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The standard method for identification of male fertility status is a semen analysis. This is performed in fertility and pathology laboratories accredited by different bodies in the UK such as the HFEA or UKAS, and is based on whether they perform licenced clinical treatment or diagnostic testing. The WHO laboratory semen analysis criteria provide the most comprehensive guidance for best practice, yet this is not strictly adhered to. Our objective was to determine any differences in semen analyses between laboratories in the UK, based on the regulatory body they are registered with. A cross-sectional survey was sent to NEQAS for andrology registrants (n = 184 laboratories), HFEA (n = 117 clinics), and individual ARCS members (n = 682). Most ARCS members are associated with NEQAS and/or the HFEA. A ∼50% laboratory response rate (n = 106 included responses) was found. Results were grouped based on accreditation: Group 1, UKAS accredited only (n = 38); Group 2, both UKAS accredited and HFEA licenced (n = 17); Group 3, HFEA licenced only (n = 42); and Group 4, no accreditation (n = 9). Over 85% of UKAS accredited laboratories (Groups 1 and 2) state they perform semen analysis according to WHO 2010 recommendations and adhere to best practice guidelines. A significantly fewer number of HFEA only laboratories (<74% Group 3, p < 0.01) adhere to both guidelines. Non-HFEA laboratories (Groups 1 and 4) are almost all performing sperm counts according to WHO criteria, while <60% HFEA clinics (Groups 2 and 3) perform counts according to regulation (Group 1 vs. Groups 2 and 3: Fixed sperm, p < 0.05 ; Neubauer chamber: p < 0.005). QC is implemented in most laboratories, however there is a significant difference (p < 0.01) between non-UKAS (Groups 3 and 4) and UKAS laboratories (Groups 1 and 2). There is a significant difference in semen analysis performance between UKAS and HFEA laboratories with regards to implementation of best practice guidelines and QC procedures. This may have a detrimental effect on result accuracy and consequently lead to patient misdiagnosis and mismanagement. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA‐seq), real‐time quantitative PCR (RT‐qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex‐I inhibitors. The treatment downregulated genes mediating hypoxia‐inducible factor (HIF)‐1α stability, metabolism and survival, activated adenosine monophosphate‐activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia‐inducible factor‐1α (HIF‐1α) signaling. HIF‐1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF‐1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF‐1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2‐regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC. [ABSTRACT FROM AUTHOR]

Aim: This inquiry aimed to; (1) examine the psychosocial and emotional sequelae associated with cancer patient‐hood experience in healthcare professionals (HCPs) in Uganda, (2) generate evidence to inform clinical and nursing practice about the needs of HCP patients with cancer. Design: This was a qualitative phenomenological study. Methods: The study was conducted among HCP cancer patients and survivors recruited from oncology and palliative care settings in Uganda. Data were collected via audio‐taped, face‐to‐face or telephone open‐ended interviews. Interviews were transcribed verbatim. Thematic analysis was used. Results: Eight HCP cancer patients and survivors participated in the study. Their mean age was 56 years, range 29–85 years. Three major themes emerged: (1) From a healthcare provider to a patient, (2) Socioeconomic challenges, and (3) Coping and support strategies. [ABSTRACT FROM AUTHOR]

The separation of germ cell populations from the soma is part of the evolutionary transition to multicellularity. Only genetic information present in the germ cells will be inherited by future generations, and any molecular processes affecting the germline genome are therefore likely to be passed on. Despite its prevalence across taxonomic kingdoms, we are only starting to understand details of the underlying micro‐evolutionary processes occurring at the germline genome level. These include segregation, recombination, mutation and selection and can occur at any stage during germline differentiation and mitotic germline proliferation to meiosis and post‐meiotic gamete maturation. Selection acting on germ cells at any stage from the diploid germ cell to the haploid gametes may cause significant deviations from Mendelian inheritance and may be more widespread than previously assumed. The mechanisms that affect and potentially alter the genomic sequence and allele frequencies in the germline are pivotal to our understanding of heritability. With the rise of new sequencing technologies, we are now able to address some of these unanswered questions. In this review, we comment on the most recent developments in this field and identify current gaps in our knowledge. [ABSTRACT FROM AUTHOR]

