Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials

Background: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. Background: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. Methods: We searched MEDLINE and Embase from Jan 1, 1950, to Dec 31, 2015, to identify unconfounded, randomised trials of a gastroprotectant drug (defined as a PPI, prostaglandin analogue, or H2RA) versus control, or versus another gastroprotectant. Two independent researchers reviewed the search results and extracted the prespecified outcomes and key characteristics for each trial. We did meta-analyses of the effects of gastroprotectant drugs on ulcer development, bleeding, and mortality overall, according to the class of gastroprotectant, and according to the individual drug within a gastroprotectant class. Findings: We identified comparisons of gastroprotectant versus control in 849 trials (142 485 participants): 580 prevention trials (110 626 participants), 233 healing trials (24 033 participants), and 36 trials for the treatment of acute upper gastrointestinal bleeding (7826 participants). Comparisons of one gastroprotectant drug versus another were available in 345 trials (64 905 participants), comprising 160 prevention trials (32 959 participants), 167 healing trials (28 306 participants), and 18 trials for treatment of acute upper gastrointestinal bleeding (3640 participants). The median number of patients in each trial was 78 (IQR 44·0–210·5) and the median duration was 1·4 months (0·9–2·8). In prevention trials, gastroprotectant drugs reduced development of endoscopic ulcers (odds ratio [OR] 0·27, 95% CI 0·25–0·29; p<0·0001), symptomatic ulcers (0·25, 0·22–0·29; p<0·0001), and upper gastrointestinal bleeding (0·40, 0·32–0·50; p<0·0001), but did not significantly reduce mortality (0·85, 0·69–1·04; p=0·11). Larger proportional reductions in upper gastrointestinal bleeding were observed for PPIs than for other gastroprotectant drugs (PPIs 0·21, 99% CI 0·12–0·36; prostaglandin analogues 0·63, 0·35–1·12; H2RAs 0·49, 0·30–0·80; phet=0·0005). Gastroprotectant drugs were effective in preventing bleeding irrespective of the use of non-steroidal anti-inflammatory drugs (phet=0·56). In healing trials, gastroprotectants increased endoscopic ulcer healing (3·49, 95% CI 3·28–3·72; p<0·0001), with PPIs more effective (5·22, 99% CI 4·00–6·80) than prostaglandin analogues (2·27, 1·91–2·70) and H2RAs (3·80, 3·44–4·20; phet<0·0001). In trials among patients with acute bleeding, gastroprotectants reduced further bleeding (OR 0·68, 95% CI 0·60–0·78; p<0·0001), blood transfusion (0·75, 0·65–0·88; p=0·0003), further endoscopic intervention (0·56, 0·45–0·70; p<0·0001), and surgery (0·72, 0·61–0·84; p<0·0001), but did not significantly reduce mortality (OR 0·90, 0·72–1·11; p=0·31). PPIs had larger protective effects than did H2RAs for further bleeding (phet=0·0107) and blood transfusion (phet=0·0130). Interpretation: Gastroprotectants, in particular PPIs, reduce the risk of peptic ulcer disease and its complications and promote healing of peptic ulcers in a wide range of clinical circumstances. However, this meta-analysis might have overestimated the benefits owing to small study bias

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Survival from testicular cancer in England and Wales up to 2001

www.bjcancer.com For many years testicular cancer has been the prime example of the tumour that is chemocurable, even when metastatic. The disappointment in oncology is that these results have so far not been replicated in the more common solid tumours. Why this should be is not clear but germ-cell tumours retain sensitivity to chemotherapy in vitro and a number of mechanisms including reduced DNA repair capacity and proneness to apoptosis have been proposed (Mayer et al, 2003). Most patients with testicular cancer present after finding a lump in the testicle that may or may not be painful. A small proportion of patients present with symptoms of metastatic disease. With the exception of some patients with metastatic disease, initial treatment after first assessment is to remove the tumour by inguinal orchidectomy. Patients are staged by tumour marke

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

<p>Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.</p> <p>Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).</p> <p>Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).</p&gt

Improving Adherence to Essential Birth Practices Using the WHO Safe Childbirth Checklist With Peer Coaching: Experience From 60 Public Health Facilities in Uttar Pradesh, India.

BACKGROUND: Adherence to evidence-based essential birth practices is critical for improving health outcomes for mothers and newborns. The WHO Safe Childbirth Checklist (SCC) incorporates these practices, which occur during 4 critical pause points: on admission, before pushing (or cesarean delivery), soon after birth, and before discharge. A peer-coaching strategy to support consistent use of the SCC may be an effective approach to increase birth attendants' adherence to these practices. METHODS: We assessed data from 60 public health facilities in Uttar Pradesh, India, that received an 8-month staggered coaching intervention from December 2014 to September 2016 as part of the BetterBirth Trial, which is studying effectiveness of an SCC-centered intervention on maternal and neonatal harm. Nurse coaches recorded birth attendants' adherence to 39 essential birth practices. Practice adherence was calculated for each intervention month. After 2 months of coaching, a subsample of 15 facilities was selected for independent observation when the coach was not present. We compared adherence to the 18 practices recorded by both coaches and independent observers. RESULTS: Coaches observed birth attendants' behavior during 5,971 deliveries. By the final month of the intervention, 35 of 39 essential birth practices had achieved >90% adherence in the presence of a coach, compared with only 7 of 39 practices during the first month. Key behaviors with the greatest improvement included explanation of danger signs, temperature measurement, assessment of fetal heart sounds, initiation of skin-to-skin contact, and breastfeeding. Without a coach present, birth attendants' average adherence to practices and checklist use was 24 percentage points lower than when a coach was present (range: -1% to 62%). CONCLUSION: Implementation of the WHO Safe Childbirth Checklist with coaching improved uptake of and adherence to essential birth practices. Coordination and communication among facility staff, as well as behaviors with an immediate, tangible benefit, showed the greatest improvement. Difficult-to-perform behaviors and those with delayed or theoretical benefits were less likely to be sustained without a coach present. Coaching may be an important component in implementing the Safe Childbirth Checklist at scale.Note: At the time of publication of this article, the results of evaluation of the impact of the BetterBirth intervention were pending publication in another journal. After the impact findings have been published, we will update this article on the effect of the intervention on birth practices with a reference to the impact findings

