Immune Checkpoint Blockade in Lower Gastrointestinal Cancers: A Systematic Review.

BACKGROUND: Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours. PATIENTS AND METHODS: Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy. RESULTS: In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment.

Complete pathological response in rectal cancer utilising novel treatment strategies for neo-adjuvant therapy: A systematic review.

BACKGROUND: Locally advanced rectal cancer is routinely treated with neo-adjuvant long course chemoradiotherapy or short course radiotherapy, followed by total mesorectal excision. Not all patients respond to this treatment and there has been an emergence of novel treatment strategies designed to improve outcomes for these patients. This systematic review aims to assess the current novel neo-adjuvant treatment strategies being utilised in the treatment of patients with rectal cancer and how these impact pathological complete response (pCR) rates. METHODS: A systematic review of the literature was performed to evaluate pathological response in patients with rectal cancer receiving novel neo-adjuvant therapy. EMBASE and Medline electronic databases were searched for relevant articles. Articles published between January 2008 and February 2019 were retrieved. Included studies underwent critical appraisal and complete pathological response rates were recorded. RESULTS: Of the initial 1074 articles identified, 217 articles fulfilled the inclusion criteria, of these 60 articles (4359 patients) were included. Neo-adjuvant therapy delivered included novel long course chemoradiation therapy, neoadjuvant chemotherapy alone, addition of a biological agent, total neo-adjuvant therapy, novel short course radiation therapy and studies utilising biomarkers to select patients for therapy. Complete pathological response rates ranged from 0 to 60%. CONCLUSION: A validated novel neo-adjuvant therapy that significantly increases pCR rates in patients with rectal cancer has not been identified.

Comparison of Rural Childhood BMI Percentiles: Prevalence and Trends in a Midwest County, 2008-2016.

The number of children who are obese and overweight continues as a public health challenge despite decades of research. The purpose of this article is to describe trends in body mass index (BMI) percentile data collected from 11- to 14-year-old school children in 2008-2009 and 2015-2016 in rural Wisconsin. The BMI percentiles from 1,347 students were compared using time, gender, age, and school (public vs. parochial) as predictors. The trend over time indicated a decrease in students of healthy weight and an increase in those overweight or obese. Also noted was a significantly higher proportion of children who were overweight or obese in parochial compared to public schools. Discussed are the observed trends, community-wide initiatives implemented, as well as how schools can employ a more comprehensive approach to childhood obesity that first ensures community readiness and involves school, home, and community.

Solving the problems of gas leakage at laparoscopy.

Gas leakage during minimally invasive surgery is an aerosolization hazard. Sensitive optical and thermographic imaging can demonstrate and differentiate between mechanistic categories, enabling engineering solutions to fortify surgical care against pollutants and pathogens affecting operating room teams. Areas for improvement.

Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear.

OBJECTIVES: Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. METHODS: Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. RESULTS: At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. CONCLUSIONS: GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred.Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57-65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1.

ADHD in children: a path to free medicines.

BACKGROUND: Recent media coverage has highlighted discrepancies in the entitlements of children to free ADHD medication across the country. The Department of Health has since ruled that children with ADHD under 16 are entitled to receive free medications. AIMS: This study examines the cost to the State of ADHD medication and implications for universal coverage under the long-term illness (LTI) scheme for under 16s. We estimate a potential cost for universal coverage for under 16s. METHODS: Drug reimbursement entitlements were explored for children with ADHD. Data were retrieved from the Primary Care Reimbursement Services for the Community Drug Schemes for 2011. The cumulative and percentage-spent on the LTI scheme was calculated. RESULTS: €107,894 (4.4 %) of the €2.4 million State spent on ADHD medicines was under the LTI scheme in 2011. We estimate a potential cost of €8.4 million for costs of ADHD medicines for the state based on current prescribing patterns. CONCLUSIONS: There appears to be a significant underutilisation of the LTI scheme affording children free ADHD medication. Public and professional awareness campaigns are required to ensure families get the benefits to which they are entitled, and cost does not become a barrier to treatment adherence and improved outcomes. Leading from this, we propose suggestions for cost-effective prescribing to minimise potential cost implications.

The effect of primary midwife-led care on women's experience of childbirth: results from the COSMOS randomised controlled trial.

