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Background: Procalcitonin (PCT) is a blood marker used to help diagnose bacterial infections and guide antibiotic treatment. PCT testing was widely used/adopted during the COVID-19 pandemic in the UK., Objectives: Primary: to measure the difference in length of early (during first 7 days) antibiotic prescribing between patients with COVID-19 who did/did not have baseline PCT testing during the first wave of the pandemic. Secondary: to measure differences in length of hospital/ICU stay, mortality, total days of antibiotic prescribing and resistant bacterial infections between these groups., Methods: Multi-centre, retrospective, observational, cohort study using patient-level clinical data from acute hospital Trusts/Health Boards in England/Wales. Inclusion: patients ≥16 years, admitted to participating Trusts/Health Boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020., Results: Data from 5960 patients were analysed: 1548 (26.0%) had a baseline PCT test and 4412 (74.0%) did not. Using propensity-score matching, baseline PCT testing was associated with an average reduction in early antibiotic prescribing of 0.43 days [95% confidence interval (CI): 0.22-0.64 days, P < 0.001) and of 0.72 days (95% CI: 0.06-1.38 days, P = 0.03] in total antibiotic prescribing. Baseline PCT testing was not associated with increased mortality or hospital/ICU length of stay or with the rate of antimicrobial-resistant secondary bacterial infections., Conclusions: Baseline PCT testing appears to have been an effective antimicrobial stewardship tool early in the pandemic: it reduced antibiotic prescribing without evidence of harm. Our study highlights the need for embedded, rapid evaluations of infection diagnostics in the National Health Service so that even in challenging circumstances, introduction into clinical practice is supported by evidence for clinical utility., Study Registration Number: ISRCTN66682918., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Community pharmacies in England offer convenient and safe disposal of unwanted medicines, including antimicrobials, and better uptake of this service could limit environmental antimicrobial resistance. However, there is limited information on the extent and nature of antibiotic returns to community pharmacies. The impact of an antibiotic amnesty campaign promoting antibiotic disposal through community pharmacies was evaluated with the intention of collecting detailed information on the antibiotics returned., Methods: An antibiotic amnesty campaign was delivered by community pharmacies in the Midlands (England) with an audit of returned antibiotics conducted in 19 community pharmacies in Leicestershire. Detailed information on antibiotics returned for disposal was gathered during the month-long amnesty campaign and again 3 months later in the same pharmacies., Results: Antibiotics accounted for 3.12%-3.35% of all returned medicines. The amnesty campaign led to a significant increase in defined daily doses of returned antibiotics compared to the post-amnesty period ( P  = 0.0165), but there was no difference in the overall number of returned medicines. Penicillins were the most commonly returned antibiotics in both periods (29.3% and 42.5% of packs, respectively), while solid oral dose formulations predominated. A total of 36.6% of antibiotics returned during the amnesty period were expired, increasing to 53.4% in the post-amnesty period. Amnesty conversations had a significant impact on the number of antibiotic returns but campaign posters did not., Conclusions: Antibiotic conversations can increase the amount of antibiotics returned to community pharmacies for safe disposal, and passive campaign materials had limited impact. More research is needed to identify the most effective interventions to increase returns., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Sudden death syndrome (SDS), caused by Fusarium virguliforme , is an important yield-limiting disease of soybean ( Glycine max ). From 1996 to 2022, cumulative yield losses attributed to SDS in North America totaled over 25 million metric tons, which was valued at over US $7.8 billion. Seed treatments are widely used to manage SDS by reducing early season soybean root infection by F. virguliforme . Fluopyram (succinate dehydrogenase inhibitor [SDHI] - FRAC 7), a fungicide seed treatment for SDS management, has been registered for use on soybean in the United States since 2014. A baseline sensitivity study conducted in 2014 evaluated 130 F. virguliforme isolates collected from five states to fluopyram in a mycelial growth inhibition assay and reported a mean EC 50 of 3.35 mg/liter. This baseline study provided the foundation for the objectives of this research: to detect any statistically significant change in fluopyram sensitivity over time and geographical regions within the United States and to investigate sensitivity to the fungicide pydiflumetofen. We repeated fluopyram sensitivity testing on a panel of 80 historical F. virguliforme isolates collected from 2006 to 2013 (76 of which were used in the baseline study) and conducted testing on 123 contemporary isolates collected from 2016 to 2022 from 11 states. This study estimated a mean absolute EC 50 of 3.95 mg/liter in isolates collected from 2006 to 2013 and a mean absolute EC 50 of 4.19 mg/liter in those collected in 2016 to 2022. There was no significant change in fluopyram sensitivity ( P = 0.1) identified between the historical and contemporary isolates. A subset of 23 isolates, tested against pydiflumetofen under the same conditions, estimated an absolute mean EC 50 of 0.11 mg/liter. Moderate correlation was detected between fluopyram and pydiflumetofen sensitivity estimates ( R = 0.53; P < 0.001). These findings enable future fluopyram and pydiflumetofen resistance monitoring and inform current soybean SDS management strategies in a regional and national context., Competing Interests: The author(s) declare no conflict of interest.

In the UK nearly 54,000 infections were caused by serious resistant bacteria in 2022 but there is a lack of evidence regarding the long-term impact on patients' lives nor what support they need. This research aimed to answer the question: "What are the key elements of experience and support needs of people living with AMR in the UK?". In-depth semi-structured interviews were undertaken with nine people who had been living with resistant infections or colonisation for 12-months or longer. Interpretive Phenomenological Analysis was used to study the accounts and illustrate individuals' experiences and support-needs. Participants experienced marginalisation and isolation but also empowerment; described across three major themes: (1) I live in fear and stigma: The long-term impact of AMR; (2) I am battling on my own: A journey toward self-advocacy; and (3) I like to share my story: The role of AMR communities. All participants perceived a lack of knowledge, information, and support from clinicians; difficulties accessing reliable and understandable information; and lack of understanding from family and friends. Charities and online groups provided support with coping with their situation and improving mental health and wellbeing. Understandable and relatable information regarding the science of AMR, transmission, prevention, and living with AMR needs to be provided by clinicians and healthcare services around the time of diagnosis to readily available after diagnosis., (© 2024. The Author(s).)

