Understanding SARS-CoV-2 Delta and Omicron variant transmission and vaccine impact in schools and child-care settings in Australia: a population-based study.

Background: Over 214 million students globally have been affected by school closures during the COVID-19 pandemic. To address knowledge gaps on transmission of SARS-CoV-2 delta (B.1.617.2) and omicron (B.1.1.529) variants in educational settings we examined virus transmission in schools and early childhood education and care settings (ECECs) in New South Wales (NSW), Australia in relation to mitigation measures, including COVID-19 vaccination. Methods: Secondary transmission from children and adults with laboratory-confirmed SARS-CoV-2 infection who attended a school (n = 3170) or ECECs (n = 5800) while infectious was investigated over two periods: 1) June 16 to September 18, 2021 (delta outbreak), and; 2) October 18 to December 18, 2021 (delta and omicron; schools only). Close contacts of cases underwent 14 days quarantine and SARS-CoV-2 nucleic acid testing. Secondary attack rates (SARs) were calculated and compared with state-wide notification data, school attendance, and vaccination status. Findings: 1187 schools and 300 ECECs had students (n = 1349) or staff (n = 440) attend while infectious. Of 24,277 contacts investigated, most (91.8%; 22,297/24,277) were tested and 912 secondary cases identified. The secondary attack rate (SAR) was 5.9% in 139 ECECs and 3.5% in 312 schools. The risk of becoming a secondary case was higher in unvaccinated school staff (OR 4.7; 95% CI: 1.7-13.3), particularly ECEC staff (OR 9.0; 95% CI: 3.6-22.7) and unvaccinated school students than in vaccinated school staff. SARs were similar for delta (4.9%) and omicron BA.1 (4.1%) in the unvaccinated and higher compared with vaccinated contacts (0.9% and 3.4%, respectively). Increasing school attendance rates raised case incursions and secondary case numbers, but not community-wide infection rates. Interpretation: Vaccination reduced SARS-CoV-2 transmission rates in schools, although less so for omicron than delta variants. Despite higher community-based transmission rates, in-school transmission remained low and stable with high attendance, suggesting that community restrictions, rather than school closures, best mitigated COVID-19 impacts. Funding: NSW Government Department of Health.

Dose intensity in anthracycline-based chemotherapy for metastatic breast cancer: mature results of the randomised clinical trial ANZ 9311.

PURPOSE: The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy. METHODS: This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life. RESULTS: In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity. CONCLUSION: For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy. Australian Clinical Trials Registry registration number ACTRN12605000478617.

Pck-ing up steam: Widening the salmonid gluconeogenic gene duplication trail.

Rainbow trout have, as salmonid fish species, undergone sequential genome duplication events in their evolutionary history. In addition to a teleost-specific whole genome duplication approximately 320-350 million years ago, rainbow trout and salmonids in general underwent an additional salmonid lineage-specific genome duplication event approximately 80 million years ago. Through the recent sequencing of salmonid genome sequences, including the rainbow trout, the identification and study of duplicated genes has become available. A particular focus of interest has been the evolution and regulation of rainbow trout gluconeogenic genes, as recent molecular and gene expression evidence points to a possible contribution of previously uncharacterized gluconeogenic gene paralogues to the rainbow trout long-studied glucose intolerant phenotype. Since the publication of the initial rainbow trout genome draft, resequencing and annotation have further improved genome coverage. Taking advantage of these recent improvements, we here identify a salmonid-specific genome duplication of ancestral mitochondrial phosphoenolpyruvate carboxykinase 2 isoenzyme, we termed pck2a and pck2b. Cytosolic phosphoenolpyruvate carboxykinase (Pck1) and, more recently mitochondrial Pck2, are considered to be the rate-limiting enzymes in de novo gluconeogenesis. Following in silico confirmation of salmonid pck2a and pck2b evolutionary history, we simultaneously profiled cytosolic pck1 and mitochondrial pck2a and pck2b expression in rainbow trout liver under several experimental conditions known to regulate hepatic gluconeogenesis. Cytosolic pck1 abundance was increased by nutritional (diets with a high protein to carbohydrate ratio compared to diets with a low carbohydrate to protein ratio) and glucoregulatory endocrine factors (glucagon and cortisol), revealing that the well-described transcriptional regulation of pck1 in mammals is present in rainbow trout. Conversely, and in contrast to mammals, we here describe endocrine regulation of pck2a (decrease in abundance in response to glucagon infusion), and nutritional, social-status-dependent and hypoxia-dependent regulation of pck2b. Specifically, pck2b transcript abundance increased in trout fed a diet with a low protein to carbohydrate ratio compared to a diet with a high protein to carbohydrate ratio, in dominant fish compared to subordinate fish as well as hypoxia. This specific and differential expression of rainbow trout pck2 ohnologues is indicative of functional diversification, and possible functional consequences are discussed in light of the recently highlighted gluconeogenic roles of mitochondrial pck2 in mammalian models.