The quality of porcine oocytes for use in IVF is commonly graded according to the number of layers of cumulus cells (CCs) surrounding the oocyte; together these form the cumulus oocyte complex (COC). At least three compact layers of CCs is regarded as important for efficient IVP. To test this, oocytes were scored according to cumulus investment, with grade A representing COCs with three or more cumulus layers including granulosa cell‐cumulus oocyte complexes, grade B those with an intact corona radiata surrounded by another layer of cumulus cells and grades C and D representing COCs with lower CC investment. These oocytes were then monitored for in vitro maturation (IVM), as assessed by tubulin immunostaining for meiotic progression, the development of a cortical granule ring, and by glutathione levels. Results indicate that grading correlates closely with nuclear maturation and cytoplasmic maturation, suggesting that grading oocytes by cumulus investment is a reliable method to predict IVM success. Importantly, Grade A and B oocytes showed no significant differences in any measure and hence using a cut‐off of two or more CC layers may be optimal. We also determined the effect of assisted aspiration for oocyte retrieval, comparing the effect of needle size and applied pressure on the retrieval rate. These data indicated that both variables affected oocyte recovery rates and the quality of recovered oocytes. In combination, these experiments indicate that grade A and B oocytes have a similar developmental potential and that the recovery of oocytes of these grades is maximised by use of an 18‐gauge needle and 50 mmHg aspiration pressure. [ABSTRACT FROM AUTHOR]

While improved management of agricultural landscapes is promoted as a promising natural climate solution, available estimates of the mitigation potential are based on coarse assessments of both agricultural extent and aboveground carbon density. Here we combine 30 meter resolution global maps of aboveground woody carbon, tree cover, and cropland extent, as well as a 1 km resolution map of global pasture land, to estimate the current and potential carbon storage of trees in nonforested portions of agricultural lands. We find that global croplands currently store 3.07 Pg of carbon (C) in aboveground woody biomass (i.e., trees) and pasture lands account for an additional 3.86 Pg C across a combined 3.76 billion ha. We then estimate the climate mitigation potential of multiple scenarios of integration and avoided loss of trees in crop and pasture lands based on region‐specific biomass distributions. We evaluate our findings in the context of nationally determined contributions and find that the majority of potential carbon storage from integration and avoided loss of trees in crop and pasture lands is in countries that do not identify agroforestry as a climate mitigation technique. [ABSTRACT FROM AUTHOR]

Background: Globally, the rising cost of anticancer therapy has motivated efforts to quantify the overall value of new cancer treatments. Multicriteria decision analysis offers a novel approach to incorporate multiple criteria and perspectives into value assessment.Methods: The authors recruited a diverse, multistakeholder group who identified and weighted key criteria to establish the drug assessment framework (DAF). Construct validity assessed the degree to which DAF scores were associated with past pan-Canadian Oncology Drug Review (pCODR) funding recommendations and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS; version 1.1) scores.Results: The final DAF included 10 criteria: overall survival, progression-free survival, response rate, quality of life, toxicity, unmet need, equity, feasibility, disease severity, and caregiver well-being. The first 5 clinical benefit criteria represent approximately 64% of the total weight. DAF scores ranged from 0 to 300, reflecting both the expected impact of the drug and the quality of supporting evidence. When the DAF was applied to the last 60 drugs (with reviewers blinded) reviewed by pCODR (2015-2018), those drugs with positive pCODR funding recommendations were found to have higher DAF scores compared with drugs not recommended (103 vs 63; Student t test P = .0007). DAF clinical benefit criteria mildly correlated with ESMO-MCBS scores (correlation coefficient, 0.33; 95% CI, 0.009-0.59). Sensitivity analyses that varied the criteria scores did not change the results.Conclusions: Using a structured and explicit approach, a criterion-based valuation framework was designed to provide a transparent and consistent method with which to value and prioritize cancer drugs to facilitate the delivery of affordable cancer care. [ABSTRACT FROM AUTHOR]