Objective: To explore and model factors affecting antibiotic prescribing decision-making early in the pandemic., Design: Semistructured qualitative interview study., Setting: National Health Service (NHS) trusts/health boards in England and Wales., Participants: Clinicians from NHS trusts/health boards in England and Wales., Method: Individual semistructured interviews were conducted with clinicians in six NHS trusts/health boards in England and Wales as part of the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients study, a wider study that included statistical analysis of procalcitonin (PCT) use in hospitals during the first wave of the pandemic. Thematic analysis was used to identify key factors influencing antibiotic prescribing decisions for patients with COVID-19 pneumonia during the first wave of the pandemic (March to May 2020), including how much influence PCT test results had on these decisions., Results: During the first wave of the pandemic, recommendations to prescribe antibiotics for patients with COVID-19 pneumonia were based on concerns about secondary bacterial infections. However, as clinicians gained more experience with COVID-19, they reported increasing confidence in their ability to distinguish between symptoms and signs caused by SARS-CoV-2 viral infection alone, and secondary bacterial infections. Antibiotic prescribing decisions were influenced by factors such as clinician experience, confidence, senior support, situational factors and organisational influences. A decision-making model was developed., Conclusion: This study provides insight into the decision-making process around antibiotic prescribing for patients with COVID-19 pneumonia during the first wave of the pandemic. The importance of clinician experience and of senior review of decisions as factors in optimising antibiotic stewardship is highlighted. In addition, situational and organisational factors were identified that could be optimised. The model presented in the study can be used as a tool to aid understanding of the complexity of the decision-making process around antibiotic prescribing and planning antimicrobial stewardship support in the context of a pandemic., Trial Registration Number: ISRCTN66682918., Competing Interests: Competing interests: All authors (with the exception of RH) and members of the PEACH consortium received funding from NIHR COVID Learning and Recovery Call programme (NIHR132254) for the PEACH Study and for the delivery of this manuscript. ET-J, JE, LB-H, PP and WM (main authors) and ST (consortium) all received funding from NIHR-HTA programme for delivery of the PRONTO trial (NIHR17/136/13). EC, ET-J, PP and LB-H received funding from NIHR for the BATCH trial (15/188/42). EC, ET-J and PP received funding from MRC-NIHR EME for contribution to the PRECISE study (NIHR129960). PH received funding from Abbot Laboratories for attending the European Network for Antimicrobial Stewardship in Point of Care. PH has also previously held post as Vice Chancellor for British Society for Antimicrobial Chemotherapy (BSAC) and is currently a committee member., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Formaldehyde has been classified as carcinogenic to humans by International Agency for Research on Cancer and found in personal care (PC) products containing formaldehyde-donor (FD) preservatives. However, the cancer risk associated with the use of FD-containing PC products has not been well established. Our study provides the quantitative cancer risk assessment of formaldehyde in FD-containing PC products. The carbon-13 nuclear magnetic resonance ( 13 C-NMR) spectroscopy was used in this risk assessment to provide reliable exposure information to formaldehyde in PC products and aqueous solutions containing sodium hydroxymethylglycinate. The risk assessment was conducted using the margin of exposure (MOE) approach with benchmark doses (BMDs) for 10% effect. For hemolymphoreticular neoplasias in male rats, a BMD of 28.03 mg/kg/day and a BMD lower confidence limit (BMDL) of 2.52 mg/kg/day were calculated from available long-term animal experiments. The worst-case consumer exposure to formaldehyde from FD-containing PC products was 0.007 μg/kg/day. Comparing the consumer exposure with BMDL, the resulting MOE was 360,000 for the worst-case scenario. The consumer exposure to formaldehyde (0.007 μg/kg/day) from using FD-containing PC products represents less than 1.0 × 10 -6 % of background level endogenous formaldehyde (878-1310 mg/kg/day). The cancer risk from formaldehyde to consumers using FD-containing PC products is negligible., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pharmacists play a key role in antimicrobial stewardship (AMS). Consensus-based national AMS competencies for undergraduate healthcare professionals in the UK reflect the increasing emphasis on competency-based healthcare professional education. However, the extent to which these are included within undergraduate pharmacy education programmes in the UK is unknown., Objectives: To explore which of the AMS competencies are delivered, including when and at which level, within UK undergraduate MPharm programmes., Methods: A cross-sectional online questionnaire captured the level of study of the MPharm programme in which each competency was taught, the method of delivery and assessment of AMS education, and examples of student feedback., Results: Ten institutions completed the survey (33% response rate). No institution reported covering all 54 AMS competencies and 5 of these were taught at half or fewer of the institutions. Key gaps were identified around taking samples, communication, outpatient parenteral antimicrobial therapy and surgical prophylaxis. The minimum time dedicated to AMS teaching differed between institutions (range 9-119 h), teaching was generally through didactic methods, and assessment was generally through knowledge recall and objective structured clinical examinations. Feedback from students suggests they find AMS and antimicrobial resistance (AMR) to be complex yet important topics., Conclusions: UK schools of pharmacy should utilize the competency framework to identify gaps in their AMS, AMR and infection teaching. To prepare newly qualified pharmacists to be effective at delivering AMS and prescribing antimicrobials, schools of pharmacy should utilize more simulated environments and clinical placements for education and assessment of AMS., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment., Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity., Methods: The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool., Results: Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m 2 . Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified., Conclusion: All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written., Trial Registration Number: PROSPERO (CRD42021250022)., Competing Interests: Competing interests: KJF, AJ, CJ, PR and OT have no declarations of interest to declare. RAH has received educational grants from Pfizer (2021) and attended advisory board for A.Menarini (2022). SH has consulted for Pfizer (2020-21), Eumedica (2020), Kent Pharma (2021), Shionogi (2021), BowMed (2021) and Gilead (2021)., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aloe has a long history of topical and systemic use with testimonials of countless health benefits and is one of the most popular botanical medicines in the world for the management of a wide variety both of benign and serious ailments including irritable bowel syndromes, osteoarthritis, Type II diabetes mellitus, and viral respiratory illness. The human consumption of Aloe vera extract in beverage form has substantially grown over the last several decades, in no small part, due to the increased consumer interest in alternative approaches to health benefits. The principal aim of the present paper is to characterize the research to date that has explored the genotoxic potential of Aloe vera inner leaf gel extract and decolorized whole leaf extract used in commercially available food-grade drinkable products which contain no more than 10 ppm aloin. Despite prevailing public health opinion, especially in Europe, the consensus of the reviewed studies retrieved from the peer-reviewed literature together with a mutagenic evaluation of an Aloe vera whole leaf decolorized spray-dried powder is that these products are not genotoxic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Pharmacy staff working in hospitals are at risk of contracting and disseminating influenza. Previous research focuses on community pharmacists' attitudes towards influenza and vaccination. This survey investigates the beliefs and attitudes of pharmacists and other pharmacy staff working in English Hospitals regarding influenza and the vaccine and how this relates to vaccine uptake., Methods: A self-administered survey was provided to pharmacy staff at three hospitals in the East Midlands of England. Job role, age and vaccination status (vaccinated, intended to be vaccinated, and not vaccinated) were collected alongside ratings of agreement with 20 statements regarding influenza and vaccination using a Likert scale., Results: 170 pharmacy staff responded; 50.6% had been vaccinated, 17.1% intended to be vaccinated and 32.4% were not vaccinated. Increasing age showed a significant (p = 0.017) positive correlation with increased vaccine uptake as did the beliefs that vaccination protects the individual from influenza (p = 0.049) and that vaccination should be mandatory for NHS staff (p = 0.006). Fear of needles and believing their immune system is strong enough to protect against influenza were negatively correlated with vaccine uptake (p = 0.016 and p = 0.010, respectively). Job role was also strongly correlated with vaccine uptake (p = 0.001), with those holding a pharmacy degree more likely to report being vaccinated or intending to be vaccinated compared to all other pharmacy staff groups., Conclusions: This is the first survey to focus on vaccine behaviours of all pharmacy staff groups working in hospitals. Current uptake of the influenza vaccine may be increased through engagement of senior pharmacy colleagues and providing education on influenza, vaccines, and vaccination. Similar studies should be undertaken on a larger scale to fully interrogate the differences between pharmacy staff groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The emergence of carbapenemase-producing Enterobacterales (CPE) as a major cause of invasive infection both within the UK and internationally poses a very real concern for all providers of healthcare. The burden of morbidity and mortality associated with CPE infections is well described. The need for early, targeted, effective and safe antimicrobial therapy remains key for the management of these infected patients yet reliable antimicrobial treatment options remain scarce. In the absence of a universal treatment for these CPE invasive infections, individual treatment options tailored to susceptibilities and severity of infection are required. This working group from within the UK Clinical Pharmacy Association (UKCPA) Pharmacy Infection Network has developed evidence-based treatment recommendations to support infection specialists in managing these complex infections. A systematic review of peer-reviewed research was performed and analysed. We report consensus recommendations for the management of CPE-associated infections. The national expert panel makes therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, dosing, dosage adjustment and monitoring of parameters for novel and established antimicrobial therapies with CPE activity. This manuscript provides the infection specialist with pragmatic and evidence-based options for the management of CPE infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Purpose: To generate insights into the personal meaning and value of a running/walking program for women after a diagnosis of breast cancer., Methods: After completing a 12-week running/walking program with a 5-km training goal, eight women were interviewed and seven participated in a focus group. The interviews and focus group were audio-recorded and transcribed verbatim. Data were thematically analyzed., Results: Data portrayed the personal benefits and value of the clinic. Four themes were identified: (1) receiving practical information and addressing targeted concerns, (2) pushing personal limits, (3) enabling a committed mindset, and (4) seeing benefits and challenges of running/walking with a group., Conclusions: Findings provide initial understanding of how women experience a running/walking program after a diagnosis of breast cancer and what they find to be important about their experiences. The range of positive benefits experienced by women suggests a running/walking program can help fill a gap in care for women diagnosed with breast cancer, and thus be part of cancer rehabilitation. However, because some women felt isolated at times, future research should seek to examine how running/walking programs can be modified and tailored so that all women find it socially beneficial. Implications for Rehabilitation The diagnosis and treatment of breast cancer can result in side effects and increase the risk of long-term disability. Physical activity can help women manage the side effects and lessen the risk of long-term disability. In a relatively small sample, this study shows that participation in a running/walking program can be an important part of breast cancer recovery.