The Ionospheric Connection Explorer Mission: Mission Goals and Design.

The Ionospheric Connection Explorer, or ICON, is a new NASA Explorer mission that will explore the boundary between Earth and space to understand the physical connection between our world and our space environment. This connection is made in the ionosphere, which has long been known to exhibit variability associated with the sun and solar wind. However, it has been recognized in the 21st century that equally significant changes in ionospheric conditions are apparently associated with energy and momentum propagating upward from our own atmosphere. ICON's goal is to weigh the competing impacts of these two drivers as they influence our space environment. Here we describe the specific science objectives that address this goal, as well as the means by which they will be achieved. The instruments selected, the overall performance requirements of the science payload and the operational requirements are also described. ICON's development began in 2013 and the mission is on track for launch in 2017. ICON is developed and managed by the Space Sciences Laboratory at the University of California, Berkeley, with key contributions from several partner institutions.

Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II.

Background: Anastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS)-II prevention and ductal carcinoma in situ (DCIS) trials, and its association with early symptoms. Patients and methods: In the prevention trial, 3864 postmenopausal women were randomized to placebo versus anastrozole. A total of 2980 postmenopausal women with DCIS were randomized to tamoxifen versus anastrozole. Adherence to trial medication was calculated using the Kaplan-Meier method and all P-values were two-sided. Results: In the prevention trial, adherence was 65.8% [anastrozole (65.7%) versus placebo (65.9%); HR = 0.97 (0.87-1.09), P = 0.6]. Adherence was lower for those reporting arthralgia in the placebo group (P = 0.02) or gynecological symptoms in the anastrozole group (P = 0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% [anastrozole (67.5%) versus tamoxifen (65.8%); HR = 1.06 (0.94-1.20), P = 0.4]. Hot flashes were associated with greater adherence in the anastrozole arm (P = 0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials. Conclusions: In the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

A drop in the circulating concentrations of soluble receptor for advanced glycation end products is associated with seroconversion to autoantibody positivity but not with subsequent progression to clinical disease in children en route to type 1 diabetes.

BACKGROUND: Advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) have been studied for their role in the pathogenesis and complications of type 1 diabetes. Decreased concentrations of soluble RAGE (sRAGE) have been reported in acute autoimmune inflammation. We set out to analyze the changes in sRAGE concentration during preclinical diabetes in children seroconverting to islet autoantibody positivity. METHODS: We measured serum concentrations of sRAGE in 168 children who progressed to clinical disease and 43 children who turned positive for at least 2 diabetes-associated autoantibodies but remained nondiabetic. We analyzed the sRAGE before seroconversion in the first autoantibody-positive sample and annually thereafter until the diagnosis of type 1 diabetes or end of follow-up. RESULTS: Both groups had similar sRAGE before seroconversion, but subsequently, sRAGE concentrations were lower (P < .001) in the progressors. The progressors had significantly higher sRAGE concentrations before than after seroconversion (P < .001). The nonprogressors did not experience a similar decrease. The sRAGE concentrations remained stable after seroconversion in both groups. CONCLUSIONS: These data indicate that sRAGE may be involved in the initiation of beta-cell autoimmunity but not in the progression from beta-cell autoimmunity to clinical disease.

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.

BACKGROUND: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. PATIENTS AND METHODS: This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. RESULTS: Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. CONCLUSION: These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493.

Sports-Related Concussion in Helmeted vs. Unhelmeted Athletes: Who Fares Worse?

