Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate‐release tacrolimus (IR‐TAC) is not available. Alternative options explored include extended‐release tacrolimus (ER‐TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER‐TAC formulations are of non‐inferior efficacy compared to IR‐TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy‐proven rejection, but improved tolerance from classic adverse effects of IR‐TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third‐party payors is an obstacle in non‐KTRs. In the setting of IR‐TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156148/2/ctr13903.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156148/1/ctr13903_am.pd

Exercise training as a novel primary treatment for localised prostate cancer: a multi-site randomised controlled phase II study

Alternative management strategies for localised prostate cancer are required to reduce morbidity and overtreatment. The aim of this study was to evaluate the feasibility, safety and acceptability of exercise training (ET) with behavioural support as a primary therapy for low/intermediate risk localised prostate cancer. Men with low/intermediate-risk prostate cancer were randomised to 12 months of ET or usual care with physical activity advice (UCwA) in a multi-site open label RCT. Feasibility included acceptability, recruitment, retention, adherence, adverse events and disease progression. Secondary outcomes included quality of life and cardiovascular health indices. Of the 50 men randomised to ET (n=25) or UCwA (n=25), 92% (n=46) completed 12 month assessments. Three men progressed to invasive therapy (two in UCwA). In the ET group, men completed mean: 140 mins per week for 12 months (95% CI 129,152mins) (94% of target dose) at 75% Hrmax. Men in the ET group demonstrated improved body mass (mean reduction: 2.0 kg; 95% CI -2.9,-1.1), reduced systolic (mean: 13 mmHg; 95% CI 7,19) and diastolic blood pressure (mean:8 mmHg; 95% CI 5,12) and improved quality of life (EQ5D mean:13 points; 95% CI 7,18). There were no serious adverse events. ET in men with low/intermediate risk prostate cancer is feasible and acceptable with a low progression rate to radical treatment. Early signals on clinically relevant markers were found which warrant further investigation

A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer

Although prostate cancer (PrCa) is one of the most common cancers in men in Western countries, little is known about the inherited factors that influence PrCa risk. On the basis of the fact that BRIP1/FANCJ interacts with BRCA1 and functions as a regulator of DNA double-strand break repair pathways, and that germline mutations within the BRIP1/FANCJ gene predispose to breast cancer, we chose this gene as a candidate for mutation screening in familial and young-onset PrCa cases. We identified a truncating mutation, R798X, in the BRIP1/FANCJ gene in 4 out of 2714 UK PrCa cases enriched for familial (2 out of 641; 0.3%) and young-onset cases (2 out of 2073; 0.1%). On screening 2045 controls from the UK population, we found one R798X sequence alteration (0.05%; odds ratio 2.4 (95% CI 0.25–23.4)). In addition, using our data from a genome-wide association study, we analysed 25 SNPs in the genomic region of the BRIP1/FANCJ gene. Two SNPs showed evidence of association with familial and young-onset PrCa (rs6504074; Ptrend=0.04 and rs8076727; Ptrend=0.01). These results suggest that truncating mutations in BRIP1/FANCJ might confer an increased risk of PrCa and common SNPs might also contribute to the alteration of risk, but larger case–control series will be required to confirm or refute this association

Stuttered swallowing: Electric stimulation of the right insula interferes with water swallowing. A case report

<p>Abstract</p> <p>Background</p> <p>Various functional resonance imaging, magnetoencephalographic and lesion studies suggest the involvement of the insular cortex in the control of swallowing. However, the exact location of insular activation during swallowing and its functional significance remain unclear.</p> <p>Case presentation</p> <p>Invasive electroencephalographic monitoring was performed in a 24-year-old man with medically intractable stereotyped nocturnal hypermotor seizures due to a ganglioglioma. During stimulation of the right inferior posterior insular cortex with depth electrodes the patient spontaneously reported a perception of a "stutter in swallowing". Stimulation of the inferior posterior insular cortex at highest intensity (4 mA) was also associated with irregular and delayed swallows. Swallowing was not impaired during stimulation of the superior posterior insular cortex, regardless of stimulation intensity.</p> <p>Conclusions</p> <p>These results indicate that the right inferior posterior insular cortex is involved in the neural circuitry underlying the control of swallowing.</p

Evidence based post graduate training. A systematic review of reviews based on the WFME quality framework

<p>Abstract</p> <p>Background</p> <p>A framework for high quality in post graduate training has been defined by the World Federation of Medical Education (WFME). The objective of this paper is to perform a systematic review of reviews to find current evidence regarding aspects of quality of post graduate training and to organise the results following the 9 areas of the WFME framework.</p> <p>Methods</p> <p>The systematic literature review was conducted in 2009 in Medline Ovid, EMBASE, ERIC and RDRB databases from 1995 onward. The reviews were selected by two independent researchers and a quality appraisal was based on the SIGN tool.</p> <p>Results</p> <p>31 reviews met inclusion criteria. The majority of the reviews provided information about the training process (WFME area 2), the assessment of trainees (WFME area 3) and the trainees (WFME area 4). One review covered the area 8 'governance and administration'. No review was found in relation to the mission and outcomes, the evaluation of the training process and the continuous renewal (respectively areas 1, 7 and 9 of the WFME framework).</p> <p>Conclusions</p> <p>The majority of the reviews provided information about the training process, the assessment of trainees and the trainees. Indicators used for quality assessment purposes of post graduate training should be based on this evidence but further research is needed for some areas in particular to assess the quality of the training process.</p

