Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.

OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation. RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration. CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.

The effect of sunscreen on vitamin D: a review.

BACKGROUND: Sunscreen use can prevent skin cancer, but there are concerns that it may increase the risk of vitamin D deficiency. OBJECTIVES: We aimed to review the literature to investigate associations between sunscreen use and vitamin D3 or 25 hydroxyvitamin D [25(OH)D] concentration. METHODS: We systematically reviewed the literature following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. We identified manuscripts published in English between 1970 and 21 November 2017. Eligible studies were experimental [using an artificial ultraviolet radiation (UVR) source], field trials or observational studies. The results of each of the experimental studies and field trials are described in detail. Two authors extracted information from observational studies, and applied quality scoring criteria that were developed specifically for this question. These have been synthesized qualitatively. RESULTS: We included four experimental studies, three field trials (two were randomized controlled trials) and 69 observational studies. In the experimental studies sunscreen use considerably abrogated the vitamin D3 or 25(OH)D production induced by exposure to artificially generated UVR. The randomized controlled field trials found no effect of daily sunscreen application, but the sunscreens used had moderate protection [sun protection factor SPF) ~16]. The observational studies mostly found no association or that self-reported sunscreen use was associated with higher 25(OH)D concentration. CONCLUSIONS: There is little evidence that sunscreen decreases 25(OH)D concentration when used in real-life settings, suggesting that concerns about vitamin D should not negate skin cancer prevention advice. However, there have been no trials of the high-SPF sunscreens that are now widely recommended. What's already known about this topic? Previous experimental studies suggest that sunscreen can block vitamin D production in the skin but use artificially generated ultraviolet radiation with a spectral output unlike that seen in terrestrial sunlight. Nonsystematic reviews of observational studies suggest that use in real life does not cause vitamin D deficiency. What does this study add? This study systematically reviewed all experimental studies, field trials and observational studies for the first time. While the experimental studies support the theoretical risk that sunscreen use may affect vitamin D, the weight of evidence from field trials and observational studies suggests that the risk is low. We highlight the lack of adequate evidence regarding use of the very high sun protection factor sunscreens that are now recommended and widely used.

Clinical outcomes following unilateral adrenalectomy in patients with primary aldosteronism.

BACKGROUND: In approximately half of cases of primary aldosteronism (PA), the cause is a surgically-resectable unilateral aldosterone-producing adrenal adenoma. However, long-term data on surgical outcomes are sparse. AIM: We report on clinical outcomes post-adrenalectomy in a cohort of patients with PA who underwent surgery. DESIGN: Retrospective review of patients treated for PA in a single UK tertiary centre. METHODS: Of 120 consecutive patients investigated for PA, 52 (30 male, median age 54, range 30-74) underwent unilateral complete adrenalectomy. Blood pressure, number of antihypertensive medications, and serum potassium were recorded before adrenalectomy, and after a median follow-up period of 50 months (range 7-115). Recumbent renin and aldosterone were measured, in the absence of interfering antihypertensive medication, ≥3months after surgery, to determine if PA had been biochemically cured. RESULTS: Overall, blood pressure improved from a median (range) 160/95 mmHg (120/80-250/150) pre-operatively to 130/80 mmHg (110/70-160/93), P < 0.0001. 24/52 patients (46.2%) had cured hypertension, with a normal blood pressure post-operatively on no medication. 26/52 (50%) had improved hypertension. 2/52 patients (3.8%) showed no improvement in blood pressure post-operatively. Median (range) serum potassium level increased from 3.2 (2.3-4.7) mmol/l pre-operatively to 4.4 mmol/l (3.3-5.3) post-operatively, P < 0.0001). Median (range) number of antihypertensive medications used fell from 3 (0-6) pre- to 1 post-operatively (range 0-4), P < 0.0001. CONCLUSIONS: Unilateral adrenalectomy provides excellent long-term improvements in blood pressure control, polypharmacy and hypokalaemia in patients with lateralizing PA. These data may help inform discussions with patients contemplating surgery.

Determinants of survival and attempted resection in patients with non-metastatic pancreatic cancer: An Australian population-based study.