In the management of sports-related concussion, little is known about the effect of wearing or not wearing a helmet (i. e., helmet status) on the acute outcomes of concussed athletes. We endeavored to assess acute neurocognitive and symptom changes after SRC in helmeted vs. unhelmeted athletes. In a retrospective study, 1 025 athletes from 2 regional databases sustained a SRC. Athletes were matched by age, gender, number of prior concussions, and days to post-concussion test, yielding a final cohort of 138 athletes. For each group of 69, differences in post-concussion neurocognitive and symptom scores were compared using group mean differences as well as reliable change index (RCI) scores set at the 80% confidence interval. With gender, prior concussions, and days to post-concussion test similar in each group, using group mean change scores and RCI methodology, we found no significant differences between the helmeted and unhelmeted groups in 4 neurocognitive tests and one total symptom score. In a cohort of carefully matched athletes from 2 regional concussion centers, helmet status was unrelated to neurocognitive scores and total symptoms in athletes after suffering a SRC. These findings suggest that acute outcomes in helmeted vs. unhelmeted sports are quite similar.

Low-flow hypothermic crystalloid perfusion is superior to cold storage during prolonged heart preservation.

BACKGROUND: Preservation of donor hearts for transplantation has traditionally been performed with the use of static cold storage. We have developed and tested a novel gravity-powered system of cold crystalloid perfusion for prolonged donor heart preservation. METHODS: Greyhounds were anesthetized; their hearts were arrested with cold cardioplegic solution and excised. Hearts were allocated to 12 hours of perfusion preservation (n = 6) or cold storage in ice (n = 5). Non-preserved hearts (n = 5) served as a normal reference group. Perfusion hearts were perfused (20 mL/min, 8-12°C) with a novel oxygenated nutrient-containing preservation solution. After preservation, the recovery of the hearts was assessed in a blood-perfused working heart rig over 2 hours in terms of function, blood lactate level, myocardial adenosine triphosphate, and histology. RESULTS: After 2 hours of reperfusion, in comparison with cold storage hearts, perfused heart function curves showed superior recovery of cardiac output (P = .001), power (P = .001), and efficiency (0.046 ± 0.01 vs 0.004 ± 0.003 joules/mL O2, P = .034). Myocardial adenosine triphosphate content (mmol/mg protein) was reduced significantly from the normal level of 26.5 (15.9, 55.8) to 5.08 (0.50, 10.4) (P = .049) in cold storage hearts but not in perfused hearts. Over a period of 2 hours, lactate levels in the blood perfusate were significantly lower in the perfusion group than in the cold storage group (P < .05). CONCLUSIONS: Continuous hypothermic crystalloid perfusion provides myocardial preservation superior to cold storage for long-term heart preservation, with potential applicability to marginal and donation after circulatory death hearts.

Improving decision making about clinical trial participation - a randomised controlled trial of a decision aid for women considering participation in the IBIS-II breast cancer prevention trial.

BACKGROUND: Decision aids may improve informed consent in clinical trial recruitment, but have not been evaluated in this context. This study investigated whether decision aids (DAs) can reduce decisional difficulties among women considering participation in the International Breast Cancer Intervention Study-II (IBIS-II) trial. METHODS: The IBIS-II trial investigated breast cancer prevention with anastrazole in two cohorts: women with increased risk (Prevention), and women treated for ductal carcinoma in situ (DCIS). Australia, New Zealand and United Kingdom participants were randomised to receive a DA (DA group) or standard trial consent materials (control group). Questionnaires were completed after deciding about participation in IBIS-II (post decision) and 3 months later (follow-up). RESULTS: Data from 112 Prevention and 34 DCIS participants were analysed post decision (73 DA; 73 control); 95 Prevention and 24 DCIS participants were analysed at follow-up (58 DA; 61 control). There was no effect on the primary outcome of decisional conflict. The DCIS-DA group had higher knowledge post decision, and the Prevention-DA group had lower decisional regret at follow-up. CONCLUSIONS: This was the first study to evaluate a DA in the clinical trial setting. The results suggest DAs can potentially increase knowledge and reduce decisional regret about clinical trial participation.

Neoadjuvant chemotherapy with sequential anthracycline-docetaxel with gemcitabine for large operable or locally advanced breast cancer: ANZ 0502 (NeoGem).