Background: Lower urinary tract transitional cell carcinoma (TCC) is an important but rarely described disease of cats. Objectives: To report the clinical characteristics, treatments, and outcomes in a cohort of cats with lower urinary tract TCC and to test identified variables for prognostic relevance. Animals: One‐hundred eighteen client‐owned cats with lower urinary tract carcinoma. Methods: Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed statistically. Results: Median age of affected cats was 15 years (range, 5.0‐20.8 years) and median duration of clinical signs was 30 days (range, 0‐730 days). The trigone was the most common tumor location (32/118; 27.1%) as assessed by ultrasound examination, cystoscopy, or both. Treatment was carried out in 73 of 118 (61.9%) cats. Metastatic disease was documented in 25 of 118 (21.2%) cats. Median progression‐free survival and survival time for all cats were 113 days (95% confidence interval [CI], 69‐153) and 155 days (95% CI, 110‐222), respectively. Survival increased significantly (P <.001) when comparing cats across the ordered treatment groups: no treatment, treatment without partial cystectomy, and treatment with partial cystectomy. Partial cystectomy (hazard ratio [HR], 0.31; 95% CI, 0.17‐0.87) and treatment with nonsteroidal anti‐inflammatory drugs (HR, 0.55; 95% CI, 0.33‐0.93) were significantly associated with longer survival times. Conclusions and Clinical Importance: The results support treatment using partial cystectomy and NSAIDs in cats with TCC. [ABSTRACT FROM AUTHOR]

Selective logging in tropical forests changes the local number of animal species (alpha diversity), but it also likely affects species turnover (beta diversity). Whilst such changes are documented in many ecosystems under different disturbances, they are poorly understood in selectively logged tropical forests.By using soundscape recordings across broad spatial scales, we measured soundscape saturation and dissimilarity of pairs of soundscapes, as a proxy of alpha and beta diversity, respectively, in selectively logged and protected tropical forest in Indonesian Borneo.Soundscapes of selectively logged forests were more homogeneous than the soundscapes of never logged forest, and that soundscape saturation of protected forest was higher during the day and lower at night in comparison with selective logging concessions.Synthesis and applications. Selectively logged forests act as an important reservoir of biodiversity. Optimizing such production forests for biodiversity conservation requires the consideration of the total continuous area that is assigned to selective logging, and spatial arrangement of annual cutting blocks, as these could affect beta diversity and its recovery. [ABSTRACT FROM AUTHOR]

Non‐consumer researchers collaborating with consumer researchers can benefit from greater relevance of research and improved congruence between research processes and health policy. As with all research collaborations, such partnerships are both constrained and facilitated by research ecosystems. However, it seems that collaborations with consumer researchers are impacted in particular ways by the research ecosystem. Drawing on ecological systems theory, this study aims to improve understandings of how ecological structures impact collaborations between non‐consumer and consumer researchers. Interviews were conducted with 11 non‐consumer researchers from a range of mental health disciplines about their experiences collaborating with consumer researchers. One theme developed through analysis of the data set related to the research ecosystem. Data from this theme were extracted and discursively analysed using the principles of discursive psychology. Findings emphasize distinct factors that influence collaborations at each level of the ecosystem, encompassing both local research culture and broader research systems. Findings suggest that external pressures (such as deadlines for funding applications, or bureaucratic processes) from the broader ecosystemic levels need to be challenged at the local collaboration level. Non‐consumer researchers might support collaborations through, for instance, working to create enhanced flexibility in research timelines, or making time for relationship building, thus fostering more meaningful collaborations. [ABSTRACT FROM AUTHOR]

The article discusses the role of lentiviral vector‐based insertional mutagenesis screen in identifying mechanisms of resistance to MAPK inhibitors in melanoma. It mentions that insertional mutagenesis is a forward genetic screening approach that uses specialized vectors which integrate into the genome. It reveals use of a BRAFV600E short‐term melanoma culture that had been characterized for somatic mutations.

Technological advancements in recent years have sparked the use of large databases for research. The availability of these large databases has administered a need for anonymization and de-identification techniques, prior to publishing the data. This de-identification alters the data, which in turn can impact the results derived post de-identification and potentially lead to false conclusions. The objective of this study is to investigate if alterations to a de-identified time-to-event data set may improve the accuracy of the estimates. In this data set, a missing time bias was present among censored patients as a means to preserve patient confidentiality. This study investigates five methods intended to reduce the bias of time-to-event estimates. A simulation study was conducted to evaluate the effectiveness of each method in reducing bias. In situations where there was a large number of censored patients, the results of the simulation showed that Method 4 yielded the most accurate estimates. This method adjusted the survival times of censored patients by adding a random uniform component such that the modified survival time would occur within the final year of the study. Alternatively, when there was only a small number of censored patients, the method that did not alter the de-identified data set (Method 1) provided the most accurate estimates. [ABSTRACT FROM AUTHOR]

