Development and operation of the defence COVID-19 lab as a SARS-CoV-2 diagnostic screening capability for UK military personnel.

BACKGROUND: In the face of the COVID-19 pandemic, the Defence Science and Technology Laboratory (Dstl) and Defence Pathology combined to form the Defence Clinical Lab (DCL), an accredited (ISO/IEC 17025:2017) high-throughput SARS-CoV-2 PCR screening capability for military personnel. LABORATORY STRUCTURE AND RESOURCE: The DCL was modular in organisation, with laboratory modules and supporting functions combining to provide the accredited SARS-CoV-2 (envelope (E)-gene) PCR assay. The DCL was resourced by Dstl scientists and military clinicians and biomedical scientists. LABORATORY RESULTS: Over 12 months of operation, the DCL was open on 289 days and tested over 72 000 samples. Six hundred military SARS-CoV-2-positive results were reported with a median E-gene quantitation cycle (Cq) value of 30.44. The lowest Cq value for a positive result observed was 11.20. Only 64 samples (0.09%) were voided due to assay inhibition after processing started. CONCLUSIONS: Through a sustained effort and despite various operational issues, the collaboration between Dstl scientific expertise and Defence Pathology clinical expertise provided the UK military with an accredited high-throughput SARS-CoV-2 PCR test capability at the height of the COVID-19 pandemic. The DCL helped facilitate military training and operational deployments contributing to the maintenance of UK military capability. In offering a bespoke capability, including features such as testing samples in unit batches and oversight by military consultant microbiologists, the DCL provided additional benefits to the UK Ministry of Defence that were potentially not available from other SARS-CoV-2 PCR laboratories. The links between Dstl and Defence Pathology have also been strengthened, benefitting future research activities and operational responses.

Antibacterial activities of plant leaf extracts against multi-antibiotic resistant Staphylococcus aureus associated with skin and soft tissue infections.

BACKGROUND: The antibacterial activities of aqueous leaf extracts of Moringa oleifera, Vernonia amygdalina, Azadirachta indica and Acalypha wilkesiana against multidrug resistance (MDR) Staphylococcus aureus associated with skin and soft tissue infections were investigated. METHODS: Staphylococcus aureus (n = 183) from the skin and soft tissue infections with evidence of purulent pus, effusions from aspirates, wounds, and otorrhea were biotyped, and evaluated for biofilm production. The phenotypic antibiotic resistance and MDR strains susceptibility to plant leaves extract were determined using disc diffusion and micro-broth dilution assays respectively. The correlation of plant extract bioactive components with inhibitory activities was determined. RESULTS: High occurrence rate of S. aureus were recorded among infant and adult age groups and 13.2% mild biofilm producers from the wound (p < 0.05). Of 60.2% MDR strains with overall significant MARI of more than 0.85 (p < 0.05), high resistant rates to linozidine (92.7%; 95% CI:7.27-10.52), ofloxacin (94.2%; 95% CI:6.09-8.15), chloramphenicol (91.2%; 95% CI:6.11-8.32), gentamicin (97.3%; 95% CI:6.20-8.22), ciprofloxacin (92.7%; 95% CI: 5.28-7.99) and vancomycin (86.6%; 95% CI:6.81-9.59) were observed. Vernonia amygdalina and Azadirachta indica showed significant antimicrobial activity at 100 mg/ml and 75 mg/ml, with low susceptibility of less than 10% to 25 mg/ml, 50 mg/ml, and 75 mg/ml Moringa oleifera. Alkaloids, saponin and terpenoids were significant in Moringa oleifera, Acalypha wilkesiana, Azadirachta indica and Vernonia amygdalina leaves extracts (p < 0.05). High inhibitory concentrations at IC50; 3.23, 3.75 and 4.80 mg/ml (p = 0.02, CI: - 0.08 - 11.52) and IC90; 12.9, 7.5, and 9.6 mg/ml (p = 0.028, CI: 2.72-23.38) were shown by Acalypha wilkesiana, Vernonia amygdalina and Moringa oleifera respectively. Comparative outcome of the plant extracts showed Acalypha wilkesiana, Vernonia amygdalina and Moringa oleifera to exhibit significant inhibition activities (p < 0.05) compared to other extracts. Significant median inhibitory concentration (15.3 mg/ml) of Azadirachta indica were observed (p < 0.01) and strong associations of phytochemical compounds of Azadirachta indica (eta = 0.527,p = 0.017), Vernonia amygdalina (eta = 0.123,p = 0.032) and Acalypha wilkesiana (eta = 0.492,p = 0.012) with their respective inhibitory values. CONCLUSION: Observed high occurrence rate of skin and soft tissue infections caused by biofilm-producing MDR S. aureus requires alternative novel herbal formulations with rich bioactive compounds from Moringa oleifera, Acalypha wilkesiana, Azadirachta indica and Vernonia amygdalina as skin therapeutic agents.