BACKGROUND: Neoadjuvant chemotherapy has a sound rationale for use in women with large operable breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer. In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results. This phase II study investigated the efficacy and safety of incorporating gemcitabine into neoadjuvant therapy. METHODS: Female patients with operable breast cancer that was clinically T2 (≥3 cm) or T3-4, N0-1, M0 were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clinical and radiological response rates, disease free survival and safety. RESULTS: 81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with HER2-negative, and 9 (53%) with HER2-positive disease. At the first interim analysis, addition of prophylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to accrual because it did not meet the pre-specified target for pCR, and the HER2-positive cohort was closed due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a relapse of their breast cancer. CONCLUSION: Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide, did not reach the pre-specified expectations for pCR rate in HER2-negative tumours. Excess neutropenia was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule cannot be recommended. Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au) registration number ACTRN12606000191594.

Culturally adapting the prevention of diabetes and obesity in South Asians (PODOSA) trial.

Type 2 diabetes is extremely common in South Asians, e.g. in men from Pakistani and Indian populations it is about three times as likely as in the general population in England, despite similarities in body mass index. Lifestyle interventions reduce the incidence of diabetes. Trials in Europe and North America have not, however, reported on the impact on South Asian populations separately or provided the details of their cross-cultural adaptation processes. Prevention of diabetes and obesity in South Asians (PODOSA) is a randomized, controlled trial in Scotland of an adapted, lifestyle intervention aimed at reducing weight and increasing physical activity to reduce type 2 diabetes in Indians and Pakistanis. The trial was adapted from the Finnish Diabetes Prevention Study. We describe, reflect on and discuss the following key issues: The core adaptations to the trial design, particularly the delivery of the intervention in homes by dietitians rather than in clinics. The use of both a multilingual panel and professional translators to help translate and/or develop materials. The processes and challenges of phonetic translation. How intervention resources were adapted, modified, newly developed and translated into Urdu and Gurmukhi (written Punjabi). The insights gained in PODOSA (including time pressures on investigators, imperfections in the adaptation process, the power of verbal rather than written information, the utilization of English and the mother-tongue languages simultaneously by participants and the costs) might help the research community, given the challenge of health promotion in multi-ethnic, urban societies.

Symptoms of endocrine treatment and outcome in the BIG 1-98 study.

There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen. Data on patients randomized into the monotherapy arms of the BIG 1-98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n = 4,798) and at the 12-month landmark (n = 4,682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed for disease-free survival (DFS) and for breast cancer free interval (BCFI), using regression analysis to estimate hazard ratios (HR) and 95 % confidence intervals (CI). Median follow-up was 7.0 years. Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses [e.g., 12-month landmark, HR (95 % CI) for DFS = 0.65 (0.49-0.87), and for BCFI = 0.70 (0.49-0.99)]. By contrast, reporting of vasomotor symptoms was less clearly associated with DFS [12-month DFS HR (95 % CI) = 0.82 (0.70-0.96)] and BCFI (12-month DFS HR (95 % CI) = 0.97 (0.80-1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes. While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.

Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial.