OBJECTIVE: To determine the effect of primary midwife-led care ('caseload midwifery') on women's experiences of childbirth. DESIGN: Randomised controlled trial. SETTING: Tertiary care women's hospital in Melbourne, Australia. POPULATION: A total of 2314 low-risk pregnant women. METHODS: Women randomised to caseload care received antenatal, intrapartum and postpartum care from a primary midwife, with some care provided by a 'back-up' midwife. Women in standard care received midwifery-led care with varying levels of continuity, junior obstetric care or community-based medical care. MAIN OUTCOME MEASURES: The primary outcome of the study was caesarean section. This paper presents a secondary outcome, women's experience of childbirth. Women's views and experiences were sought using seven-point rating scales via postal questionnaires 2 months after the birth. RESULTS: A total of 2314 women were randomised between September 2007 and June 2010; 1156 to caseload and 1158 to standard care. Response rates to the follow-up questionnaire were 88 and 74%, respectively. Women in the caseload group were more positive about their overall birth experience than women in the standard care group (adjusted odds ratio 1.50, 95% CI 1.22-1.84). They also felt more in control during labour, were more proud of themselves, less anxious, and more likely to have a positive experience of pain. CONCLUSIONS: Compared with standard maternity care, caseload midwifery may improve women's experiences of childbirth. TWEETABLE ABSTRACT: Primary midwife-led care ('caseload midwifery') improves women's experiences of childbirth.

T lymphocytes are not required for the development of fatty degeneration after rotator cuff tear.

OBJECTIVES: Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as 'fatty degeneration'. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified. METHODS: A full-thickness, massive supraspinatus and infraspinatus tear was induced in adult T-cell deficient rats. We hypothesised that, compared with controls, 28 days after inducing a tear we would observe a decrease in muscle force production, an accumulation of type IIB fibres, and an upregulation in the expression of genes involved with muscle atrophy, fibrosis and inflammation. RESULTS: Chronic cuff tears in nude rats resulted in a 30% to 40% decrease in muscle mass, a 23% reduction in production of muscle force, and an induction of genes that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. Marked large lipid droplet accumulation was also present. CONCLUSIONS: The extent of degenerative changes in nude rats was similar to what was observed in T-cell competent rats. T cells may not play an important role in regulating muscle degeneration following chronic muscle unloading. The general similarities between nude and T-cell competent rats suggest the nude rat is likely an appropriate preclinical model for the study of xenografts that have the potential to enhance the treatment of chronically torn rotator cuff muscles. Cite this article: Bone Joint Res 2014;3:262-72.

Effects of continuity of care by a primary midwife (caseload midwifery) on caesarean section rates in women of low obstetric risk: the COSMOS randomised controlled trial.

OBJECTIVE: To determine whether primary midwife care (caseload midwifery) decreases the caesarean section rate compared with standard maternity care. DESIGN: Randomised controlled trial. SETTING: Tertiary-care women's hospital in Melbourne, Australia. POPULATION: A total of 2314 low-risk pregnant women. METHODS: Women randomised to caseload received antenatal, intrapartum and postpartum care from a primary midwife with some care by 'back-up' midwives. Women randomised to standard care received either midwifery or obstetric-trainee care with varying levels of continuity, or community-based general practitioner care. PRIMARY OUTCOME: caesarean birth. Secondary outcomes included instrumental vaginal births, analgesia, perineal trauma, induction of labour, infant admission to special/neonatal intensive care, gestational age, Apgar scores and birthweight. RESULTS: In total 2314 women were randomised-1156 to caseload and 1158 to standard care. Women allocated to caseload were less likely to have a caesarean section (19.4% versus 24.9%; risk ratio [RR] 0.78; 95% CI 0.67-0.91; P = 0.001); more likely to have a spontaneous vaginal birth (63.0% versus 55.7%; RR 1.13; 95% CI 1.06-1.21; P < 0.001); less likely to have epidural analgesia (30.5% versus 34.6%; RR 0.88; 95% CI 0.79-0.996; P = 0.04) and less likely to have an episiotomy (23.1% versus 29.4%; RR 0.79; 95% CI 0.67-0.92; P = 0.003). Infants of women allocated to caseload were less likely to be admitted to special or neonatal intensive care (4.0% versus 6.4%; RR 0.63; 95% CI 0.44-0.90; P = 0.01). No infant outcomes favoured standard care. CONCLUSION: In settings with a relatively high baseline caesarean section rate, caseload midwifery for women at low obstetric risk in early pregnancy shows promise for reducing caesarean births.

A review of the clinical toleration studies of polydextrose in food.