BACKGROUND: There are indications that pancreatic cancer survival may differ according to sociodemographic factors, such as residential location. This may be due to differential access to curative resection. Understanding factors associated with the decision to offer a resection might enable strategies to increase the proportion of patients undergoing potentially curative surgery. METHODS: Data were extracted from medical records and cancer registries for patients diagnosed with pancreatic cancer between July 2009 and June 2011, living in one of two Australian states. Among patients clinically staged with non-metastatic disease we examined factors associated with survival using Cox proportional hazards models. To investigate survival differences we examined determinants of: 1) attempted surgical resection overall; 2) whether patients with locally advanced disease were classified as having resectable disease; and 3) attempted resection among those considered resectable. RESULTS: Data were collected for 786 eligible patients. Disease was considered locally advanced for 561 (71%) patients, 510 (65%) were classified as having potentially resectable disease and 365 (72%) of these had an attempted resection. Along with age, comorbidities and tumour stage, increasing remoteness of residence was associated with poorer survival. Remoteness of residence and review by a hepatobiliary surgeon were factors influencing the decision to offer surgery. CONCLUSIONS: This study indicated disparity in survival dependent on patients' residential location and access to a specialist hepatobiliary surgeon. Accurate clinical staging is a critical element in assessing surgical resectability and it is therefore crucial that all patients have access to specialised clinical services.

Cerebrospinal fluid chimerism analysis in patients with neurological symptoms after allogeneic cell transplantation.

Central nervous system (CNS) complications have been described in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). Cerebrospinal fluid (CSF) analysis is included in the diagnostic workup in patients with neurological symptoms after alloHCT. CSF donor-recipient chimerism analysis usually is not used to evaluate patients with neurological complications after alloHCT. To assess the potential contribution of CSF donor-recipient chimerism in patients with neurological complications, we analyzed 85 CSF samples from 50 patients with neurological complications after alloHCT. After alloHCT, 21 patients showed the presence of recipient-derived DNA. In 13 of these patients, recurrence of the underlying disease was detected in CSF. There was a moderate correlation between the recipient DNA percentage as detected by short tandem repeat (STR) amplification and the cell concentration in CSF (Spearmann r: 0.66 P=0.004). The percentage of cells with immunophenotypic abnormalities from patients relapsing in the CNS detected by flow cytometry showed a strong correlation with the percentage of recipient-derived DNA in CSF assessed by STR analysis (Spearmann r: 0.83 P=0.0008). Donor-recipient chimerism analysis in CSF in patients with neurological symptoms after alloHCT is a practical, feasible and useful complementary method to the already established methodologies included in the diagnostic workup.

Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

BACKGROUND: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. PATIENTS AND METHODS: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. RESULTS: Risk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07-1.19, P = 7.4 × 10(-6), P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10-1.55, P = 2.4 × 10(-3), P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake. CONCLUSION: Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.

The effectiveness of a specialised oral nutrition supplement on outcomes in patients with chronic wounds: a pragmatic randomised study.

BACKGROUND: Nutrition supplements enriched with immune function enhancing nutrients have been developed to aid wound-healing, although evidence regarding their effectiveness is limited and systematic reviews have lead to inconsistent recommendations. The present pragmatic, randomised, prospective open trial evaluated a wound-specific oral nutrition supplement enriched with arginine, vitamin C and zinc compared to a standard supplement with respect to outcomes in patients with chronic wounds in an acute care setting. METHODS: Twenty-four patients [11 males and 13 females; mean (SD) age: 67.8 (22.3) years] with chronic wounds (14 diabetic or venous ulcers; 10 pressure ulcers or chronic surgical wounds) were randomised to receive either a wound-specific supplement (n = 12) or standard supplement (n = 12) for 4 weeks, with ongoing best wound and nutrition care for an additional 4 weeks. At baseline, and at 4 and 8 weeks, the rate of wound-healing, nutritional status, protein and energy intake, quality of life and product satisfaction were measured. Linear mixed effects modelling with random intercepts and slopes were fitted to determine whether the wound-specific nutritional supplement had any effect. RESULTS: There was a significant improvement in wound-healing in patients receiving the standard nutrition supplement compared to a wound-specific supplement (P = 0.044), although there was no effect on nutritional status, dietary intake, quality of life and patient satisfaction. CONCLUSIONS: The results of the present study indicate that a standard oral nutrition supplement may be more effective at wound-healing than a specialised wound supplement in this clinical setting.

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML.

A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m(2) and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients ≥ 65 years old who relapsed >12 months after the first allograft (n=20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse.

Soluble HLA-G molecules and HLA-G 14-base pair polymorphism after allogeneic hematopoietic cell transplantation.