BACKGROUND: Venous thromboembolism is a common, potentially avoidable cause of death and morbidity in patients in hospital, including those with stroke. In surgical patients, intermittent pneumatic compression (IPC) reduces the risk of deep vein thrombosis (DVT), but no reliable evidence exists about its effectiveness in patients who have had a stroke. We assessed the effectiveness of IPC to reduce the risk of DVT in patients who have had a stroke. METHODS: The CLOTS 3 trial is a multicentre parallel group randomised trial assessing IPC in immobile patients (ie, who cannot walk to the toilet without the help of another person) with acute stroke. We enrolled patients from day 0 to day 3 of admission and allocated them via a central randomisation system (ratio 1:1) to receive either IPC or no IPC. A technician who was masked to treatment allocation did a compression duplex ultrasound (CDU) of both legs at 7-10 days and, wherever practical, at 25-30 days after enrolment. Caregivers and patients were not masked to treatment assignment. Patients were followed up for 6 months to determine survival and later symptomatic venous thromboembolism. The primary outcome was a DVT in the proximal veins detected on a screening CDU or any symptomatic DVT in the proximal veins, confirmed on imaging, within 30 days of randomisation. Patients were analysed according to their treatment allocation. TRIAL REGISTRATION: ISRCTN93529999. FINDINGS: Between Dec 8, 2008, and Sept 6, 2012, 2876 patients were enrolled in 94 centres in the UK. The included patients were broadly representative of immobile stroke patients admitted to hospital and had a median age of 76 years (IQR 67-84). The primary outcome occurred in 122 (8·5%) of 1438 patients allocated IPC and 174 (12·1%) of 1438 patients allocated no IPC; an absolute reduction in risk of 3·6% (95% CI 1·4-5·8). Excluding the 323 patients who died before any primary outcome and 41 without any screening CDU, the adjusted OR for the comparison of 122 of 1267 patients vs 174 of 1245 patients was 0·65 (95% CI 0·51-0·84; p=0·001). Deaths in the treatment period occurred in 156 (11%) patients allocated IPC and 189 (13%) patients allocated no IPC died within the 30 days of treatment period (p=0·057); skin breaks on the legs were reported in 44 (3%) patients allocated IPC and in 20 (1%) patients allocated no IPC (p=0·002); falls with injury were reported in 33 (2%) patients in the IPC group and in 24 (2%) patients in the no-IPC group (p=0·221). INTERPRETATION: IPC is an effective method of reducing the risk of DVT and possibly improving survival in a wide variety of patients who are immobile after stroke. FUNDING: National Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme, UK; Chief Scientist Office of Scottish Government; Covidien (MA, USA).

Differences in the association between childhood trauma and BMI in black and white South African women.

OBJECTIVE: Childhood trauma has previously been associated with adult obesity. The aim of this study was to determine if ethnicity altered the relationship between childhood trauma and obesity in South African women. METHODS: Forty-four normal-weight (BMI < 25kg/m(2)) and obese (BMI > 30kg/m(2)), black and white premenopausal women completed the Childhood Trauma Questionnaire (CTQ), which retrospectively assessed emotional and physical neglect, and emotional, physical and sexual abuse in childhood. RESULTS: Body composition did not differ by ethnicity in the normal-weight and obese groups. However,independent of BMI group, there were significant differences in socioeconomic status (SES) between black and white women (P < 0.01). Total CTQ score, as well as the sub-scales, physical and emotional neglect, and physical and sexual abuse were higher in black than white women (all P < 0.05), but these scores did not differ between BMI groups. Apart from the sexual abuse score, the differences in physical and emotional neglect and physical abuse scores were no longer significant after adjusting for ethnic differences in age and SES. For sexual abuse, there was a significant interaction between ethnicity and BMI group(P = 0.04), with scores in normal weight women being higher in black than white women, but scores in obese women not differing by ethnicity. CONCLUSION: Ethnicity alters the association between childhood sexual abuse and BMI status. Larger studies are required to verify this finding, including measures of body image and body size satisfaction that may explain these findings.

Bone geometry and strength are adapted to muscle force in children and adolescents perinatally infected with HIV.

OBJECTIVES: To determine if bone health is compromised in perinatally HIV-infected youth. METHODS: We assessed BMC at the proximal femur, lumbar spine and total body using DXA in perinatally HIV-infected youth (n=31; 9-18y). Using pQCT, we assessed muscle CSA, total and cortical bone area, cortical BMD and thickness and strength strain index at the tibial shaft. Thirty and 18 participants returned at 12- and 24-months, respectively. We calculated age- and sex-specific z-scores for the HIV-infected youth using data from a healthy cohort (n=883; 9-18y). RESULTS: At baseline, height and MCSA were reduced in HIV-infected youth (-0.79 to -0.23, p<0.05). BMC z-scores adjusted for height and lean mass were lower than controls at all sites except the lumbar spine (-0.57 to -0.27, p<0.05). Bone area and strength z-scores were not different from zero after adjusting for tibial length and MCSA. In contrast, cortical BMD z-scores were greater in HIV-infected youth (0.46, p=0.011). Z-scores for all bone outcomes showed positive trends over time in HIV-infected youth. CONCLUSION: Although HIV infection may be associated with bone mass deficits during growth, bone geometry and strength appear adapted to muscle force. Further, deficits in bone mass may dissipate over time in this population.

Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results.

BACKGROUND: Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. PATIENTS AND METHODS: Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. RESULTS: At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). CONCLUSIONS: Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

Systematic review of head cooling in adults after traumatic brain injury and stroke.

BACKGROUND: Brain injuries resulting from trauma and stroke are common and costly. Cooling therapy may reduce damage and potentially improve outcome. Head cooling targets the site of injury and may have fewer side effects than systemic cooling, but there has been no systematic review and the evidence base is unclear. OBJECTIVE: To assess the effect of non-invasive head cooling after traumatic brain injury (TBI) and stroke on intracranial and/or core body temperature, functional outcome and mortality, determine adverse effects and evaluate cost-effectiveness. REVIEW METHODS: Search strategy Major international databases [including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, the British Library's Electronic Table of Contents (Zetoc)], The Cochrane Library, trial registers, country-specific databases (including China, Japan), Google Scholar, hypothermia conference reports and reference lists of papers were searched with no publication or language restrictions. The searches were conducted from March 2010 to April 2011, with no back date restriction. Selection criteria For formal analysis of effect of head cooling on functional outcome and mortality: randomised controlled trials (RCTs) of non-invasive head cooling in TBI or stroke in adults (aged ≥ 18 years). RCT prespecified in protocol to include adequate randomisation and blinded outcome assessment. For assessment of effect on temperature and adverse effects of cooling methods/devices: studies of any type in TBI, stroke, cardiac arrest and neonatal hypoxic-ischaemic encephalopathy (adverse effects only). Data collection and analysis A study assessment and data collection form was developed and piloted. Data on functional outcome, mortality, temperature change and adverse effects of devices were sought and extracted. Two authors independently assessed RCTs for quality using the Cochrane Renal Group checklist. RESULTS: Out of 46 head-cooling studies in TBI and stroke, there were no RCTs of suitable quality for formal outcome analysis. Twelve studies had useable data on intracranial and core body temperature. These included 99 patients who were cooled after TBI or stroke and 198 patients cooled after cardiac arrest. The data were too heterogeneous for a single summary measure of effect (many studies had no measure of spread) and are therefore presented descriptively. The most effective techniques for which there were adequate data (nasal coolant and liquid cooling helmets) could reduce intracranial temperature by ≥ 1 °C in 1 hour. The main device-related adverse effects were localised skin problems, which were generally mild and self-limiting. There were no suitable data for economic modelling, but an exploratory model of possible treatment effects and cost-effectiveness of head cooling in TBI was created using local patient data. LIMITATIONS: We conducted extensive and sensitive searches but found no good-quality RCTs of the effect of head cooling on functional outcome that met the review inclusion criteria. Most trials were small and/or of low methodological quality. However, if the trial reports did not reflect the true quality of the research, there may be some excluded trials that should have been included. Temperature data were often poorly reported which made it difficult to assess the effect of head cooling on temperature. CONCLUSIONS: Whether head cooling improves functional outcome or has benefits and fewer side effects compared with systemic cooling or no cooling could not be established. Some methods of head cooling can reduce intracranial temperature, which is an important first step in determining effectiveness, but there is insufficient evidence to recommend its use outside of research trials. The principal recommendations for research are that active cooling devices show the most promise for further investigation and more robust proof of concept of intracranial and core body temperature reduction with head cooling is required, clearly showing whether temperature has changed and by how much. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Dehydrated amniotic membrane allografts for the treatment of chronic wounds: a case series.

A retrospective case series demonstrating the use of dehydrated human amniotic membrane (dHAM) allografts in the treatment of wounds of various aetiologies. Amniotic membrane was applied to a series of chronic wounds referred to a formal wound clinic for aggressive management, after prior, traditional treatment methods were found ineffective, over a period of 1 month. In each case, failure of traditional therapy was followed by placement of a dehydrated amniotic membrane allograft and the healing time course was documented with charted measurements. Wounds treated with the amniotic membrane allograft demonstrated improved healing, with a change in the healing trajectory from that previously noted. Dehydrated human amniotic membrane represents a potentially effective addition to existing wound care therapies, with further formal clinical studies indicated.

Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report.

BACKGROUND: Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years. RESULTS: Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. CONCLUSION: PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1-3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0-7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.