Polydextrose is a non-digestible 1 kcal/g polysaccharide used primarily as a sugar replacer and dietary fiber in foods. At typical use levels, polydextrose provides physiological effects similar to those of other dietary fibers. However, excessive consumption of non-digestible carbohydrates can lead to gastrointestinal distress. Nine clinical studies were conducted with polydextrose to evaluate the extent of such symptoms. These studies determined laxation endpoints in adults and children, and showed that polydextrose was better tolerated than most other low digestible carbohydrates (e.g. polyols). This is because of a higher molecular weight and partial colonic fermentation, leading to a lower risk of osmotic diarrhea. After evaluating these studies, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Commission Scientific Committee for Food (EC/SCF) concluded that polydextrose has a mean laxative threshold of approximately 90 g/d (1.3 g/kg bw) or 50 g as a single dose.

Chronic toxicity and carcinogenicity of sucrose fatty acid esters in Fischer 344/DuCrj rats.

A 13-week and a 2-year feeding study were conducted in Fischer 344/DuCrj rats to evaluate the oral toxicity and carcinogenicity of S-570, a mixture of mono-, di-, tri-, and higher esters of sucrose with fatty acids derived from edible fats and oils. In both studies, S-570 was fed at 0, 1, 3, or 5% (w/w) of the diet to groups of 20 male and 20 female rats in the 13-week study and 50 male and 50 female rats in the carcinogenicity study. Animals in satellite groups of 14 rats/sex/group were sacrificed at 12 months to evaluate chronic toxicity. There were no S-570-related effects on survival, tumor incidence or time to tumor, ophthalmology, hematology, clinical chemistry, organ weights, or histopathology. These results indicate that S-570 is not toxic or carcinogenic when fed to rats at up to 5% of the diet for 2 years.

Photoinduced DNA cleavage by cyclopentadienyl metal complexes conjugated to DNA recognition elements.

[structure: see text]. DNA recognition elements have been attached to CpW(CO)3CH3 and CpW(CO)3Ph, which produce methyl and phenyl radicals that cleave DNA upon photolysis. The inclusion of binding moieties in 3 increases the efficiency but not the selectivity of strand scission over that seen in the simple unfunctionalized complex, while 11 cleaves preferentially at T sites within AT-rich tracts.

Safety evaluation of lipase produced from Candida rugosa: summary of toxicological data.

The toxicity of lipase AY, an enzyme preparation used in lipid hydrolysis to produce flavors, was evaluated in a series of studies. A 13-week dietary toxicity study in Sprague-Dawley (Crj:CD) rats was conducted in which animals received lipase AY in the feed at concentrations of 0, 625, 1250, or 2500 mg/kg body wt. No adverse treatment-related effects were observed. Lack of genotoxic potential was demonstrated by the results of an in vitro reverse mutation assay in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and in Escherichia coli strain WP2 uvrA, by an in vitro forward mutation assay in L5178Y mouse lymphoma cells, and by an in vitro chromosome aberration test in CHL/IU cells derived from fibroblasts of the lungs of Chinese hamsters. Finally, the particular strain of Candida rugosa, the yeast strain used to prepare lipase AY, has been shown to be nonpathogenic upon a single injection into the tail vein of rats of viable spores at doses up to 1.5x10(7) colony-forming units per animal. The results of these studies demonstrate that the enzyme preparation may be considered safe to workers and consumers when employed in the production of flavors from fats.

Safety evaluation of phosphodiesterase produced from Penicillium citrinum: summary of toxicological data.

The toxicity of Enzyme RP-1, an enzyme preparation used to hydrolyze yeast RNA to produce flavor enhancers for use in the food industry, was evaluated in a series of studies. A 5-week dietary toxicity study in Wistar rats was conducted in which animals received Enzyme RP-1 in feed at concentrations of 0, 500, 2000, or 8000 mg/kg body wt/day. A 13-week dietary toxicity study in Sprague-Dawley rats was conducted in which animals received RP-1 concentrate at 0, 0.125, 0.5, or 2% in their diets. At the highest dose levels in both studies, submandibular glands in the oral cavity were enlarged, an effect attributed to protease activity of the enzyme preparation. The no-observed-effect level in rats in the 13-week study was 0.5%, equivalent to 317 mg/kg body wt/day for males and 346 mg/kg body wt/day for females. Based on estimated dietary exposure to the enzyme preparation, the margin of exposure is estimated to be greater than 38,000. Lack of genotoxic potential was demonstrated by an in vitro reverse mutation assay in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and in Escherichia coli strain WP2uvr and by an in vitro chromosome aberration test in CHL/IU cells derived from fibroblasts from the lungs of Chinese hamsters. Finally, the particular strain of Penicillium citrinum, the fungal strain used to prepare Enzyme RP-1, was shown to have low pathogenicity upon a single injection into the tail vein of rats of viable spores at doses up to 2.8x10(5) colony-forming units per animal. The results of these studies demonstrate that the enzyme preparation may be considered safe to workers and consumers when employed in the production of flavor enhancers from yeast.