Comparison of sulfolane effects in Sprague Dawley rats, B6C3F1/N mice, and Hartley guinea pigs after 28 days of exposure via oral gavage.

Sulfolane is a solvent used in industrial refining with identified environmental exposure in drinking water. Due to potential large species differences, the National Toxicology Program (NTP) conducted 28-day toxicity studies in male and female Hsd:Sprague Dawley® SD® rats, B6C3F1/N mice, and Hartley guinea pigs. A wide dose range of 0, 1, 10, 30, 100, 300, and 800 mg/kg was administered via gavage. Histopathology, clinical pathology, and organ weights were evaluated after 28 days of exposure. In addition, plasma concentrations of sulfolane were evaluated 2 and 24 h after the last dose. Increased mortality was observed in the highest dose group of guinea pigs and mice while decreased body weight was observed in rats compared to controls. Histopathological lesions were observed in the kidney (male rat), stomach (male mice), esophagus (male and female guinea pigs), and nose (male guinea pigs). Plasma concentrations were generally higher in rats and guinea pigs compared to mice with evidence of saturated clearance at higher doses. Male rats appear to be the most sensitive with hyaline droplet accumulation occurring at all doses, although the human relevance of this finding is questionable.

A new respiratory scoring system for evaluation of respiratory outcomes in children with spinal muscular atrophy type1 (SMA1) on SMN enhancing drugs.

Nusinersen (NUS), the first treatment approved for Spinal Muscular Atrophy type 1 (SMA1), was made available in the UK for SMA1 through the Expanded Access Program (EAP) in 2017. The Great Ormond Street Respiratory (GSR) score was developed as an objective respiratory assessment for children with SMA1 during their treatment. Aims: Track respiratory status of SMA1 children over the course of Nusinersen treatment and compare GSR scores amongst SMA1 sub-types. Single centre study on SMA1 patients using the GSR score at set time points: prior to first NUS dose; 2 weeks post end of loading doses; 2 weeks post-subsequent doses. GSR score ranges 1-28, being 1-9 = Stable minimal support, thorough to 23-28 = Poor reserve with maximum support. 20 SMA1 children underwent NUS treatment between January 2017 - November 2018. Median age of diagnosis was 5.0 months. NUS started at median of 9.57 months. From 5th dose onwards, GSR scores were significantly lower for Type 1C patients compared to Type 1B By month 18, irrespective of subtypes, the whole cohort appears to stabilise GSR Scores. As treatment duration increases, an overall stabilisation of respiratory status across the cohort was observed. Further longitudinal studies are needed to validate the GSR.

Corrigendum to "Toxicokinetics of perfluorobutane sulfonate (PFBS), perfluorohexane-1-sulphonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) in male and female Hsd:Sprague Dawley SD rats after intravenous and gavage administration" [Toxicol. Rep. 6 (2019) 645-655].

[This corrects the article DOI: 10.1016/j.toxrep.2019.06.016.].

Toxicokinetics of 8:2 fluorotelomer alcohol (8:2-FTOH) in male and female Hsd:Sprague Dawley SD rats after intravenous and gavage administration.

