There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether ...hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis.
Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), α (dose-response slope using very low doses per fraction), and the ratio α/β that characterizes dose-fractionation sensitivity.
There was no significant difference between the α/β value for the three risk groups, and the value of α/β for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the α/β value.
The overall α/β value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings.
Despite MN being one of the most common causes of nephrotic syndrome worldwide, its biological and environmental determinants are poorly understood in large-part due to it being a rare disease. ...Making use of the UK Biobank, a unique resource holding a clinical dataset and stored DNA, serum and urine for ~500,000 participants, this study aims to address this gap in understanding.
The primary outcome was putative MN as defined by ICD-10 codes occurring in the UK Biobank. Univariate relative risk regression modelling was used to assess the associations between the incidence of MN and related phenotypes with sociodemographic, environmental exposures, and previously described increased-risk SNPs.
502,507 patients were included in the study of whom 100 were found to have a putative diagnosis of MN; 36 at baseline and 64 during the follow-up. Prevalence at baseline and last follow-up were 72 and 199 cases/million respectively. At baseline, as expected, the majority of those previously diagnosed with MN had proteinuria, and there was already evidence of proteinuria in patients diagnosed within the first 5 years of follow-up. The highest incidence rate for MN in patients was seen in those homozygous for the high-risk alleles (9.9/100,000 person-years).
It is feasible to putatively identify patients with MN in the UK Biobank and cases are still accumulating. This study shows the chronicity of disease with proteinuria present years before diagnosis. Genetics plays an important role in disease pathogenesis, with the at-risk group providing a potential population for recall.
Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted ...reproductive technologies (ARTs) occur during the sensitive periconceptional window of development, it has recently become a matter of urgency to investigate risk in ART-conceived children.
We have conducted the first large-scale, national cohort study of early growth in ART children from birth to school age, linking the register of ART, held by the UK's Human Fertilisation and Embryology Authority, to Scottish maternity and child health databases.
In this study of 5200 ART and 20,800 naturally conceived (NC) control children, linear regression analysis revealed the birthweight of babies born from fresh embryo transfer cycles is 93.7 g 95% CI (76.6, 110.6)g less than NC controls, whereas babies born from frozen embryo transfer (FET) cycles are 57.5 g 95% CI (30.7, 86.5)g heavier. Fresh ART babies grew faster from birth (by 7.2 g/week) but remained lighter (by 171 g), at 6-8 weeks, than NC babies and 133 g smaller than FET babies; FET and NC babies were similar. Length and occipital-frontal circumference followed the same pattern. By school entry (4-7 years), weight, length and BMI in boys and girls conceived by fresh ART and FET were similar to those in NC children.
ART babies born from fresh embryo transfer grow more slowly in utero and in the first few weeks of life, but then show postnatal catch up growth by school age, compared to NC and FET babies. As low birth weight and postnatal catch-up are independent risk factors for cardiometabolic disease over the life-course, we suggest that further studies in this area are now warranted.
The global network of scientific collaboration created by researchers opens new opportunities for developing countries to engage in the process of knowledge creation historically lead by institutions ...in the developed world. The results discussed here explore how Cubans working in European science and technology might contribute to extending the scientific collaboration of the country through their ties with Cuban institutions mainly in the academic sector. A bibliometric method was used to explore the pattern of collaboration of Cuban researchers in Europe using the institutional affiliation of authors and collaborators. The records of scientific publications of the defined sample were obtained from
Scopus
database for the period between 1995 and 2014. The network of collaboration was generated using the affiliations of Cuban authors in Europe and co-authors with worldwide affiliations shown in the records of publications of each Cuban researcher of the study. The analysis of aggregate values of the output of Cuban researchers in Europe (1995–2014) reveals that their collaboration with Cuba correlates moderately with their performance in Europe. However, when taking into account their time publishing in Europe, the collaboration with Cuba decreases the longer they remain away from home. The network of collaborating Cuban researchers in Europe comprises 991 different affiliations from 58 countries: 698 from Europe, 118 from North America, 96 from Latin America and 79 from the rest of the world.
K
-core analysis of centrality shows two Cuban universities sharing the central position with another 24 institutions worldwide of which 18 belong to higher education.
To assess implementation of the Saving Babies Lives (SBL) Care Bundle, a collection of practice recommendations in four key areas, to reduce stillbirth in England.
A retrospective cohort study of ...463,630 births in 19 NHS Trusts in England using routinely collected electronic data supplemented with case note audit (n = 1,658), and surveys of service users (n = 2,085) and health care professionals (n = 1,064). The primary outcome was stillbirth rate. Outcome rates two years before and after the nominal SBL implementation date were derived as a measure of change over the implementation period. Data were collected on secondary outcomes and process outcomes which reflected implementation of the SBL care bundle.
