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.

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.

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.

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.

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.

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.

Decrease in resting metabolic rate during abstinence from bulimic behavior.

Among eight normal-weight bulimic women studied during 1 week of binge eating and vomiting and 7 weeks of abstinence without weight loss, resting metabolic rate and T3 and T4 levels fell significantly during abstinence. These data suggest that a physiological consequence of binge eating and vomiting is an increase in metabolic rate, in part due to increased thyroid hormone activity.

Assessment of jejunoileostomy for obesity--some observations since 1976.

In this review, which only partially covers the data available, it is pointed out that the evaluation of the results of jejunoileostomy may depend upon the criteria used by the observers, and disclosure of the true effects of the operation may depend upon the long-term follow-up of the patients. With increasing length of observation, it has become apparent that problems such as vitamin D deficiency, renal stone formation, continued steatorrhea, gallstones, zinc and copper deficiency, and even renal failure may be seen with disturbing frequency. Some of these may be preventable, others may be correctable and, indeed, the overall incidence of genuinely severe problems may, in the long run, be sufficiently low so as to make the benefits of jejunoileostomy outweigh the hazards. The rate of patient satisfaction is high, quality of life is generally improved and psychosocial and economic benefits of jejunoileostomy are apparent. The operation may also be a better alternative than the physical hazards of continuing obesity. Whether or not gastric bypass represents a true improvement over jejunoileostomy will depend upon the conclusions reached after applying to it the same searching scrutiny that is being used to examine the long-term results of jejunoileostomy.

Fecal fat, bile acid, and sterol excretion abd biliary lipid changes in jejunoileostomy patients.

Fecal fat, bile acid, and neutral sterol excretion and biliary bile acid, phospholipid, and cholesterol were studied in 36 patients 6 to 12 months after jejunoileostomy for obesity. No relationship was observed between the degree of steatorrhea and weight loss, although fecal fat rose sharply in all except 2 patients. Mean neutral sterol excretion in feces was unchanged after operation except in cholecystectomized patients. No relationship could be demonstrated between serum cholesterol decrease and fecal biel acid, which rose 3-fold, or between cholesterol and the sum of fecal fat and neutral sterol. Fecal excretion of cholic and deoxycholic acid together increased more than the total excretion of cxcretion patterns were demonstrable: moderate fecal fat (24 g or less on 65-g intake) was associated with a predominance of secondary bile acids in feces and in bile; high fecal fat (above 24 g/day) was associated with predominantly primary bile acids. A high incidence of gallstones or previous cholecystectomy (36%) was found preoperatively and of 25 patients with normal cholecystograms, four developed stones and five had nonvisualization of gallbladder 6 to 12 months postoperatively. Bile saturation ratio and lithogenic index were not consistently changed postoperatively. No clear cut increase in lithogenic potential or in bile acid (lithocholic acid) hepatotoxic potential after jejunoileostomy was demonstrable.

Food selection and intake of obese women with binge-eating disorder.

We studied food selection and intake of 19 women [body mass index (in kg/m2) > 30] [corrected], 10 of whom met proposed DSM-IV criteria for binge-eating disorder (BED). All subjects ate two multicourse meals in the laboratory, and were given tape-recorded instructions at each meal either to binge or eat in a normal fashion. Subjects with BED consumed significantly more energy than did subjects without BED at both the binge [12,400 vs 8440 kJ (2963 vs 2017 kcal), P < 0.005] and normal [9810 vs 6870 kJ (2343 vs 1640 kcal), P < 0.02] meals. During the binge meal subjects with BED consumed a greater percentage of energy as fat (38.9% vs 33.5%, P < 0.002) and a lesser percentage as protein (11.4% vs 15.4%, P < 0.01) than did subjects without BED. There were no differences in macronutrient composition of food choices between groups in the normal meal. Obese women who meet criteria for BED show differences in both intake and macronutrient composition of food choices from obese women who do not meet these criteria when asked to eat in a laboratory setting, supporting the validity of this new diagnosis.

Differences in body composition of black and white girls.