Almond kernels contain phytochemicals and nutrients that potentially have positive health benefits in relation to heart disease, diabetes and obesity. One important mechanism associated with these benefits is an imposed limit on bioaccessibility (release) of nutrients, such as lipids, from almond tissue during mastication and digestion. Recent studies have demonstrated the importance of food structure during the digestion of plant foods. In particular, in the almond kernel, depending on its structure and degree of processing, the amount of lipid released from the almond tissue matrix and the fatty acids produced from lipolysis has been found to vary substantially. This review aims at discussing the commercial methods of almond processing and the different almond forms produced for human consumption, mainly with respect to their impact on nutrient composition, digestion and metabolism. [ABSTRACT FROM AUTHOR]

Background The Affordable Care Act initiated several care coordination programs tailored to reduce emergency department ( ED) use for Medicaid-enrolled frequent ED users. It is important to clarify from the patient's perspective why Medicaid enrollees who want to receive care coordination services to improve primary care utilization frequently use the ED. Methods We conducted a qualitative data analysis of patient summary reports obtained from Medicaid enrolled frequent ED users who agreed to participate in a randomized control trial ( RCT) evaluating the impact of patient navigation intervention compared with standard of care on ED use and hospital admissions. We defined frequent ED users as those who used the ED four to 18 times in the past year. The study was conducted at an urban, teaching hospital ED with approximately 90,000 visits per year. The research staff conducted interviews (~30-40 minutes), regarding the patient's medical history, reasons for ED visits, health care access issues, and social distresses. The aforementioned findings were summarized in a 1- to 2-page report and presented to the RCT's project team (social worker, emergency medicine physician, primary care physician, and patient navigators) on a weekly basis to further understand the needs of this patient population. A diverse team of researchers (program staff and physicians) coded all reports and reached consensus using reflexive team analysis. We reconciled differences in code interpretations and generated themes. Results One-hundred patients enrolled in the RCT from March 2013 to February 2014, and all 100 patient summary reports were evaluated. We identified three key themes associated with Medicaid enrollee frequent ED use: 1) negative personal experiences with the healthcare system, 2) challenges associated with having low socioeconomic status, and 3) significant chronic mental and physical disease burden. Conclusions Medicaid frequent ED users engaged in receiving patient navigation services with the goal to reduce ED use and hospital admissions describe barriers that go beyond timely primary care access issues. These include sociodeterminants of health, lack of trust in primary care providers, and healthcare system. [ABSTRACT FROM AUTHOR]

Infrared microspectroscopy is a tool with potential for studies of the microstructure, chemical composition and functionality of plants at a subcellular level. Here we present the use of high-resolution bench top-based infrared microspectroscopy to investigate the microstructure of Triticum aestivum L. (wheat) kernels and Arabidopsis leaves. Images of isolated wheat kernel tissues and whole wheat kernels following hydrothermal processing and simulated gastric and duodenal digestion were generated, as well as images of Arabidopsis leaves at different points during a diurnal cycle. Individual cells and cell walls were resolved, and large structures within cells, such as starch granules and protein bodies, were clearly identified. Contrast was provided by converting the hyperspectral image cubes into false-colour images using either principal component analysis ( PCA) overlays or by correlation analysis. The unsupervised PCA approach provided a clear view of the sample microstructure, whereas the correlation analysis was used to confirm the identity of different anatomical structures using the spectra from isolated components. It was then demonstrated that gelatinized and native starch within cells could be distinguished, and that the loss of starch during wheat digestion could be observed, as well as the accumulation of starch in leaves during a diurnal period. [ABSTRACT FROM AUTHOR]