HLA-G 14-base pair (bp) polymorphism and soluble human leukocyte antigen G were previously reported to be implicated in allogeneic hematopoietic cell transplantation (allo-HSCT) outcome. However, soluble HLA-G blood levels and the 14-bp insertion-deletion polymorphism were separately assessed in the context of allo-HSCT. The aim of the present study was to examine the influence of the 14-bp insertion/deletion polymorphism of the HLA-G gene together with the soluble HLA-G plasma levels on allo-HSCT complications. We investigated the possible impact of HLA-G 14-bp polymorphism together with the pretransplantation and posttransplantation concentration of soluble HLA-G in 59 patients undergoing allo-HSCT. No association was found between the HLA-G 14-bp polymorphism, the soluble HLA-G level and acute graft-versus-host disease (GvHD), disease recurrence, or death. In contrast with previous reports the present data suggest a weak or negligible involvement of both 14-bp polymorphism on HLA-G gene and sHLA-G concentration in posttransplantation complications such as acute or chronic GvHD, relapse, or death.

Nutritional status of long-term patients in the acute care setting.

The nutritional status of 926 patients (51.4% female) at an acute tertiary private hospital with a length of stay ≥14 days was assessed using Subjective Global Assessment. The prevalence of malnutrition was 42.5% (37.2% length of stay of 14-27 days, 51.6% ≥28 days). From logistic regression analysis, length of stay and age were independent predictors of malnutrition. It is important that the nutritional status of longer stay patients is monitored and appropriate nutrition support is commenced.

Organic matter loading affects lodgepole pine seedling growth.

Organic matter plays important roles in returning nutrients to the soil, maintaining forest productivity and creating habitats in forest ecosystems. Forest biomass is in increasing demand for energy production, and organic matter has been considered as a potential supply. Thus, an important management question is how much organic matter should be retained after forest harvesting to maintain forest productivity. To address this question, an experimental trial was established in 1996 to evaluate the responses of lodgepole pine seedling growth to organic matter loading treatments. Four organic matter loading treatments were randomly assigned to each of four homogeneous pine sites: removal of all organic matter on the forest floor, organic matter loading quantity similar to whole-tree-harvesting residuals left on site, organic matter loading quantity similar to stem-only-harvesting residuals, and organic matter loading quantity more similar to what would be found in disease- or insect-killed stands. Our 10-year data showed that height and diameter had 29 and 35 % increase, respectively, comparing the treatment with the most organic matter loading to the treatment with the least organic matter loading. The positive response of seedling growth to organic matter loading may be associated with nutrients and/or microclimate change caused by organic matter, and requires further study. The dynamic response of seedling growth to organic matter loading treatments highlights the importance of long-term studies. Implications of those results on organic matter management are discussed in the context of forest productivity sustainability.

Role of overcrowding in meticillin-resistant Staphylococcus aureus transmission: Bayesian network analysis for a single public hospital.

The transmission of multiple antibiotic-resistant organisms (MROs) in hospitals is affected by many inter-related factors. These include the background prevalence of the organism (burden), hand hygiene, the efficiency of patient screening, the isolation or cohorting of carriers, the quality of hospital cleaning, and bed occupancy. In addition, the prevalence of one MRO may influence the transmission of another by occupying isolation beds, and thus reducing isolation resources for the latter. For example, the overuse of third generation cephalosporin antibiotics can increase extended-spectrum ß-lactamase-producing Klebsiella pneumoniae, thus indirectly influencing the transmission of meticillin-resistant Staphylococcus aureus (MRSA). In order to study this complex system of interrelationships, we have employed a Bayesian network. We report results of the first two years of analysis for a single public hospital. We conclude that, within this institution, the association between high bed occupancy and increased transmission of MRSA may be subject to a dynamic multidimensional threshold and tipping point. This may be influenced by other factors such as MRSA burden and whether the high bed occupancy interferes with preparation and cleaning of beds for new patients and with hand hygiene and efforts to isolate or cohort carriers.

Analysis of aggregated hospital infection data for accountability.

Analysis and reporting of among-institution aggregated hospital-acquired infection data are necessary for transparency and accountability. Different analytical methods are required for ensuring transparency and accountability for within-institution sequential analysis. In addition, unbiased summary information is needed for planning and informing the public. We believe that implementation of systems based on evidence is the key to improving institutional performance and safety. This must be accompanied by compliance, outcome audit and sequential analysis of outcome data, e.g. using statistical process control methods. Checklists can be a valuable aid for ensuring implementation of evidence-based systems. Aggregated outcome data analysis for transparency and accountability should concentrate primarily on accurately presenting the outcomes together with their precision. We describe tabulations, funnel plots and random-effects (shrinkage) analysis and avoid comparisons using league tables, star ratings and confidence intervals.