Microaerobic (oxygen limited) conditions are advantageous for several industrial applications since a majority of the carbon atoms can be directed for synthesis of desired products. Oxygen limited conditions, however, can result in high levels of undesirable by-products such as acetate, which subsequently can have an impact on biomass and product yields. The molecular mechanisms involved in acetate accumulation under oxygen limited conditions are not well understood. Our results indicate that a majority of the genetic modifications known to decrease acetate under aerobic conditions results in similar or even higher acetate under oxygen limitation. Deletion of arcA, whose gene product is a global transcriptional regulator, was the only modification among those evaluated that significantly decreased acetate under both transient and prolonged oxygen limitation. Transcriptome results indicate that the arcA deletion results in an increased expression of the operon involving acs and actP (whose gene products are involved in acetate assimilation and uptake respectively) and some genes in the TCA cycle, thereby promoting increased acetate assimilation. These results provide useful cues for strain design for improved manufacturing of biopharmaceuticals under oxygen limited conditions. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:303-314, 2018., (© 2017 American Institute of Chemical Engineers.)

Cancer incidence and/or mortality among individuals varies with diet, socio-culture, ethnicity, race, gender, and age. Similarly, environmental temperature modulates many biological functions. To study the effect of environment temperature on cancer incidence, the US population was selected. Because, county-wise cancer incidence rate data of various anatomical site-specific cancers and different races/ethnicities for both males and females are available. Moreover, the differences amongst the aforementioned factors among individuals are much less, as compared to the world population. Statistical analysis showed a negative correlation between the average annual temperature and cancer incidence rate at all anatomical sites and individually for 13 types (out of 16 types) of anatomical site-specific cancer incidence rates (e.g. uterine, bladder, thyroid, breast, esophagus, ovary, melanoma, non-Hodgkin lymphoma, leukemia, brain, pancreas, etc.) for females. Further analysis found a similar inverse trend in all races/ethnicities of the female population but not in all male races/ethnicities or anatomical site-specific cancers. Moreover, the majority of the counties having the top-most cancer incidence rate in females are located above the latitude 36.5°N. These findings indicate that living in a cold county in the United States might have a higher risk of cancer irrespective of cancer type (except cervical and liver) and races/ethnicities for females but not in all such cases for the male population.

Background: First Nations people with cancer in Canada confront several critical inequities in physical and psychosocial domains. First Nations women are at a particular disadvantage as they are disproportionately affected by social determinants of health, but how they navigate these challenges within their communities is poorly understood., Objective: Our study explores survivorship experiences of First Nations women with cancer and their caregivers. Drawing from a larger data set on survivorship, we identify several major barriers to cancer communication and support in First Nations communities., Methods: Our team conducted a participatory, arts-based study using several data collection methods (interviews, sharing sessions, photovoice, and other creative activities) with 43 participants (24 cancer survivors and 19 caregivers) from four First Nations communities in Canada., Results: Two major themes have emerged out of our data analyses: (1) suffering without support leads to cycles of silence and (2) community-based supports can disrupt these cycles. We identified several social, historical, and institutional barriers to speaking about cancer and finding/providing support; however, communities met the challenge of silence through voluntary and unsolicited provision of support., Conclusions: Widespread silence around cancer reflects both the limited access First Nations people have to formal, supportive programs and services, as well as the creative ways they provide emotional, social, and financial support within their informal networks. Beyond the support of their communities, they also required institutional provision of care that is culturally safe, addressing the colonial impacts on cancer communication and the disproportionate burdens of disease in First Nations communities., (Copyright © 2016 John Wiley & Sons, Ltd.)

Purpose: This study reports on the effect of a group-based nutrition and physical activity intervention program on nutrition knowledge and eating habits in a cohort of people with obesity., Methods: A quasi-experimental design with pre- and post-test measures. The intervention consisted of physical activity led by certified exercise physiologists and a nutritional education component led by registered dietitians over a 6-month period followed by 6 months of self-management. Participants' nutrition knowledge and eating habits were assessed using the modified Nutrition Assessment, the Nutrition Knowledge Survey, and the Food Choice Questionnaires at baseline, after the 6-month intervention, and after 6 months of self-management., Results: Complete data were available for 59 (40%) of participants after 12 months because of attrition. Nutritional knowledge and behaviours improved. Participants reported increasing their consumption of healthy foods during the active intervention and maintained these changes through the self-management phase. Knowledge of healthy foods was improved and a greater likelihood of choosing food for weight control and health properties was reported., Conclusions: Knowledge and reported consumption of healthier nutrition improved during the active intervention and was maintained during the self-management period for individuals who completed the program. Registered dietitians can play an important role in managing patients with obesity in group settings.

Aging is associated with a decline in peripheral nerve function of both motor and sensory nerves. The decline in function of peripheral sensorimotor nerves with aging has been linked to sarcopenia, the age-related decline in muscle mass and function that significantly compromises the quality of life in older humans. In this study, we report a significant increase in oxidized fatty acids and insoluble protein carbonyls in sciatic nerves of aged C57BL/6 male mice (28-30mo) that exhibit a profound decline in motor nerve function and degenerative changes in both axon and myelin structure, compared to young mice (6-8mo). Our data further suggests that this age-related loss of function of peripheral motor nerves is likely precipitated by changes in mechanisms that protect and/or repair oxidative damage. We predict that interventions that target these mechanisms may protect against age-related decline in peripheral sensorimotor nerve function and likely improve the debilitating outcome of sarcopenia in older humans., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Secondary lymphedema after cancer may result in distress, yet few interventions exist to support coping skills in this population. As part of a community-based intervention, we piloted the use of creative practices to promote active orientations to hope. A total of 19 participants completed the workshops; 11 collaged. The main themes address the collage processes as well as their content. The former addresses sub-themes such as selecting/composing. The latter includes sub-themes related to movement depicted in the collages. Collages and their associated discussions concretized hoping as an active and accessible process for participants living with two chronic illnesses., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2016.)