Are diet–prostate cancer associations mediated by the IGF axis? A cross-sectional analysis of diet, IGF-I and IGFBP-3 in healthy middle-aged men

We examined the association of diet with insulin-like growth factors (IGF) in 344 disease-free men. Raised levels of IGF-I and/or its molar ratio with IGFBP-3 were associated with higher intakes of milk, dairy products, calcium, carbohydrate and polyunsaturated fat; lower levels with high vegetable consumption, particularly tomatoes. These patterns support the possibility that IGFs may mediate some diet-cancer associations

VLPs and particle strategies for cancer vaccines

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Modelling Malpighian tubule crystals within the predatory soil mite Pergamasus longicornis (Mesostigmata: Parasitidae)

The occurrence of refractive crystals (aka guanine) is characterised in the Malpighian tubules of the free-living predatory parasitiform soil mite Pergamasus longicornis (Berlese) from a temporal series of histological sections during and after feeding on larval dipteran prey. The tubular system behaves as a single uniform entity during digestion. Malpighian mechanisms are not the 'concentrative' mechanism sought for the early stasis in gut size during the second later phase of prey feeding. Nor are Malpighian changes associated with the time of 'anal dabbing' during feeding. Peak gut expansion precedes peak Malpighian tubule guanine crystal occurrence in a hysteretic manner. There is no evidence of Malpighian tubule expansion by uid alone. Crystals are not found during the slow phase of liquidised prey digestion. Malpighian tubules do not appear to be osmoregulatory. Malpighian guanine is only observed 48h to 10d after the commencement of feeding. Post digestion guanine crystal levels in the expanded Malpighian tubules are high - peaking as a pulse 5d after the start of feeding (i.e. after the gut is void of food at 52.5h). The half-life of guanine elimination from the tubules is 53h. Evidence for a physiological input cascade is found - the effective half-life of guanine appearance in the Malpighian tubules being 7.8-16.7h. Crystals are found present at all times in the lumen of the rectal vesicle and not anywhere else lumenally in the gut at all. No guanine was observed inside gut cells. There is no evidence for the storage in the rectal vesicle of a `pulse' of Malpighian excretory products from a discrete `pulse' of prey ingestion. A latent egestive common catabolic phase in the gut is inferred commencing 12.5h after the start of feeding which may cause the rectal vesicle to expand due to the catabolism of current or previous meals. Malpighian tubules swell as the gut contracts in size over time post-prandially. There is evidence that at a gross level the contents of the rectal vesicle are mechanically voided by the physical mechanism of overall gut expansion altering the effective idiosomal volume available during prey ingestion. A complete cycle of feeding, digestion, egestion and excretion is approximately 9d. Hunger/starvation likely commences at 10d after the start of feeding. Up to 15d may be needed to completely clear the idiosoma of excretory material. Nomograms for predicting the likely feeding time of mites from observations of idiosomal guanine in field samples indicate that as few as 5-6 mites scoring positive for Malpighian tubule guanine out of 20 infers a high probability that the typical time from start of feeding in a population sample was about 6d (range 3-8d) ago

Prostate cancer risk related to foods, food groups, macronutrients and micronutrients derived from the UK Dietary Cohort Consortium food diaries.

BACKGROUND/OBJECTIVES: The influence of dietary factors remains controversial for screen-detected prostate cancer and inconclusive for clinically detected disease. We aimed to examine these associations using prospectively collected food diaries. SUBJECTS/METHODS: A total of 1,717 prostate cancer cases in middle-aged and older UK men were pooled from four prospective cohorts with clinically detected disease (n=663), with routine data follow-up (means 6.6-13.3 years) and a case-control study with screen-detected disease (n=1054), nested in a randomised trial of prostate cancer treatments (ISCTRN 20141297). Multiple-day food diaries (records) completed by men prior to diagnosis were used to estimate intakes of 37 selected nutrients, food groups and items, including carbohydrate, fat, protein, dairy products, fish, meat, fruit and vegetables, energy, fibre, alcohol, lycopene and selenium. Cases were matched on age and diary date to at least one control within study (n=3528). Prostate cancer risk was calculated, using conditional logistic regression (adjusted for baseline covariates) and expressed as odds ratios in each quintile of intake (±95% confidence intervals). Prostate cancer risk was also investigated by localised or advanced stage and by cancer detection method. RESULTS: There were no strong associations between prostate cancer risk and 37 dietary factors. CONCLUSIONS: Prostate cancer risk, including by disease stage, was not strongly associated with dietary factors measured by food diaries in middle-aged and older UK men.Medical Research Council (Grant ID: MC_UU_12019/1), Medical Research Council Population Health Sciences Research Network, British Heart Foundation, Cancer Research UK (Grant ID: C8221/A19170), Department of Health, Food Standards Agency, Stroke Association, WCRF, National Institute for Health Research Health Technology Assessment Programme (Project IDs: 96/20/06, 96/20/99), National Cancer Research Institute (formed by Cancer Research UK, Medical Research Council, Department of Health)This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ejcn.2016.16