Limiting risk of hospital adverse events: avoiding train wrecks is more important than counting and reporting them.

Targets implemented at national or state levels have been employed in response to excessive numbers of adverse events (AEs) such as multiple antibiotic-resistant Staphylococcus aureus bacteraemias. Hospital resources are limited and setting such targets can result in resource diversion to dealing with the targeted AEs. There may be initial success as judged by decreasing counts but underlying problems are not necessarily addressed, and there is evidence that other non-targeted AEs may increase. Moreover, the values of individual observations can be greatly influenced by random variation. This can make it difficult using comparisons and targets to draw conclusions about the work of an institution. Although counting AEs is essential, the key to avoiding episodes of patient harm is prevention. This requires the implementation of evidence-based systems. These are already available for many AEs in the form of 'bundles' and checklists. When these systems are properly implemented and sustained, AE rates tend to occur at minimum predictable levels. Unfortunately, in spite of widespread knowledge and aggressive promotion, high levels of compliance have often been difficult to achieve and sustain. Better understanding and implementation of methods to sustain evidence-based systems are needed. Checklists, used as part of an overall system involving leadership and empowerment, application of evidence, culture change and measurement, may help to overcome this problem.

Sequential analysis of uncommon adverse outcomes.

Sequential analysis of uncommon adverse outcomes (AEs) such as surgical site infections (SSIs) is desirable. Short postoperative lengths of stay (LOS) result in many SSIs occurring after discharge and they are often superficial. Deep and organ space (complex) SSIs occur less frequently but are detected more reliably and are suitable for monitoring wound care. Those occurring post-discharge usually require readmissison and can be counted accurately. Sequential analysis of meticillin-resistant Staphylococcus aureus bacteraemia is also needed. The key to prevention is to implement systems based on evidence, e.g. using 'bundles' and checklists. Regular mortality and morbidity audit meetings are required and these may need to be followed by independent audits. Sequential statistical analysis is desirable for data presentation, to detect changes, and to discourage tampering with processes when occasional AEs occur in a reliable system. Tabulations and cumulative observed minus expected (O-E) charts and funnel plots are valuable, supplemented in the presence of apparent 'runs' of AEs by cumulative sum analysis. Used prospectively, they may enable staff to visualise and detect patterns or shifts in rates and counts that might not otherwise be apparent.

Alloreactive microenvironment after human hematopoietic cell transplantation induces genomic alterations in epithelium through an ROS-mediated mechanism: in vivo and in vitro study and implications to secondary neoplasia.

We hypothesized that chronic tissue stress due to interaction of alloreactive donor cells with host epithelium after allogeneic hematopoietic cell transplantation (allo-HCT) may cause genomic alterations. We therefore analyzed 176 buccal samples obtained from 71 unselected allotransplanted patients for microsatellite instability (MSI). MSI was observed in 52% of allotransplanted patients but never in 31 healthy or autotransplanted controls. The patient age, the donor age, a female-to-male transplantation and a low number of CD34(+) cells in the graft were significantly correlated with genomic instability. There was a trend for increasing risk of MSI for patients who experienced severe graft-vs-host disease. Secondary malignancy was diagnosed in five (14%) of the MSI(+) and only in one (3%) MSI(-) patient. In an in vitro model of mutation analysis we found significant induction of frameshift mutations and DNA strand breaks in HaCaT keratinocytes co-cultured with mixed lymphocyte cultures (MLCs) but not after their exposure to interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta (TGF-beta), MLC supernatant, peripheral blood mononuclear cells (PBMCs) or phytohemagglutinin-stimulated PBMC. A reactive oxygen species-mediated mechanism is implicated. The in vivo and in vitro data of our study show that alloreactions after allo-HCT may induce genomic alterations in epithelium. Progress in understanding DNA damage and repair after allo-HCT can potentially provide molecular biomarkers and therapeutic targets.

Why pain assessment must start with believing the patient.

Nursing students may find it difficult to change how a patient's care is managed or even to initiate any changes at all. On a busy surgical ward I attempted to assess and alleviate a patient's uncontrolled post-operative pain using a pain-assessment tool. Patient compliance was good, but ward staff responsible for managing the patient's care took little notice. This was not, I believe, because the pain-assessment tool was ineffective, but because staff gave pain control low priority, and, more fundamentally, because they did not believe the patient when she said she was in pain. This paper follows the postoperative patient from assessment through to discharge. The importance of believing patients' accounts of pain is illustrated.