Problem The CD200 tolerance-signaling molecule that is expressed by a wide variety of tissues, including placental trophoblast and epithelial tumor cells, lacks an intracytoplasmic tail and must act by binding to CD200 receptors that have a limited expression on lymphomyeloid cells. This binding can inhibit inflammation and NK cells, promote macrophage secretion of indoleamine-2,3 dioxygenase ( IDO), and promote generation of Treg cells. Recently, CD200R1 was reported on human first trimester placental villous trophoblast cells. CD200R1 has not been described on malignant tumor cells. As malignant tumor cells exhibit a number of characteristics of trophoblast, is CD200R1 expressed? Method of study Affinity-purified rabbit polyclonal antibodies to CD200 and CD200R1 were used to immunostain tissue blocks available from cases in a previous cross-sectional study of Stage 1- IIIA human breast cancer cases and term placental trophoblast. Results Affinity-purified anti- CD200R1 stained primary breast cancer cells and term placental villous trophoblasts. Tumor cells were also stained by anti- CD200 as in a previous study (correlation P = 0.0042), but CD200R1 and CD200 were not correlated. Presence or absence of strong CD200 expression in the tumor did not correlate with metastasis, and a similar result was obtained with CD200R1. Conclusions This is the first report of CD200R1 expression by human epithelial tumor cells, and specifically, early-stage human breast cancer cells. It is also the first report of CD200R1 expression by term placental villous trophoblasts. The potential biological significance of CD200R1 expression in non-hematopoietic cells is discussed. [ABSTRACT FROM AUTHOR]

Problem The CD200-tolerance signaling molecule prevents pregnancy failure and is also expressed by a wide variety of malignant tumors. The effect of CD200 mRNA expression on progression of human tumors has been variable. Method of study A cross-sectional study was performed to examine the correlation between CD200 protein expression in the primary tumors from postoperative Stage I- IIIA human breast cancer and the likelihood of regional lymph node metastasis. Results Fifty-eight percentage of patients had strong CD200+ tumor staining (71% of Stage I and 53% Stage II- IIIA). Strong staining was associated with large T2-3 primary tumors compared to T1 tumors (64 versus 50%) and T2-3 N+ versus T1 N− tumors (70 versus 63%), but this was not statistically significant. Nodal metastases were not more frequent in patients with strong CD200+ staining (57% compared to 58% for weak/negative staining cases), and the metastatic tumor cells in regional lymph nodes were often CD200− when the primary tumor was CD200+. Conclusion CD200 expression by early-stage human breast cancer cells in primary tumors did not correlate with increased regional lymph node metastasis. [ABSTRACT FROM AUTHOR]

Adoption of reduced-impact logging ( RIL) methods could reduce CO2 emissions by 30-50% across at least 20% of remaining tropical forests. We developed two cost effective and robust indices for comparing the climate benefits (reduced CO2 emissions) due to RIL. The indices correct for variability in the volume of commercial timber among concessions. We determined that a correction for variability in terrain slope was not needed. We found that concessions certified by the Forest Stewardship Council ( FSC, N = 3), when compared with noncertified concessions ( N = 6), did not have lower overall CO2 emissions from logging activity (felling, skidding, and hauling). On the other hand, FSC certified concessions did have lower emissions from one type of logging impact (skidding), and we found evidence of a range of improved practices using other field metrics. One explanation of these results may be that FSC criteria and indicators, and associated RIL practices, were not designed to achieve overall emissions reductions. Also, commonly used field metrics are not reliable proxies for overall logging emissions performance. Furthermore, the simple distinction between certified and noncertified concessions does not fully represent the complex history of investments in improved logging practices. To clarify the relationship between RIL and emissions reductions, we propose the more explicit term ' RIL-C' to refer to the subset of RIL practices that can be defined by quantified thresholds and that result in measurable emissions reductions. If tropical forest certification is to be linked with CO2 emissions reductions, certification standards need to explicitly require RIL-C practices. [ABSTRACT FROM AUTHOR]

Objective To identify patients' and physicians' perceptions of physician-related verbal and nonverbal facilitators and barriers to patient involvement in treatment decision making (TDM) occurring during clinical encounters for women with early stage breast cancer (ESBC). Methods Eligible women were offered treatment options including surgery and adjuvant therapy. Eligible physicians provided care for women with ESBC in either a teaching hospital or an academic cancer centre. In Phase 1, women were interviewed 1-2 weeks after their initial consultation. In Phase 2, women and their physicians were interviewed separately while watching their own consultation on a digital video disk. All interviews were audiotaped, transcribed and analysed. Results Forty women with ESBC and six physicians participated. Patients and physicians identified thirteen categories of physician facilitators of women's involvement. Of these, seven categories were frequently identified by women: conveyed a rationale for patient involvement in TDM; explained the risk of cancer recurrence; explained treatment options; enhanced patient understanding of information; gave time for TDM; offered a treatment recommendation; and made women feel comfortable. Physicians described similar information-giving facilitators but less often mentioned other facilitators. Few physician barriers to women's involvement in TDM were identified. Conclusions Women with ESBC and cancer physicians shared some views of how physicians involve patients in TDM, although there were important differences. Physicians may underestimate the importance that women's place on understanding the rationale for their involvement in TDM and on feeling comfortable during the consultation. [ABSTRACT FROM AUTHOR]