Are men and women equally violent to intimate partners?

Violence against women is a significant public health issue. One form of violence against women, intimate partner abuse or domestic violence, is prevalent in Australia. In this article, we summarise the main theoretical and methodological debates informing prevalence research in this area. We explain why studies finding equivalent victimisation and perpetration rates between the sexes are conceptually and methodologically flawed and why coercion and control are fundamental to the definition and measurement of partner abuse. We conclude that while male victims of partner abuse certainly exist, male victims of other forms of male violence are more prevalent. A focus on gendered risk of violence in public health policy should target male-to-male public violence and male-to-female intimate partner abuse.

Anticipatory guidance about child safety seat misuse: lessons from safety seat "checkups".

OBJECTIVES: To quantify the frequency of improper child safety seat use and to identify the most common mistakes in safety seat use, so that priorities for anticipatory guidance about misuse can be identified. DESIGN: Descriptive survey of types and frequency of safety seat misuse. SETTING: Eleven safety seat "checkups" sponsored by the Louisiana SAFE KIDS Coalition in southeastern Louisiana in 1998. PARTICIPANTS: Convenience sample of parents recruited for checkups through local media and sponsoring businesses. Three hundred seventeen child safety seats were checked. RESULTS: Of the 266 forward- and rear-facing seats checked, 250 (94%) were installed incorrectly. Sixty-one (23%) of the seats had minor misuse or were correctly used, 107 (40%) were partially misused, and 98 (37%) were extensively misused. The 3 most frequently found problems were seat not belted into vehicle tightly (142 [88%] of forward-facing seats and 84 [81%] of rear-facing seats), safety seat harness straps not snug (70 [43%] of forward-facing seats and 49 [47%] of rear-facing seats), and harness retainer clip not at armpit level (55 [34%] of forward-facing seats and 38 [37%] of rear-facing seats). CONCLUSIONS: As part of the routine anticipatory guidance offered during well-child visits, health care providers (ie, physician, nurse, or nurse practitioner) should counsel parents specifically about these 3 frequent errors in child safety seat use.

Parent-teen communication about sexual topics.

PIP: This study examined parent-teen communication about sexual topics in matched samples of 666 mother-teen and 510 father-teen pairs in the US. Parents and their 8th- through 12th-grade children completed parallel surveys that assessed demographic, relationship, and attitudinal variables hypothesized to be associated with sexual communication. Logistic regression analyses were used to determine which variables were linked to teens¿ reports of ¿one good talk¿ about each of three sexual topics (whether teen sex is okay, the dangers of AIDS and other sexually transmitted diseases, and birth control) in the past year. Aside from gender of parents and teens, demographic variables were largely nonsignificant in the final models. Instead, relationship and attitudinal variables were linked to sexual discussions in both mother-teen and father-teen dyads. Implications for program development and directions for future research were discussed.^ieng

Respiratory isolation in a teaching hospital with low-to-moderate rate of tuberculosis: compliance with Centers for Disease Control and Prevention guidelines for identifying patients who may have active tuberculosis.

BACKGROUND: Because of the limitation of isolation spaces suitable for tuberculosis, proper use of these spaces is prudent. We examined the current approach to respiratory isolation to determine the compliance with Centers for Disease Control and Prevention (CDC) guidelines for identifying active tuberculosis. METHODS: A retrospective review was performed of all patients placed in respiratory isolation and those with pulmonary tuberculosis. RESULTS: Seventy-seven instances of isolation and three admissions without isolation were encountered. Isolated patients met CDC guidelines for infectiousness in 59 of 77 instances (76.6%). The remaining patients were isolated with findings not characteristic of active tuberculosis (10 instances), normal chest radiograph (6 occasions), or without chest radiograph (2 instances). The time of implementing isolation was the first hospital day in 58 instances (75.3%) and 2 to 14 days in 19 instances (24.7%). Isolated human immunodeficiency virus-infected patients were more likely to meet CDC guidelines for infectiousness (21/22 [95.5%] vs 38/55 [69.1%] instances) and to be isolated on a timely basis (18/22 [81.8%] vs 40/55 [72.7%]). Tuberculosis was documented in 15 instances and isolation was delayed or never implemented in 5 and 3 instances, respectively. CONCLUSIONS: Compliance with CDC guidelines for respiratory isolation in patients not infected with human immunodeficiency virus is suboptimal. Many isolated patients do not meet these guidelines, and isolation is delayed or not implemented in patients who may have tuberculosis.