The total stillbirth rate, declined from 4.2 to 3.4 per 1,000 births between the two time points (adjusted Relative Risk (aRR) 0.80, 95% Confidence Interval (95% CI) 0.70 to 0.91, P<0.001). There was a contemporaneous increase in induction of labour (aRR 1.20 (95%CI 1.18-1.21), p<0.001) and emergency Caesarean section (aRR 1.10 (95%CI 1.07-1.12), p<0.001). The number of ultrasound scans performed (aRR 1.25 (95%CI 1.21-1.28), p<0.001) and the proportion of small for gestational age infants detected (aRR 1.59 (95%CI 1.32-1.92), p<0.001) also increased. Organisations reporting higher levels of implementation had improvements in process measures in all elements of the care bundle. An economic analysis estimated the cost of implementing the care bundle at ~£140 per birth. However, neither the costs nor changes in outcomes could be definitively attributed to implementation of the SBL care bundle.
Implementation of the SBL care bundle increased over time in the majority of sites. Implementation was associated with improvements in process outcomes. The reduction in stillbirth rates in participating sites exceeded that reported nationally in the same timeframe. The intervention should be refined to identify women who are most likely to benefit and minimise unwarranted intervention.
The study was registered on (NCT03231007); www.clinicaltrials.gov.
Background. Chronic pulmonary aspergillosis (CPA) is a severe, progressive respiratory infection characterized by multiple pulmonary cavities and increased levels of antibodies to Aspergillus ...species. We report the first use of posaconazole in patients with CPA. Methods. A retrospective study was performed. A composite clinical and radiological evaluation was used to assess response to posaconazole therapy. The rates of clinical response and failure after 6 and 12 months of therapy were determined. Kaplan-Meier survival models were developed to describe the time to clinical response and failure. The underlying diagnosis, the type of therapy (primary or salvage), Aspergillus antibody titer, and posaconazole serum concentrations were assessed as covariates. Aspergillus species were identified and minimum inhibitory concentrations (MICs) of triazoles were determined using standard techniques. Results. There were 79 patients that initially received posaconazole 400 mg twice per day. The median age of patients was 61 years, and 57% were male. Response to posaconazole was observed in 61% of patients at 6 months and in 46% at 12 months. Kaplan-Meier plots showed that the first response to posaconazole was observed in some patients only after approximately 1 year of therapy. Covariates were not significant. Adverse reactions were observed in 12 patients (15%) (nausea in 5, rash in 5, headache in 1, and lethargy in 1), leading to withdrawal of treatment for 9 patients. Aspergillus species were recovered from 22 patients. A posaconazole MIC of >8 mg/L was found in 4 isolates; in 1 of these isolates, this emerged during therapy. Treatment failed in all 4 patients from whom these 4 isolates had been recovered. Conclusion. Posaconazole is a safe and partially effective treatment for CPA. Prospective comparative studies are now required.
Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA ...DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention.
Context: Physical frailty is associated with reduced muscle strength, impaired physical function, and quality of life. Testosterone (T) increases muscle mass and strength in hypogonadal patients. It ...is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T.
Objective: Our objective was to determine the effects of 6 months T treatment in intermediate-frail and frail elderly men, on muscle mass and strength, physical function, and quality of life.
Design and Setting: We conducted a randomized, double-blind, placebo-controlled, parallel-group, single-center study.
Participants: Participants were community-dwelling intermediate-frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter.
Methods: Two hundred seventy-four participants were randomized to transdermal T (50 mg/d) or placebo gel for 6 months. Outcome measures included muscle strength, lean and fat mass, physical function, and self-reported quality of life.
Results: Isometric knee extension peak torque improved in the T group (vs. placebo at 6 months), adjusted difference was 8.6 (95% confidence interval, 1.3–16.0; P = 0.02) Newton-meters. Lean body mass increased and fat mass decreased significantly in the T group by 1.08 ± 1.8 and 0.9 ± 1.6 kg, respectively. Physical function improved among older and frailer men. Somatic and sexual symptom scores decreased with T treatment; adjusted difference was −1.2 (−2.4 to −0.04) and −1.3 (−2.5 to −0.2), respectively.
Conclusions: T treatment in intermediate-frail and frail elderly men with low to borderline-low T for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition, quality of life, and physical function. Further investigations are warranted to extend these results.
Treatment with testosterone of intermediate-frail and frail elderly men with low to borderline-low testosterone levels for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition, quality of life, and physical function.
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