Obesity is one of the most prevalent health problems facing the United States today, with a recent JAMA article published in 2014 estimating the prevalence of one third of all adults in the United States being obese. Also, due to technological advancements, the incidence of spine surgeries is growing. Considering these overall increases in both obesity and the performance of spinal surgeries, it can be inferred that more spinal surgery candidates will be obese. Due to this, certain factors must be taken into consideration when dealing with spine surgeries in the obese. Obesity is closely correlated with additional medical comorbidities, including hypertension, coronary artery disease, congestive heart failure, and diabetes mellitus. The pre-operative evaluation may be more difficult, as a more extensive medical evaluation may be needed. Also, adequate radiographic images can be difficult to obtain due to patient size and equipment limitations. Administering anesthesia becomes more difficult, as does proper patient positioning. Post-operatively, the obese patient is at greater risk for reintubation, difficulty with pain control, wound infection and deep vein thrombosis. However, despite these concerns, appropriate clinical outcomes can still be achieved in the obese spine surgical candidate. Obesity, therefore, is not a contraindication to spine surgery, and appropriate patient selection remains the key to obtaining favorable clinical outcomes.

Study Design: An anatomic and radiographic study of placement of sacroiliac screws., Objective: The aim of this study was to quantitatively assess the risk of partial cut-out of sacroiliac screws from the sacral ala slope via inlet and outlet view., Summary of Background Data: The partial cut-out of sacroiliac screws from the superior surface of sacral ala can jeopardize the L5 nerve root, which is difficult to identify on the pelvic inlet and outlet views., Methods: Computed tomography images of 60 patients without pelvic ring deformity or injury were used to measure the width (on inlet view) and height (on outlet view) of the sacral ala. The angle of the sacral ala slope was measured on lateral view. According to the measured parameters, the theoretical safe trajectories of screw placement were calculated using inverse trigonometric functions. Under fluoroscopic guidance, a sacroiliac screw was placed close to the midline on both inlet and outlet views, including posterosuperior, posteroinferior, anterosuperior, and anteroinferior regions to the midline. The incidence of screw partial cut-out from the superior surface of sacral ala was identified., Results: The measured widths and heights of the sacral alas were 28.1 ± 2.8 and 29.8 ± 3.1 mm, respectively. The average angle between the superior aspect of the S1 vertebral body and the superior aspect of the sacral ala was 37.2 ± 2.5 degrees. The rate of partial cut-out of the screws from the superior surface of sacral ala slope was 12.5% (5/40) in posterosuperior, 0% (0/40) in posteroinferior, 70% (28/40) in anterosuperior, and 20% (8/40) in anteroinferior., Conclusion: To avoid the risk of partial cut-out from sacroiliac screw placement, more precise description should be added to the conventional description: the sacroiliac screws should be placed at the inferior half portion on outlet view and at the posterior half portion on inlet view., Level of Evidence: 4.

The mammalian target of rapamycin (mTOR) plays an important role in cardiac development and function. Inhibition of mTOR by rapamycin has been shown to attenuate pathological cardiac hypertrophy and improve the function of aging heart, accompanied by an inhibition of the cardiac proteasome activity. The current study aimed to determine the potential mechanism(s) by which mTOR inhibition modulates cardiac proteasome. Inhibition of mTOR by rapamycin was found to reduce primarily the immunoproteasome in both H9c2 cells in vitro and mouse heart in vivo, without significant effect on the constitutive proteasome and protein ubiquitination. Concurrent with the reduction of the immunoproteasome, rapamycin reduced two important inflammatory response pathways, the NF-κB and Stat3 signaling. In addition, rapamycin attenuated the induction of the immunoproteasome in H9c2 cells by inflammatory cytokines, including INFγ and TNFα, by suppressing NF-κB signaling. These data indicate that rapamycin indirectly modulated immunoproteasome through the suppression of inflammatory response pathways. Lastly, the role of the immunoproteasome during the development of cardiac hypertrophy was investigated. Administration of a specific inhibitor of the immunoproteasome ONX 0914 attenuated isoproterenol-induced cardiac hypertrophy, suggesting that the immunoproteasome may be involved in the development of cardiac hypertrophy and therefore could be a therapeutic target. In conclusion, rapamycin inhibits the immunoproteasome through its effect on the inflammatory signaling pathways and the immunoproteasome could be a potential therapeutic target for pathological cardiac hypertrophy., (Copyright © 2015. Published by Elsevier Ltd.)

Objective: To test the effectiveness of a non-pharmaceutical programme for obese participants in a rural Eastern Canadian Province using certified health professionals., Design: A prospective quasi-experimental design with repeated premeasure and postmeasure., Participants: 146 participants with obesity (body mass index >30 kg/m(2)) from rural and urban communities in an Eastern Canadian Province were divided into four groups., Intervention: A 6-month intensive active community-based lifestyle intervention (InI) delivered by Certified Exercise Physiologists, Certified Personal Trainers and Registered Dietitians, followed by 6 months of self-management. A second intervention (InII) was nested in InI and consisted of group-mediated cognitive-behavioral intervention (GMCBI) delivered by an exercise psychologist to two of the four InI groups., Outcomes: (1) Improving health outcomes among the participants' preactive and postactive 6-month intervention and self-management period, (2) Documenting the impact of InII (GMCBI) and location of the intervention (urban vs rural)., Results: The 6-month active InI significantly improved cardiovascular health for participants who completed the intervention. InII (GMCBI) significantly lowered the attrition rate among the participants. The self-management period was challenging for the participants and they did not make further gains; however, most were able to maintain the gains achieved during the active intervention. The location of the intervention, urban or rural, had little impact on outcomes., Conclusions: A community-based programme utilising healthcare professionals other than physicians to treat obese patients was effective based on premeasure and postmeasure. During the self-management phase, the participants were able to maintain the gains. Psychological support is essential to participant retention., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

miRNAs (miRs), or small approximately 22-nucleotide-long single-stranded noncoding RNA molecules, interact with 3' untranslated regions of target mRNAs, leading to inhibition of protein production. miR-214 is often dysregulated in various cancers, which governs both tumorigenic and tumor suppressive functions. This review focuses on the current knowledge of miR-214 switching in diverse forms of cancer either by its upregulation or downregulation and sheds light on the mechanism of its tumorigenic and suppressive roles. This article describes known targets and signaling pathways that impact tumorigenesis and tumor suppression and summarizes all information available on circulating levels of miR-214 to address whether miR-214 may function as a potential biomarker and therapy for cancer patients in the future.