Fluorotelomer alcohols (FTOHs) are used in the production of persistent per- and polyfluorinated alkyl substances (PFAS). Rodents and humans metabolize FTOHs to perfluoralkyl carboxylic acids which have several associated toxicities. Thus, understanding the toxicokinetics of these FTOHs and their metabolites will be useful for interpreting their toxicity for humans. Here, male and female Hsd:Sprague-Dawley SD rats were administered a single dose of 8:2-FTOH via gavage (males: 12, 24, 48 mg/kg; females: 40, 80, 160 mg/kg) or IV (males: 12 mg/kg; females: 40 mg/kg). Toxicokinetics of 8:2-FTOH and two primary metabolites, perfluorooctanoic acid (PFOA) and 7:3-fluorotelomer acid (7:3-FTA) were determined in plasma. Concentrations (total) of these chemicals were determined in the liver, kidney, and brain. There was rapid absorption and distribution of 8:2-FTOH after gavage administration in male rats. The plasma elimination half-life ranged from 1.1 to 1.7 hours. Kinetic parameters of 8:2-FTOH in females were similar to that in males. Bioavailability of 8:2-FTOH ranged from 22 to 41% for both sexes with no dose-dependent trends. 8:2-FTOH metabolites, PFOA and 7:3-FTA were detected in plasma following administration of the parent FTOH. Consistent with existing literature, the plasma half-life of PFOA was longer in males than in females (198-353 hours and 4.47-6.9 hours, respectively). The plasma half-life of 7:3-FTA was around 2-3 days in both sexes. 8:2-FTOH and 7:3-FTA were detected in all tissues; PFOA was found in the liver and kidney but not the brain. Detectable concentrations of metabolites persisted longer than the parent FTOH. These data demonstrate that in rats given a single gavage dose, 8:2-FTOH is rapidly absorbed, metabolized to form PFOA and 7:3-FTA, distributed to tissues, and eliminated faster than its metabolites. Sex differences were observed in the tissue distribution and elimination of PFOA, but not 8:2-FTOH and 7:3-FTA.

Toxicokinetics of perfluorobutane sulfonate (PFBS), perfluorohexane-1-sulphonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) in male and female Hsd:Sprague Dawley SD rats after intravenous and gavage administration.

Perfluorinated alkyl substances (PFAS) are persistent contaminants that have been detected in the environment and in humans. With the PFAS chemical class, there are perfluorinated alkyl acids, many of which have been associated with certain toxicities. Because toxicity testing cannot feasibly be conducted for each individual PFAS, the National Toxicology Program (NTP) designed studies to compare toxicities across different subclasses of PFAS and across PFAS of different chain lengths to better understand the structure-toxicity relationship. Pharmacokinetic studies were conducted in parallel to these toxicity studies to facilitate comparisons across PFAS and to provide context for human relevance. Here, the toxicokinetic parameters of perfluorobutane sulfonate (PFBS), perfluorohexane-1-sulphonic acid (PFHxS), or perfluorooctane sulfonate (PFOS) after a single intravenous or gavage administration in male and female Hsd:Sprague-Dawley rats are reported. Concentrations of these PFAS were measured in the liver, kidney, and brain. Plasma half-life increased with longer chain length after gavage administration: PFBS- males averaged 3.3 h, females 1.3 h; PFHxS- males averaged 16.3 days, females 2.1 days; PFOS- males and females averaged ˜ 20 days. There were dose-dependent changes in clearance and systemic exposure for all administered chemicals and the direction of change was different in PFOS compared to the others. Liver:plasma ratios of PFOS were the highest followed by PFHxS and PFBS, while brain:plasma ratios were low in all three sulfonates. Sex differences in plasma half-life and tissue distribution were observed for PFBS and PFHxS, but not PFOS. These data provide a direct comparison of the kinetics of three different perfluoroalkyl sulfonic acids and allow for the contextualization of toxicity data in rats for human risk assessment of this chemical class.

Blind estimation of DED camera gain in Electron Microscopy.

The introduction of Direct Electron Detector (DED) videos in the Electron Microscope field has boosted Single Particle Analysis to a point in which it is currently considered to be a key technique in Structural Biology. In this article we introduce an approach to estimate the DED camera gain at each pixel from the movies themselves. This gain is needed to have the set of recorded frames into a coherent gray level range, homogeneous over the whole image. The algorithm does not need any other input than the DED movie itself, being capable of providing an estimate of the camera gain image, helping to identify dead pixels and cases of incorrectly calibrated cameras. We propose the algorithm to be used either to validate the experimentally acquired gain image (for instance, to follow its possible change over time) or to verify that there is no residual gain image after experimentally correcting for the camera gain. We show results for a number of DED camera models currently in use (DE, Falcon II, Falcon 3, and K2).

