AgNOR numbers despite low proliferative indices and universal DNA diploidy, suggesting that AgNOR numbers may be related to nuclear events other than proliferation and DNA ploidy.
Background The national field trauma triage guidelines have been widely implemented in US trauma systems, but never prospectively validated. We sought to prospectively validate the guidelines, as ...applied by out-of-hospital providers, for identifying high-risk trauma patients. Study Design This was an out-of-hospital prospective cohort study from January 1, 2011 through December 31, 2011 with 44 Emergency Medical Services agencies in 7 counties in 2 states. We enrolled injured patients transported to 28 acute care hospitals, including 7 major trauma centers (Level I and II trauma hospitals) and 21 nontrauma hospitals. The primary exposure term was Emergency Medical Services' use of one or more field triage criteria in the national field triage guidelines. Outcomes included Injured Severity Score ≥16 (primary) and critical resource use within 24 hours of emergency department arrival (secondary). Results We enrolled 53,487 injured children and adults transported by Emergency Medical Services to an acute care hospital, 17,633 of which were sampled for the primary analysis; 13.9% met field triage guidelines, 3.1% had Injury Severity Score ≥16, and 1.7% required early critical resources. The sensitivity and specificity of the field triage guidelines were 66.2% (95% CI, 60.2–71.7%) and 87.8% (95% CI, 87.7–88.0%) for Injury Severity Score ≥16 and 80.1% (95% CI, 65.8–89.4%) and 87.3% (95% CI 87.1–87.4%) for early critical resource use. Triage guideline sensitivity decreased with age, from 87.4% in children to 51.8% in older adults. Conclusions The national field triage guidelines are relatively insensitive for identifying seriously injured patients and patients requiring early critical interventions, particularly among older adults.
Large hysteresis loops are observed during cyclic loading–unloading of Mg and Mg–Zn alloys. This is true for both tension and compression cycling, for grain sizes between 25 and 670
μm, and for Zn ...contents between 0 and 6
mass%. The loops are ascribed to anelasticity resulting from elastic
{
1
0
1
¯
2
}
twinning. The anelastic strain increases with the strain and reaches a maximum at strains between about 1 and 2%. For a given total strain, the amount of anelastic strain increases with decreasing grain size, and decreases with increasing Zn content. The maximum observed anelastic strain is about 0.3% for pure Mg, decreasing with the solute content to about 0.2% for Mg–6
mass% Zn. The phenomenon is discussed in terms of the effect of solute content and grain size on the formation and stability of twins.
Summary
Background
The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium has a collective aim to develop a prescribing algorithm to help stratify eligible patients with ...psoriasis to the most appropriate biological treatment. To facilitate the adoption of a stratified approach, it is necessary to first understand the factors driving the choice of first‐line biological therapy.
Objectives
To identify and quantify factors that influence the selection of the first‐line biological therapy for people with psoriasis.
Methods
Multinomial logistic regression was used to determine the factors that influenced the probability of treatment selection, using data from the British Association of Dermatologists Biologic Interventions Register from January 2012 to December 2015. Sensitivity analyses were performed to assess the robustness of the findings to key assumptions.
Results
The main analysis was based on a dataset comprising 3040 people with psoriasis. The identified factors affecting first‐line biological selection within the available therapies were: presence of psoriatic arthritis; patient weight; employment status; country of registration; and baseline disease severity. Importantly, the analysis showed a general shift in prescribing behaviour over time. These results were robust to sensitivity analysis.
Conclusions
This study offers important insights into the factors influencing current prescribing practice for first‐line biological therapies for people with psoriasis. It provides baseline data to inform the evaluation of future potential changes that may affect prescribing behaviour, such as stratified medicine.
What's already known about this topic?
Previous research has explored the effectiveness and safety of different biological therapies for people with psoriasis.
The factors that predict whether or not a person with psoriasis will start a biological therapy have been identified.
What does this study add?
We identify factors that influenced how dermatologists chose between adalimumab, etanercept and ustekinumab for people with psoriasis. Statistically significant factors included presence of psoriatic arthritis, patient weight, registration country, employment status and disease severity.
The study suggests that dermatologists change their prescribing behaviour in line with experiences and emerging evidence on treatment effectiveness and safety.
We provide baseline data to inform the evaluation of new strategies that may influence prescribing.
Respond to this article
Linked Comment: Puig. Br J Dermatol 2017; 177:623–624
Background: Although rates vary across studies, research in recent years shows that prevalence of post‐traumatic stress disorder (PTSD) following intensive care unit (ICU) can be high. Presently no ...screening tool assessing all three PTSD symptom categories has been validated in ICU patients. The aim of the study was to conduct a preliminary validation of such a measure, the UK‐ Post‐Traumatic Stress Syndrome 14‐Questions Inventory (UK‐PTSS‐14).
Methods: A case series cohort study performed at two ICUs in two UK district general hospitals. The UK‐PTSS‐14 was administered at three time‐points (4–14 days, 2 months and 3 months post‐ICU discharge). At time‐point three participants also completed the Post‐traumatic Stress Diagnostic Scale (PDS) and the Impact of Events Scale (IES).
Results: Forty‐four patients completed the 3‐month follow up. The UK‐PTSS‐14 was internally reliable at all three time‐points (Cronbach's α=0.89, 0.86 and 0.84, respectively). Test–retest reliability was highest between time‐points two and three (ICC=0.90). Concurrent validity at time‐point three was high against the PDS (r=0.86) and the IES (r=0.71). Predictive validity was highest at time‐point two (r=0.85 with the PDS and r=0.71 with the IES). Receiver operator characteristic curve analysis suggested the highest levels of sensitivity (86%) and specificity (97%) for diagnosis of PTSD were at time‐point two, with an optimum decision threshold of 45 points.
Conclusion: This preliminary validation study suggests that the UK‐PTSS‐14 could be reliably used as a screening instrument at 2 months post‐discharge from the ICU to identify those patients in need of referral to specialist psychological services.
Previous studies have discussed the low prevalence of psoriasis among indigenous peoples of South America. The state of Roraima, Brazil, where the present study was performed, is crossed by the ...equator line. It is likely that key factors for the absence of psoriasis in this indigenous population include genetic factors, a lack of environmental triggers and high sun exposure.
PDF