Protein oxidation and misfolding have been considered as key players for progression of aging and etiology of various pathological conditions. However, few attempts have been made to develop sensitive and reproducible assays to quantify the changes in protein oxidation and alteration in structure. Here we describe three distinct fluorescence-based assays to quantify changes in protein oxidation, namely carbonylation and disulfides and alteration in protein surface hydrophobicity as a reporter for protein conformation. These techniques will provide investigators the opportunity to address important biological questions in their experimental models.

Life with a disability is often riddled with paradoxes, one of which is being visibly marked, while personal experiences, losses, and challenges remain hidden. Our article draws attention to this paradox among people who live with secondary lymphedema after cancer (SLC). SLC is a relatively unfamiliar chronic condition within medical and lay discourses of cancer, which proves challenging for the many cancer survivors who are in search of information and understanding. Thirteen men and women with SLC were recruited from two research sites (Fredericton, NB, and Ottawa, ON, Canada) to participate in semi-structured interviews about the physical and psychosocial aspects of SLC. Using a methodology of interpretive description, our analysis of participant interviews reveals the complex ways in which men and women felt both visible and invisible within various contexts. We discuss three majors themes: (in)visibility and appearance related to material losses; (in)visibility and action connected to visible losses in function, as well as invisible struggles to care for oneself; and the loss of present and future well-being, as SLC renders some limitations visible while potentially obscuring a hopeful future indefinitely. Our research indicates that timely diagnosis of SLC would be an immediate first step in recognizing the physical and emotional dimensions of the condition. To accomplish this, increased awareness is needed. To enhance quality of life for those living with SLC, the development of new resources and psychosocial supports is also required.

Our recent study in a mouse model of familial-Amyotrophic Lateral Sclerosis (f-ALS) revealed that muscle proteins are equally sensitive to misfolding as spinal cord proteins despite the presence of low mutant CuZn-superoxide dismutase, which is considered to be the key toxic element for initiation and progression of f-ALS. More importantly, we observed differential level of heat shock proteins (Hsp's) between skeletal muscle and spinal cord tissues prior to the onset and during disease progression; spinal cord maintains significantly higher level of Hsp's compared to skeletal muscle. In this study, we report two important observations; (i) muscle cells (but not neuronal cells) are extremely vulnerable to protein misfolding and cell death during challenge with oxidative stress and (ii) muscle cells fail to mount Hsp's during challenge unlike neuronal cells. These two findings can possibly explain why muscle atrophy precedes the death of motor neurons in f-ALS mice., (Copyright © 2014. Published by Elsevier Inc.)

Skeletal muscle atrophy is a debilitating outcome of a number of chronic diseases and conditions associated with loss of muscle innervation by motor neurons, such as aging and neurodegenerative diseases. We previously reported that denervation-induced loss of muscle mass is associated with activation of cytosolic phospholipase A2 (cPLA2), the rate-limiting step for the release of arachidonic acid from membrane phospholipids, which then acts as a substrate for metabolic pathways that generate bioactive lipid mediators. In this study, we asked whether 5- and 12/15-lipoxygenase (LO) lipid metabolic pathways downstream of cPLA2 mediate denervation-induced muscle atrophy in mice. Both 5- and 12/15-LO were activated in response to surgical denervation; however, 12/15-LO activity was increased ~2.5-fold versus an ~1.5-fold increase in activity of 5-LO. Genetic and pharmacological inhibition of 12/15-LO (but not 5-LO) significantly protected against denervation-induced muscle atrophy, suggesting a selective role for the 12/15-LO pathway in neurogenic muscle atrophy. The activation of the 12/15-LO pathway (but not 5-LO) during muscle atrophy increased NADPH oxidase activity, protein ubiquitination, and ubiquitin-proteasome-mediated proteolytic degradation. In conclusion, this study reveals a novel pathway for neurogenic muscle atrophy and suggests that 12/15-LO may be a potential therapeutic target in diseases associated with loss of innervation and muscle atrophy., (© 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Protein misfolding is considered to be a potential contributing factor for motor neuron and muscle loss in diseases like Amyotrophic lateral sclerosis (ALS). Several independent studies have demonstrated using over-expressed mutated Cu/Zn-superoxide dismutase (mSOD1) transgenic mouse models which mimic familial ALS (f-ALS), that both muscle and motor neurons undergo degeneration during disease progression. However, it is unknown whether protein conformation of skeletal muscle and spinal cord is equally or differentially affected by mSOD1-induced toxicity. It is also unclear whether heat shock proteins (Hsp's) differentially modulate skeletal muscle and spinal cord protein structure during ALS disease progression. We report three intriguing observations utilizing the f-ALS mouse model and cell-free in vitro system; (i) muscle proteins are equally sensitive to misfolding as spinal cord proteins despite the presence of low level of soluble and absence of insoluble G93A protein aggregate, unlike in spinal cord, (ii) Hsp's levels are lower in muscle compared to spinal cord at any stage of the disease, and (iii) G93ASOD1 enzyme-induced toxicity selectively affects muscle protein conformation over spinal cord proteins. Together, these findings strongly suggest that differential chaperone levels between skeletal muscle and spinal cord may be a critical determinant for G93A-induced protein misfolding in ALS., (Published by Elsevier Inc.)