Race/ethnicity determines the relationships between oxidative stress markers and blood pressure in individuals with high cardiovascular disease risk.

Oxidative stress (OS) and cardiovascular (CV) reactivity are related to CV morbidity and mortality. However, little is known about the relationships between these CV risk factors and their confounders. We hypothesize that higher OS is linked to higher blood pressure (BP) reactivity to acute laboratory stressors and in the natural setting. We studied 137 subjects with a family history of hypertension and early myocardial infarction. There were 63 European Americans (EAs) (38 males) and 74 African Americans (AAs) (35 males), aged 19-36 (27.6±3.1). The protocol included a competitive video game, cold stressor and ambulatory BP recording. Blood samples were drawn six times for OS markers (8-hydroxydeoxyguanosine (8-OHdG) and 8-Isoprostane) assay. Repeated measures analyses of covariance were used to test for mean differences and Pearson correlations were used to test OS and BP associations. There were no significant race/ethnicity differences in BP reactivity to either stressor (both P's>0.48). 8-OHdG levels were significantly lower across all time points for AAs than for EAs (P<0.05), while levels of 8-isoprostane did not differ significantly (P>0.10). Averaged 8-OHdG levels significantly correlated with systolic blood pressure (SBP) reactivity (r=0.45, <0.01) and 24-h, daytime and nighttime SBP (r range=0.37-0.42, all P's<0.02) for EAs but not for AAs, whereas 8-isoprostane levels were significantly correlated with reactive SBP and nighttime diastolic blood pressure (DBP) (both r's=0.38, P<0.01) for AAs but not for EAs. These findings suggest a link between OS and BP changes in subjects at high risk for CV disease (CVD). Further, race/ethnicity determines which OS marker will impact BP variation implying race/ethnicity differences in OS-related mechanisms of CVD.

Support for the hypothesis that sexual breast stimulation is an ancestral practice and a key to understanding women's health.

Women's health is seriously impacted by sexual dysfunction, mental depression, breast cancer, and gynecological cancers. Breast feeding has been found to reduce the risk of in-situ cervical cancer, endometrial cancer of the uterus, ovarian cancer, and breast cancer. This protective effect of breast feeding supports the notion that another functional use of the breast, sexual breast stimulation, promoted by women to incite their sexual arousal and orgasm, is a practice which also reduces the risk of these same cancers, and protects against sexual dysfunction and mental depression. The significance of the practice of breast sex or "sexual breast love" lies with its deeply rooted past in the founding of our species, Homo sapiens. No other species exhibits breast sex, a human cultural activity that is implicated in women's desire, sexual satisfaction, and the development of human sociality. For species females as a whole, nipple stimulation by a partner during sex, over the adult life of a female, has occurred since the inception of H. sapiens, so that the failure to engage in this activity is counter to a species typical practice and endangers women's health. Breast sex results in nipple erection, and may micmic the effects of breast feeding, causing an increase of oxytocin in the body. Breast sex is an enriched type of sexuality that enables love between the sexes and the pair bond. The intimacy of breast sex creates a common ground of sexual knowledge, allowing empathy, cooperation, commitment, and communication. It induces reciprocity and therefore happiness. With breast sex, there is an increase of the positive emotions over the chimpanzees, promoting advanced cognition. Research into whether oxytocin release is caused by stimulation of the breasts in non-lactating women is inconclusive, but cultural studies demonstrate that breast stimulation induces sexual arousal, and research has shown that sexual arousal is associated with oxytocin release.

A moment in time: emergency nurses and the Canterbury earthquakes.