International Trade Under the Rule of Law Conference

The central focus of the conference was the dispute settlement system of the World Trade Organization (WTO), with a view toward exploring the need for a superstructure of international law governing trade and economic cooperation between countries

No. 5 - International Trade under the Rule of Law: An American Society of International Law Centennial Regional Meeting

Organized and sponsored by the Dean Rusk Center and designated an American Society of International Law Centennial Regional Meeting, this conference focused on the Dispute Settlement System (DSS) of the World Trade Organization (WTO) with a view toward discussing the need for a superstructure of international law governing trade and economic cooperation between states

Neonatal death in low- to middle-income countries: a global network study

OBJECTIVE: To determine population-based neonatal mortality rates in low- and middle-income countries and to examine gestational age, birth weight, and timing of death to assess the potentially preventable neonatal deaths. METHODS: A prospective observational study was conducted in communities in five low-income countries (Kenya, Zambia, Guatemala, India, and Pakistan) and one middle-income country (Argentina). Over a 2-year period, all pregnant women in the study communities were enrolled by trained study staff and their infants followed to 28 days of age. RESULTS: Between October 2009 and March 2011, 153,728 babies were delivered and followed through day 28. Neonatal death rates ranged from 41 per 1000 births in Pakistan to 8 per 1000 in Argentina; 54% of the neonatal deaths were >37 weeks and 46% weighed 2500 g or more. Half the deaths occurred within 24 hours of delivery. CONCLUSION: In our population-based low- and middle-income country registries, the majority of neonatal deaths occurred in babies >37 weeks´ gestation and almost half weighed at least 2500 g. Most deaths occurred shortly after birth. With access to better medical care and hospitalization, especially in the intrapartum and early neonatal period, many of these neonatal deaths might be prevented. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.Fil: Belizán, José. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: McClure, Elizabeth. Research Triangle Institute; Estados UnidosFil: Goudar, Shivaprasad. Jawaharlal Nehru Medical College; IndiaFil: Pasha, Omrana. Aga Khan University; PakistánFil: Esamai, Fabian. Moi University; KeniaFil: Patel, Archana. Lata Medical Research Foundation; India. Indira Medical College; IndiaFil: Chomba, Elwyn. University of Zambia; ZambiaFil: Garces, Ana. Universidad de San Carlos de Guatemala (univ. de San C. de Guatemala);Fil: Wright, Linda. Eunice Kennedy Shriver National Institute of Child Health and Human Development; Estados UnidosFil: Koso Thomas, Marion. Eunice Kennedy Shriver National Institute of Child Health and Human Development; Estados UnidosFil: Moore, Janet. Research Triangle Institute; Estados UnidosFil: Althabe, Fernando. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kodkany, Bhala. Jawaharlal Nehru Medical College; IndiaFil: Sami, Neelofar. Aga Khan University; PakistánFil: Manasyan, Albert. University of Zambia; ZambiaFil: Derman, Richard. Christiana Health Care; Estados UnidosFil: Liechty, Edward. Indiana University; Estados UnidosFil: Hibberd, Patricia. Massachusetts General Hospital for Children; Estados UnidosFil: Carlo, Waldemar A.. University of Alabama at Birmingahm; Estados UnidosFil: Hambidge, Michael. University of Colorado; Estados UnidosFil: Buekens, Pierre. Tulane School of Public Health and Tropical Medicine; Estados UnidosFil: Jobe, Alan. University of Cincinnati; Estados UnidosFil: Goldenberg, Robert. Columbia University; Estados Unido

Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing SCAD gene mutations and/or variants. SCAD gene variants are present in homozygous form in approximately 6% of the general population and considered to confer susceptibility to development of clinical disease. Clinically, SCADD generally appears to present early in life and to be most frequently associated with developmental delay, hypotonia, epilepsy, behavioral disorders, and hypoglycemia. However, these symptoms often ameliorate and even disappear spontaneously during follow-up and were found to be unrelated to the SCAD genotype. In addition, in some cases, symptoms initially attributed to SCADD could later be explained by other causes. Finally, SCADD relatives of SCADD patients as well as almost all SCADD individuals diagnosed by neonatal screening remained asymptomatic during follow-up. This potential lack of clinical consequences of SCADD has several implications. First, the diagnosis of SCADD should never preclude extension of the diagnostic workup for other potential causes of the observed symptoms. Second, patients and parents should be clearly informed about the potential lack of relevance of the disorder to avoid unfounded anxiety. Furthermore, to date, SCADD is not an optimal candidate for inclusion in newborn screening programs. More studies are needed to fully establish the relevance of SCADD and solve the question as to whether SCADD is involved in a multifactorial disease or represents a nondisease