Diabetic peripheral polyneuropathy is associated with decrements in motor/sensory neuron myelination, nerve conduction and muscle function; however, the mechanisms of reduced myelination in diabetes are poorly understood. Chronic elevation of oxidative stress may be one of the potential determinants for demyelination as lipids and proteins are important structural constituents of myelin and highly susceptible to oxidation. The goal of the current study was to determine whether there is a link between protein oxidation/misfolding and demyelination. We chose two distinct models to test our hypothesis: 1) the leptin receptor deficient mouse (dbdb) model of diabetic polyneuropathy and 2) superoxide dismutase 1 knockout (Sod1(-/-) ) mouse model of in vivo oxidative stress. Both experimental models displayed a significant decrement in nerve conduction, increase in tail distal motor latency as well as reduced myelin thickness and fiber/axon diameter. Further biochemical studies demonstrated that oxidative stress is likely to be a potential key player in the demyelination process as both models exhibited significant elevation in protein carbonylation and alterations in protein conformation. Since peripheral myelin protein 22 (PMP22) is a key component of myelin sheath and has been found mutated and aggregated in several peripheral neuropathies, we predicted that an increase in carbonylation and aggregation of PMP22 may be associated with demyelination in dbdb mice. Indeed, PMP22 was found to be carbonylated and aggregated in sciatic nerves of dbdb mice. Sequence-driven hydropathy plot analysis and in vitro oxidation-induced aggregation of purified PMP22 protein supported the premise for oxidation-dependent aggregation of PMP22 in dbdb mice. Collectively, these data strongly suggest for the first time that oxidation-mediated protein misfolding and aggregation of key myelin proteins may be linked to demyelination and reduced nerve conduction in peripheral neuropathies.

Excess nutrient uptake leads to obesity, insulin resistance, and type 2 diabetes. Mammalian target of the rapamycin (mTOR), a major component of the nutrient-sensing pathway also regulates mitochondrial oxidative function. Rapamycin, a pharmacological inhibitor of mTOR, causes glucose intolerance and inhibits mitochondrial oxidative function. While a number of studies have focused on the effect of rapamycin on control wild-type mice, ours is the first to study the effect of rapamycin on mitochondrial gene expression and insulin sensitivity in the db/db mouse, a model of diabetic dyslipidemia. Female db/+ and db/db mice were fed ad libitum a rapamycin-containing diet or a control diet for 6 months, starting at two months of age. Body weight, fat mass, lean mass and food intake were measured monthly. Effect of rapamycin or control diet on markers of adipogenesis, fatty acid oxidation and mitochondrial biogenesis in the gonadal white adipose tissue (WAT) as well as different serum parameters were assessed. Whole body insulin sensitivity was measured by insulin tolerance test. Rapamycin feeding to db/db mice decreased body weight (58%) and fat mass (33%), elevated markers of fatty acid oxidation and mitochondrial biogenesis in WAT, reduced circulating non-esterified free fatty acids (NEFA), elevated circulating adiponectin and improved insulin sensitivity, compared to control diet fed db/db mice. These data demonstrate that rapamycin exhibits an anti-obesity effect and improves whole body insulin sensitivity in db/db mice and suggest an unexpected effect of simultaneous inhibition mTOR and leptin signaling in mice.

The 'oxidative stress theory of aging' predicts that aging is primarily regulated by progressive accumulation of oxidized macromolecules that cause deleterious effects to cellular homeostasis and induces a decline in physiological function. However, our reports on the detection of higher level of oxidized protein carbonyls in the soluble cellular fractions of long-living rodent naked-mole rats (NMRs, lifespan ~30yrs) compared to short-lived mice (lifespan ~3.5yrs) apparently contradicts a key tenet of the oxidative theory. As oxidation often inactivates enzyme function and induces higher-order soluble oligomers, we performed a comprehensive study to measure global protein carbonyl level in different tissues of age-matched NMRs and mice to determine if the traditional concept of oxidation mediated impairment of function and induction of higher-order structures of proteins are upheld in the NMRs. We made three intriguing observations with NMRs proteins: (1) protein carbonyl is significantly elevated across different tissues despite of its exceptional longevity, (2) enzyme function is restored despite of experiencing higher level of protein carbonylation, and (3) enzymes show lesser sensitivity to form higher-order non-reducible oligomers compared to short-living mouse proteins in response to oxidative stress. These observations were made based on the global analysis of protein carbonyl and identification of two heavily carbonylated proteins in the kidney, triosephosphate isomerase (TPI) and cytosolic peroxiredoxin (Prdx1). These un-expected intriguing observations thus strongly suggest that oxidative modification may not be the only criteria for impairment of protein and enzyme function; cellular environment is likely be the critical determining factor in this process and may be the underlying mechanism for exceptional longevity of NMR., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We present a software platform developed by Genentech and MathWorks Consulting Group that allows arbitrary MATLAB (MATLAB is a registered trademark of The MathWorks, Inc.) functions to perform supervisory control of process equipment (in this case, fermentors) via the OLE for process control (OPC) communication protocol, under the direction of an industrial automation layer. The software features automated synchronization and deployment of server control code and has been proven to be tolerant of OPC communication interruptions. Since deployment in the spring of 2010, this software has successfully performed supervisory control of more than 700 microbial fermentations in the Genentech pilot plant and has enabled significant reductions in the time required to develop and implement novel control strategies (months reduced to days). The software is available for download at the MathWorks File Exchange Web site at http://www.mathworks.com/matlabcentral/fileexchange/36866.

Comparing biological processes in closely related species with divergent life spans is a powerful approach to study mechanisms of aging. The oxidative stress hypothesis of aging predicts that longer-lived species would have lower reactive oxygen species (ROS) generation and/or an increased antioxidant capacity, resulting in reduced oxidative damage with age than in shorter-lived species. In this study, we measured ROS generation in the young adult animals of the long-lived white-footed mouse, Peromyscus leucopus (maximal life span potential, MLSP = 8 yr) and the common laboratory mouse, Mus musculus (C57BL/6J strain; MLSP = 3.5 yr). Consistent with the hypothesis, our results show that skeletal muscle mitochondria from adult P. leucopus produce less ROS (superoxide and hydrogen peroxide) compared with M. musculus. Additionally, P. leucopus has an increase in the activity of antioxidant enzymes superoxide dismutase 1, catalase, and glutathione peroxidase 1 at young age. P. leucopus compared with M. musculus display low levels of lipid peroxidation (isoprostanes) throughout life; however, P. leucopus although having elevated protein carbonyls at a young age, the accrual of protein oxidation with age is minimal in contrast to the linear increase in M. musculus. Altogether, the results from young animals are in agreement with the predictions of the oxidative stress hypothesis of aging with the exception of protein carbonyls. Nonetheless, the age-dependent increase in protein carbonyls is more pronounced in short-lived M. musculus, which supports enhanced protein homeostasis in long-lived P. leucopus.