AIM: To outline the impact of the Canterbury, New Zealand (NZ) earthquakes on Christchurch Hospital, and the experiences of emergency nurses during this time. BACKGROUND: NZ has experienced earthquakes and aftershocks centred in the Canterbury region of the South Island. The location of these, around and within the major city of Christchurch, was unexpected and associated with previously unknown fault lines. While the highest magnitude quake occurred in September 2010, registering 7.1 on the Richter scale, it was the magnitude 6.3 event on 22 February 2011 which was associated with the greatest injury burden and loss of life. Staff working in the only emergency department in the city were faced with an external emergency while also being directly affected as part of the disaster. SOURCES OF EVIDENCE: This paper developed following interviews with nurses who worked during this period, and draws on literature related to healthcare responses to earthquakes and natural disasters. The establishment of an injury database allowed for an accurate picture to emerge of the injury burden, and each of the authors was present and worked in a clinical capacity during the earthquake. DISCUSSION: Nurses played a significant role in the response to the earthquakes and its aftermath. However, little is known regarding the impact of this, either in personal or professional terms. This paper presents an overview of the earthquakes and experiences of nurses working during this time, identifying a range of issues that will benefit from further exploration and research. It seeks to provide a sense of the experiences and the potential meanings that were derived from being part of this 'moment in time'. CONCLUSION: Examples of innovations in practice emerged during the earthquake response and a number of recommendations for nursing practice are identified.

What are the perceived needs and challenges of informal caregivers in home cancer palliative care? Qualitative data to construct a feasible psycho-educational intervention.

PURPOSE: Tailored and specific interventions for informal caregivers in palliative care are rare. We aimed to generate evidence to inform a subsequent appropriate intervention based on caregivers' experiences. METHOD: Single, semi-structured qualitative interviews were undertaken with 20 informal cancer caregivers of home cancer palliative care. RESULTS: Carers reported the need to be prepared for their caring role, to be visible to professionals, to receive clear and specific information about the patient's condition, and to be emotionally supported. They described challenges as uncertainty, distress at witnessing disease progression and the daily struggle with financial issues, personal time, own health and sleep problems. CONCLUSIONS: Considering the time pressures and restricted caregiver time, the intervention should be brief and should aim to enhance their visibility as service recipients, patient-specific information giving, preparation for their role, and emotional support.

Toxicokinetics of bis(2-chloroethoxy)methane following intravenous administration and dermal application in male and female F344/N rats and B6C3F1 mice.

In the National Toxicology Program's toxicity studies, rats were more sensitive than mice to Bis(2-chloroethoxy)methane (CEM) - induced cardiac toxicity following dermal application to male and female F344/N rats and B6C3F1 mice. Thiodiglycolic acid (TDGA) is a major metabolite of CEM in rats. It has been implicated that chemicals metabolized to TDGA cause cardiac toxicity in humans. Therefore, the toxicokinetics of CEM and TDGA were investigated in male and female F344/N rats and B6C3F1 mice following a single intravenous administration or dermal application of CEM to aid in the interpretation of the toxicity data. Absorption of CEM following dermal application was rapid in both species and genders. Bioavailability following dermal application was low but was higher in rats than in mice with females of both species showing higher bioavailability than males. CEM was rapidly distributed to the heart, thymus, and liver following both routes of administration. Plasma CEM C(max) and AUC(∞) increased proportionally with dose, although at the dermal dose of 400mg/kg in rats and 600mg/kg in mice non-linear kinetics were apparent. Following dermal application, dose-normalized plasma CEM C(max) and AUC(∞) was significantly higher in rats than in mice (p-value<0.0001 for all comparisons except for C(max) in the highest dose groups where p-value=0.053). In rats, dose-normalized plasma CEM C(max) and AUC(∞) was higher in females than in males: however, the difference was significant only at the lowest dose (p-value=0.009 for C(max) and 0.056 for AUC(∞)). Similar to rats, female mice also showed higher C(max) and AUC(∞) in females than in male: the difference was significant only for C(max) at the lowest dose (p-value=0.002). Dose-normalized heart CEM C(max) was higher in rats than in mice and in females than their male counterparts. The liver CEM C(max) was lower compared to that of heart and thymus in both rats and mice following intravenous administration and in rats following dermal application. This is likely due to the rapid metabolism of CEM in the liver as evidenced by the high concentration of TDGA measured in the liver. Dose-normalized plasma and heart TDGA C(max) values were higher in rats compared to mice. In rats, females had higher plasma and heart TDGA C(max) than males; however, there was no gender difference in plasma or heart TDGA C(max) in mice. These findings support the increased sensitivity of rats compared to mice to CEM-induced cardiac toxicity. Data also suggest that, either CEM C(max) or AUC can be used to predict the CEM-induced cardiac toxicity. Although, both plasma and heart TDGA C(max) was consistent with the observed species difference and the gender difference in rats, the gender difference in mice to cardiac toxicity could not be explained based on the TDGA data. This animal study suggests that toxicologically significant concentrations of CEM and TDGA could possibly be achieved in the systemic circulation and/or target tissues in humans as a result of dermal exposure to CEM.