Adults have racial differences in body composition that may modulate risks resulting from obesity. Although black and white children have been shown previously to have differences in bone mineral density and subcutaneous body fat, differences in visceral adipose tissue have not been evaluated. We studied 20 black and 20 white normal-weight girls aged 7-10 y, who were matched for weight, body mass index (BMI), bone age, chronological age, Tanner breast stage, and socioeconomic status. Each underwent anthropometric measurements, bioelectrical impedance analysis, dual-energy X-ray absorptiometry (DXA), and abdominal magnetic resonance imaging (MRI) for determination of total (TAT), visceral (VAT), and subcutaneous (SAT) adipose tissue. Serum lipids and fasting and 2-h oral-glucose-tolerance test (OGTT) glucose and insulin concentrations were also measured. There were no differences between groups in absolute waist circumference or waist-to-hip ratio, but waist-to-thigh ratio was smaller in black than in white girls. Black girls had greater bone mineral density and less TAT, VAT, and SAT than whites. VAT was not significantly correlated with any measure of insulin, or with serum lipids. However, both basal and 2-h OGTT serum insulin were significantly correlated with SAT as assessed by MRI in black girls (r2 = 0.46 for basal insulin, P = 0.001: r2 = 0.31 for 2-h insulin, P = 0.01) but not in white girls (r2 < 0.05, for basal and 2-h insulin, NS). We conclude that there are significant racial differences in body composition and differences in the strength of association between abdominal adipose tissue depots and insulin sensitivity in black and white girls.

Growth characteristics and ultrastructure of human retinal pigment epithelium in vitro.

The in vitro growth characteristics and morphology of human retinal pigment epithelium (RPE) cells from adult donor eyes (15 to 100 years of age) have been studied. Although RPE cells are viable in culture for several months, only a fraction of the cells actually divide. Rapid cell proliferation and confluency of a culture occur from 10 to 30 days after seeding. The time for confluency is both age- and media-dependent; the number of cells that are potential dividers and contribute to confluency decreases with increasing donor age. Since melanolipofuscin granules do not form in vitro and are diluted by cell division, stationary (nondividing) cells can be distinguished from the dividing cells by the presence of dense clusters of melanolipofuscin granules in the stationary cells. Confluent cultures contain a monolayer of relatively clear polygonal cells with densely pigmented stationary cells scattered throughout. Stationary cells can often represent as much as 95% of the original RPE cell population. Ultrastructurally all cells appear epithelioid, with apical-basal polarity, junctional complexes, and cytoplasmic organization characteristic of RPE cells in vivo. Stationary cells are extremely large, with melanolipofuscin granules clustered around the nucleus. Melanolipofuscin is a unique marker for nondividing cells and may facilitate studies of the age-dependent loss of replicability of human RPE.

Proteins from human retinal pigment epithelial cells: evidence that a major protein is actin.

Two-dimensional gel electrophoresis coupled to fluorography was used to obtain the major 35S-methionine labeled protein patterns of cultured human retinal pigment epithelial cells (RPE) and fibroblasts. Comparisons of these profiles showed that: a) primary and subcultures of RPE were quite similar, each showing about 200 different proteins, b) the RPE protein patterns contained at least eight major acidic proteins (from 31 to 96 kilodaltons) not readily seen in fibroblasts; c) the fibroblast pattern showed three well-labeled, very acidic proteins, one of which (58 kilodaltons) appeared to be unique to fibroblasts; and d) a major complex of acidic protein of 43 kilodaltons with isoelectric points of 5.6 to 5.9 was a common protein in RPE and fibroblasts. These latter macromolecules were found to coelectrophorese with purified chicken muscle actin. Ultrastructural studies of cultured RPE supported the presence of actin microfilaments that were demonstrated specifically by labeling with fluorescent phallotoxin.

Vitamin A utilization in human retinal pigment epithelial cells in vitro.

Vitamin A (vit A) metabolism was studied in freshly isolated and cultured human retinal pigment epithelial (RPE) cells obtained from postmortem donor eyes. Fluorometric determination of vit A in human RPE cells demonstrated that freshly isolated cells contained approximately 1.0 to 4.0 pg vit A/cell which decreased with increasing time in culture; after 48 hrs in culture cellular vit A was reduced 80%. High performance liquid chromatography (hplc) profiles of the retinyl esters in freshly isolated RPE cells showed the presence of 11-cis retinyl stearate and palmitate and all-trans retinyl stearate, palmitate and oleate; all-trans palmitate was the major ester. Hplc analyses of cell cultures supplemented with all-trans retinol, using fatty acid-free bovine serum albumin as a carrier, showed that the cells in primary and subcultures took up all-trans retinol and esterified it to form palmitate, stearate, and oleate. Palmitate was the major ester synthesized by the cells in primary cultures. In the subcultures the esters synthesized differed from that found in freshly isolated cells and in the cells in primary culture; in the subcultures, the overall synthesis of ester was reduced and oleate was more prominent. The esters that were synthesized in culture were all-trans; the formation of 11-cis isomers was not observed in human RPE cells in culture. Electron microscopy of retinol-supplemented cultures indicated that vit A doses up to 1.0 micrograms/ml had no obvious effects on the cells; at higher doses the cells no longer adhered to the culture surface.

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.

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.

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.

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.