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Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVES To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men with and without erectile dysfunction (ED). PATIENTS AND METHODS This was a multicentre, double-blind, placebo- and active-controlled, parallel-group study conducted across 45 centres in North and South America, Europe, and Australia. In all, 418 men aged ≥40 years with a clinical diagnosis of BPH, an International Prostate Symptom Score (IPSS) of ≥13, and maximum urinary flow rate (Qmax) of 5–15 mL/s for a voided volume of >150 mL were stratified into two groups (with and without ED) and randomized to one of seven treatment groups, i.e. UK-369,003 at 10, 25, 50 or 100 mg modified release (MR), UK-369,003 40 mg immediate release (IR), tamsulosin 0.4 mg prolonged release, or placebo, for 12 weeks. The primary study endpoint was the change in total IPSS after 12 weeks of treatment. Secondary efficacy measures were IPSS storage and voiding subscores, Qmax, International Index of Erectile Function–Erectile Function domain, questions 5 and 6 of the Quality of Erection Questionnaire, the International Consultation on Incontinence Questionnaire–Male LUTS, the patient-reported treatment-impact questionnaire, and a bladder diary in which patients recorded the number of voluntary urinary voids, volume of urine voided per micturition, leaks, and urgency episodes. RESULTS The mean change in the IPSS from baseline at week 12 for UK-369,003 100 mg MR and 40 mg IR was −2.91 and −2.50 better than placebo, respectively. There was increasing efficacy with increasing dose of the MR formulation. For UK-369,003 100 mg MR, Qmax improved by 2.10 mL/s compared with 0.84 mL/s in the placebo group. CONCLUSIONS UK-369,003 had clinically meaningful efficacy and was well tolerated in men with LUTS associated with BPH. The Bayesian statistical analysis gave high posterior probabilities for true differences between UK-369,003 100 mg MR and placebo. There was greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo. [ABSTRACT FROM AUTHOR]

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVES To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor, UK-369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED). PATIENTS AND METHODS This was a multicentre, double-blind, placebo-controlled, parallel-group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK-369,003; or placebo once a day) for 12 weeks. The primary study endpoints were those derived from the bladder diary that recorded the number of voluntary urinary voids, volume of urine per void, leaks and urgency episodes over a 72-h period, before baseline and again at 2, 4 and 12 weeks. Secondary efficacy measures included the International Prostate Symptom Score (total and storage and voiding subscores), International Index of Erectile Function–Erectile Function domain (IIEF-EF), questions 5 and 6 of the Quality of Erection Questionnaire (QEQ), the Overactive Bladder Questionnaire Short Form, the Patient Perception of Bladder Condition, the International Consultation on Incontinence Questionnaire–Male LUTS, and the patient-reported treatment impact questionnaire. RESULTS Overall, there were no clinically relevant treatment differences in voiding frequency, mean voided volume, urgency episode frequency, or nocturia frequency for any dose of UK-369,003 MR compared with placebo. In the subset of patients with ED there were improvements in the IIEF-EF and QEQ scores in all UK-369,003 treatment groups compared with placebo. CONCLUSIONS These data provide no evidence of efficacy for UK-369,003 in the treatment of storage LUTS in men (based on classic OAB eligibility criteria). However, although the endpoints on these classic OAB efficacy variables were negative, there is evidence to suggest a greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo. [ABSTRACT FROM AUTHOR]

Acknowledgement of the breadth of T-cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, γδ T cells are disproportionately important for immuno-protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with αβ T cells, neonate-derived γδ cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN-γ production. Emphasising the acquisition of functional competence in utero, IFN-γ was produced by γδ cells sampled from premature births, and, although one month's post-partum environmental exposure invariably increased their TNF-α production, it had no consistent effect on IFN-γ or IL-2. In sum, γδ cells seem well positioned at birth to contribute to immuno-protection and immuno-regulation, possibly compensating for selective immaturity in the αβ compartment. With regard to the susceptibilities of preterm babies to viral infection, γδ cells from preterm neonates were commonly impaired in Toll-like receptor-3 and -7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists. [ABSTRACT FROM AUTHOR]