Expression of osteopontin coregulators in primary colorectal cancer and associated liver metastases.

BACKGROUND: A transcription regulatory complex (TRC) that includes Ets1, Ets2, PEA3 and ß-catenin/T-cell factors regulates osteopontin (OPN) that is implicated in colorectal cancer (CRC) dissemination. The consistency of OPN transcriptional control between primary CRC and metastases is unclear. This study investigates expression and prognostic significance of the OPN-TRC in primary human CRC and associated colorectal liver metastases (CRLM). METHODS: Osteopontin-TRC factors were assayed by digital microscopy in 38 primary CRCs and matched CRLM specimens and assessed against clinical prognosis. RESULTS: In primary CRC, OPN expression intensity correlated with that of its co-activators, PEA3 (r=0.600; P<0.01), Ets1 (r=0.552; P<0.01), Ets2 (r=0.521; P<0.01) and had prognostic significance. Osteopontin intensity in primary CRC inversely correlated with the interval between diagnosis and resection of CRLM. Overall OPN intensity was lower in CRLM than primary CRC and correlations with co-activators were weaker, for example, Ets1 (P=0.047), PEA3 (P=0.022) or nonsignificant (Ets2). The ratio of OPN expression in CRLM vs primary CRC had prognostic significance. CONCLUSION: This study supports transcriptional control of OPN by known coregulators in both primary and secondary CRC. Weaker associations in CRLM suggest involvement of other unknown factors possibly from the liver microenvironment or resulting from additional genetic or epigenetic changes that drive tumour metastatic capability in OPN transcriptional control.

Guidelines for the welfare and use of animals in cancer research.

Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

Less is more: reducing the reliance on animal models for nausea and vomiting research.

Animals have been used as experimental models for centuries and their use has enabled researchers to make significant advances in many areas of human health and disease. However, this is not always the case and there are limitations in using animal models as surrogates for humans, which have hampered the development of efficacious therapeutics for some pathologies. Scientific limitations, together with ethical concerns, legislative changes and the current economic climate are driving researchers to look for and develop alternative non-animal research tools. Technological advances in tissue engineering, 'omics' approaches and in silico modelling for example, are enabling scientists to conduct their research without using animals in a broad range of disciplines, including complex multi-system reflexes such as nausea and vomiting.

Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts. OBJECTIVES: To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. SELECTION CRITERIA: Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment, blinding and withdrawals. MAIN RESULTS: Eleven trials representing 12,068 women were included in the review. Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38 to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23% RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR (RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR (RR 0.50 95% CI 0.34 to 0.73) and 2% ARR. For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. AUTHORS' CONCLUSIONS: At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures were observed for secondary prevention ('gold' level evidence, www.cochranemsk.org). We found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important ('gold' level evidence).

Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. OBJECTIVES: To assess the efficacy of etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. SELECTION CRITERIA: Women receiving at least one year of etidronate for postmenopausal osteoporosis were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: Study selection and data abstraction was done in duplicate. Meta-analysis of fracture outcomes was performed with data presented as relative risks and a relative change greater than 15% was considered clinically important. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals. MAIN RESULTS: Eleven studies representing a total of 1248 patients were included in the review.A significant 41% relative risk reduction (RRR) in vertebral fractures across eight studies (RR 0.59, 95% CI 0.36 to 0.96) was found. The six secondary prevention trials demonstrated a significant RRR of 47% in vertebral fractures (RR 0.53, 95% CI 0.32 to 0.87) and a 5% absolute risk reduction (ARR); compared with the pooled result for the two primary prevention trials (RR 3.03, 95% CI 0.32 to 28.44), which was not significant. There were no statistically significant risk reductions for non-vertebral (RR 0.98, 95% CI 0.68 to 1.42), hip (RR 1.20, 95% CI 0.37 to 3.88) or wrist fractures (RR 0.87, 95% CI: 0.32 to 2.36). For adverse events, no statistically significant differences were found in the included studies. However, observational data has led to concerns regarding potential risk for upper gastrointestinal injury. AUTHORS' CONCLUSIONS: Etidronate, at 400 mg per day, demonstrated a statistically significant and clinically important benefit in the secondary prevention of vertebral fractures. No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention. In addition, no statistically significant reductions in non-vertebral, hip, or wrist fractures were found, regardless of whether etidronate was used for primary or secondary prevention. The level of evidence for all outcomes is Silver (www.cochranemsk.org.).

Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Risedronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. OBJECTIVES: To assess the efficacy of residronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE. Relevant randomized controlled trials published between 1966 to 2007 were identified. SELECTION CRITERIA: Women receiving at least one year of risedronate for postmenopausal osteoporosis were compared to those receiving placebo or concurrent calcium/vitamin D or both. The outcome was fracture incidence. DATA COLLECTION AND ANALYSIS: We carried out study selection and data abstraction in duplicate. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals. Meta-analysis was preformed using relative risks and a >15% relative change was considered clinically important. MAIN RESULTS: Seven trials were included in the review representing 14,049 women. Relative (RRR) and absolute (ARR) risk reductions for the 5 mg dose were as follows. Risk estimates for primary prevention were available only for vertebral and non vertebral fractures and showed no statistically significant effect of risedronate on fractures. For secondary prevention, a significant 39% RRR in vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76) with 5% ARR was found. For non-vertebral fractures, a significant 20% RRR (RR 0.80, 95% CI 0.72 to 0.90) with 2% ARR and for hip fractures there was a significant 26% RRR (RR: 0.74, 95% CI 0.59 to 0.94) with a 1% ARR. When primary and secondary prevention studies were combined, the reduction in fractures remained statistically significant for both vertebral (RR 0.63, 0.51 to 0.77) and non vertebral fractures (RR 0.80, 0.72 to 0.90)For adverse events, no statistically significant differences were found in any of the included studies. However, observational data has led to concerns regarding the potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. AUTHORS' CONCLUSIONS: At 5 mg/day a statistically significant and clinically important benefit in the secondary prevention of vertebral, non-vertebral and hip fractures was observed, but not for wrist. The level of evidence for secondary prevention is Gold (www.cochranemsk.org) for vertebral and non-vertebral and Silver for hip and wrist. There were no statistically significant reductions in the primary prevention of vertebral and non-vertebral fractures. The level of evidence is Silver.

Direct costs of osteoporosis and hip fracture: an analysis for the Mexican healthcare system.

UNLABELLED: This study reports the direct costs related to osteoporosis and hip fractures paid for governmental and private institutions in the Mexican health system and estimates the impact of these entities on Mexico. We conclude that the economic burden due to the direct costs of hip fracture justifies wide-scale prevention programs for osteoporosis (OP). METHODS: To estimate the total direct costs of OP and hip fractures in the Mexican Health care system, a sample of governmental and private institutions were studied. Information was gathered through direct questionnaires in 275 OP patients and 218 hip fracture cases. Additionally, a chart review was conducted and experts' opinions obtained to get accurate protocol scenarios for diagnoses and treatment of OP with no fracture. Microcosting and activity-based costing techniques were used to yield unit costs. RESULTS: The total direct costs for OP and hip fracture were estimated for 2006 based on the projected annual incidence of hip fractures in Mexico. A total of 22,233 hip fracture cases were estimated for 2006 with a total cost to the healthcare system of US$ 97,058,159 for the acute treatment alone ($4,365.50 per case). We found considerable differences in costs and the way the patients were treated across the different health sectors within the country. CONCLUSION: Costs of the acute treatment of hip fractures in Mexico are high and are expected to increase with the predicted increment of life expectancy and the number of elderly in our population.