Research has shown that referral of patients in the stages of renal disease, to a Nephrologist has significant impact on the patients overall health and well-being. This article is a review of the literature discussing the key impact that late referral has on the patient. This will include looking at the preparation of the patient for dialysis—education and vascular access as well as discussing the modality choice for the patient. It will also address the longer-term impact such as patient survival on dialysis. [ABSTRACT FROM AUTHOR]

Phosphorylated histone H2AX (γH2AX) is generated in nucleosomes flanking sites of DNA double-strand breaks, triggering the recruitment of DNA-damage response proteins such as MDC1 and 53BP1. Here, we study shortened telomeres in senescent human cells. We show that most telomeres trigger γH2AX formation, which spreads up to 570 kb into the subtelomeric regions. Furthermore, we reveal that the spreading patterns of 53BP1 and MDC1 are very similar to that of γH2AX, consistent with a structural link between these factors. Moreover, different subsets of telomeres signal in different cell lines, with those that signal tending to equate to the shortest telomeres of the corresponding cell line, thus linking telomere attrition with DNA-damage signalling. Notably, we find that, in some cases, γH2AX spreading is modulated in a manner suggesting that H2AX distribution or its ability to be phosphorylated is not uniform along the chromosome. Finally, we observe weak γH2AX signals at telomeres of proliferating cells, but not in hTERT immortalised cells, suggesting that low telomerase activity leads to telomere uncapping and senescence in proliferating primary cells. [ABSTRACT FROM AUTHOR]

Aims To determine the onset and duration of action of sildenafil in patients with erectile dysfunction (ED). Methods Two randomised, double-blind, placebo-controlled, two-way crossover studies were conducted in men with ED of no known organic cause. Study I: The time to onset of erections after sildenafil (50 mg) or placebo dosing following visual sexual stimulation (VSS) was assessed in 17 patients. Patients not achieving >60% penile rigidity by 70 min postdose as measured by a RigiScan® monitoring device were assigned an onset time of 70 min. Study II: The duration of grade 3 (hard enough for penetration) and grade 4 (fully hard) erections, determined by self-assessment during 60 min of VSS starting 2 and 4 h after sildenafil (100 mg) or placebo dosing, was measured in 16 patients. Results Study I: The median time (range) to onset of erections was 27 min (in a range of 12–70) after receiving sildenafil 50 mg. In the sildenafil group, 71% of patients experienced onset of erections within 30 min of dosing, and 82% responded within 45 min. Of the patients who achieved >60% penile rigidity after sildenafil, 86% had done so by 30 min after dosing. Study II: When VSS began 2 h postdose, the median duration of grade 3 or 4 erections was 19.5 min (0–55) for sildenafil vs 0 min (0–23) for placebo. When VSS began 4 h postdose, the median duration was 5 min (0–45) for sildenafil compared with 0 min for placebo (0–27). Conclusions Sildenafil is an effective oral treatment for ED that produces a penetrative erection as early as 12 min and for most patients, within 30 min after dosing, and a duration of action lasting at least 4 h. [ABSTRACT FROM AUTHOR]

Objective To assess the understanding of and attitudes towards randomized clinical trials amongst patients attending oncology out-patient clinics. Design Cross-sectional survey. Subjects Patients attending medical oncology out-patient clinics at a Sydney teaching hospital. Main outcome Patients' willingness to participate in a randomized clinical trial. Results Sixty consecutive patients were surveyed. The mean age was 55.2 (SD 14) years. Eighty-eight per cent of respondents thought that patients should be asked to participate in trials testing new treatments, however, only a third would consider participating in a randomized trial themselves. If a trial was endorsed by an independent cancer information service such as the NSW Cancer Council, 72% of respondents would be more likely to participate. Knowledge about randomized trials was not high. Respondents scored a median of 3 out of 7 (interquartile range, 2–4) correct answers to a series of questions about randomized trials. Patients willing to participate in a randomized trial were more likely to perceive the doctor favourably (P = 0.05), less likely to perceive trials as experimental (P = 0.05) and less likely to perceive trials as representing an inconvenience or loss of control (P = 0.09). Conclusions Understanding amongst patients of the need for and mechanisms of randomized clinical trials is not good. This may contribute to the difficulties investigators face in seeking consent for clinical trials. Evaluation of new strategies to educate the public and patients about randomized trials is needed. Involvement of consumers in the design and conduct of clinical trials and evaluation of strategies to improve doctors' communication of clinical trial information is also required. [ABSTRACT FROM AUTHOR]

Examines the efficacy of randomized clinical trials for early breast cancer in Australia. Application of mammography programs; Use of radiotherapy and mastectomy; Implication of high-dose chemotherapy.

PlateIet [3H]imipramine binding, a putative biological marker for depression, varies considerably among healthy control subjects. This study examined whether changes associated with the menstrual cycle could account for part of this variability. No significant relationship was found between Bmax or Kd and the phase of the menstrual cycle, or symptoms associated with the premenstrual syndrome or progesterone or oestradiol levels. Other factors should be considered in exploring the variability of[3H] imipramine binding in healthy subjects. [ABSTRACT FROM AUTHOR]

A time series model of the monthly number of motor vehicle deaths in the United States is constructed. This model is based upon the monthly data from January 1960 to December 1973. The statistical analysis revealed a very strong seasonal variation throughout each year. This seasonality in number of deaths per month is incorporated into the forecasting model. Comparison of forecasts from the model to the actual mortality experience since January 1974 is shown to reveal a significant reduction in motor vehicle mortality. This downward shift occurred with the onset of the energy crisis and the imposition of the 55 m.p.h, highway speed limit. The mortality reduction averages 844 deaths per month for the nineteen months from January 1074 to July 1075. [ABSTRACT FROM AUTHOR]

This article presents a study which examined the annual pattern of life insurance sales in the U.S. to determine the extent of seasonality that may be present. The ability to detect trends and seasonal variations is important so that insurers will be prepared in advance to adjust securities holdings, as required in order to maintain adequate liquidity throughout the year. The method by which this study will be carried out is the Box-Jenkins technique of univariate time series analysis. Examination reveals a pronounced upward trend over time and also some apparent seasonal fluctuations which are not well defined. The Box-Jenkins technique of fitting the model to the data involves both proposing a possible model and estimating all that are included in the proposed model.

The author discusses the role of the Australian government in securing the state's economic growth and industrial development. Despite the limitations set forth by the Australian Constitution when it comes to macroeconomic policy implementation, the state government has allegedly been a help to the country's economy by upgrading its international access to markets for elaborately transformed manufacturers. It has also launched an innovative collaborative arrangement known as the National Industry Extension Service (NIES), which is instituted to draw together various types of assistance provided to industry. And for a much better management, the author further suggests state governments to cut red tape and remove unnecessary regulations that hinder business development.

Recurrences after surgery for thyroglossal cysts and fistulas were common until, in 1920, Sistrunk described his technique for removing the whole thyroglossal tract. Since that time there has been considerable argument concerning the exact path taken by the tract particularly in relation to the hyoid bone. In an attempt to elucidate this problem, studies have been made of embryos at varying stages of development, of serially step-sectioned adult larynges and of surgical specimens. These studies suggest that the thyroglossal tract occupies a constant and embryologically predictable position in relation to the hyoid bone and they support the rationale of Sistrunk's procedure. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the report of the modeling debate in the May 26, 2007 issue.

Studies have reported that in healthy humans consuming diets rich in almonds, a significant proportion of lipid material in almond seeds remains undigested. However, the amount of lipid potentially available for digestion has not been quantified. To determine lipid release (i.e. bioaccessibility) from a complex food matrix, an understanding of the food microstructure and its physical changes during mastication and processing is required. A mathematical model was developed to predict lipid release from almond seed tissue. This was achieved by obtaining information on the proportion of fractured almond cells during fragmentation and on the characteristics of individual cotyledon cells (e.g. shape, volume and particle size). The data obtained from the mathematical equation provided a good estimation of lipid bioaccessibility. Our results are in good agreement with experimental data obtained on a range of geometrically defined samples of almond tissue (e.g. cubes of different sizes). Data from parallel studies performed in vitro and in vivo appear to correlate well with our model for predicting lipid release. The use of this model could be expanded to investigate the bioaccessibility of other nutrients and phytochemicals in almonds and other plant tissues. [ABSTRACT FROM AUTHOR]