The Lunar CRater Observation and Sensing Satellite (LCROSS) mission was designed to search for evidence of water in a permanently shadowed region near the lunar south pole. An instrumented Shepherding Spacecraft followed a kinetic impactor and provided--from a nadir perspective--the only images of the debris plume. With independent observations of the visible debris plume from a more oblique view, the angles and velocities of the ejecta from this unique cratering experiment are better constrained. Here we report the first visible observations of the LCROSS ejecta plume from Earth, thereby ascertaining the morphology of the plume to contain a minimum of two separate components, placing limits on ejecta velocities at multiple angles, and permitting an independent estimate of the illuminated ejecta mass. Our mass estimate implies that the lunar volatile inventory in the Cabeus permanently shadowed region includes a water concentration of 6.3±1.6% by mass.

Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer's mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in nontransgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nontransgenic mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial β-amyloid and β-amyloid (Aβ)-binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial β-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of Alzheimer's disease (AD), which was prevented by E2. These findings provide a plausible mechanism for increased risk of Alzheimer's disease in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aging is a complex process that affects every major system at the molecular, cellular and organ levels. Although the exact cause of aging is unknown, there is significant evidence that oxidative stress plays a major role in the aging process. The basis of the oxidative stress hypothesis is that aging occurs as a result of an imbalance between oxidants and antioxidants, which leads to the accrual of damaged proteins, lipids and DNA macromolecules with age. Age-dependent increases in protein oxidation and aggregates, lipofuscin, and DNA mutations contribute to age-related pathologies. Many transgenic/knockout mouse models over expressing or deficient in key antioxidant enzymes have been generated to examine the effect of oxidative stress on aging and age-related diseases. Based on currently reported lifespan studies using mice with altered antioxidant defense, there is little evidence that oxidative stress plays a role in determining lifespan. However, mice deficient in antioxidant enzymes are often more susceptible to age-related disease while mice overexpressing antioxidant enzymes often have an increase in the amount of time spent without disease, i.e., healthspan. Thus, by understanding the mechanisms that affect healthy aging, we may discover potential therapeutic targets to extend human healthspan.

Objective: To assess the effects of physician-colleague and coworker abuse on family physicians in Canada., Design: A mixed-methods, bilingual study that included surveys and telephone interviews., Setting: Canada., Participants: Family physicians in active practice who were members of the College of Family Physicians of Canada in 2009., Methods: Surveys were mailed to a random sample of family physicians (N = 3802), and 37 family physicians who had been abused in the past year participated in telephone interviews., Main Findings: A total of 770 surveys (20%) were completed. A small number of respondents reported having been subjected to abuse by physician colleagues (9%) or coworkers (6%) in the previous month. Many of the respondents reported that the same physician colleagues or coworkers were repeat abusers. More than three-quarters (77%) of the physician-colleague abusers were men, whereas more than three-quarters (77%) of the other coworker abusers were women. Interviewed family physicians described feeling humiliated and unappreciated, and developed symptoms of anxiety or depression. As a result of the abuse, some family physicians terminated their employment or refused to work in certain environments. The most striking effect of this abuse was that respondents reported losing confidence in their professional abilities and skills., Conclusion: Although only a small number of family physicians experience abuse by physician colleagues and other coworkers, the effects can be considerable. Victims reported a loss of confidence in their clinical abilities and some subsequently were faced with mental health issues.

Introduction: Most longitudinal breast cancer studies have found that treatment-related sequelae such as arm morbidity [lymphedema, pain, and range of motion (ROM) restrictions] can have a significant impact on quality of life. In a previous study, we found that at 6-12 months after breast cancer surgery, 49% of participants had difficulties engaging in recreational activities and that arm morbidity significantly predicted difficulties with participation in recreation., Methods: A longitudinal national study employing clinical assessments and survey methods followed 178 women over 43 months (3.6 years) to assess issues related to arm morbidity post-breast cancer surgery. Hierarchical multiple regression analyses were conducted to identify which variables were predictive of recreational difficulties experienced by women 8 and 43 months post-surgery., Results: Between 8 months (T1) and 43 months (T2) post-breast cancer surgery, women demonstrated slight increases in lymphedema. Conversely, a significant decrease was observed in the number of ROM restrictions and pain when using the arm. Despite the overall improvements in arm morbidity, some women continued to report moderate pain and ROM restrictions. The two arm morbidity factors were found to be statistically significant (p < 0.001) predictors of recreational difficulties at both 8 and 43 months post-surgery, with pain accounting for the greatest proportion of variance., Discussion/conclusion: Pain and ROM restrictions were the only significant predictors of recreational difficulties during the first 3.6 years after breast cancer surgery. Specifically, women who still experience pain years after breast cancer surgery report difficulties in their recreational pursuits., Implications for Cancer Survivors: Pain and ROM restrictions may prohibit participation in recreational activity and targeted intervention should be sought.

Fluid shear stress is intimately linked with vascular oxidative stress and atherosclerosis. We posited that atherogenic oscillatory shear stress (OSS) induced mitochondrial superoxide (mtO2•-) production via NADPH oxidase and c-Jun NH(2)-terminal kinase (JNK-1 and JNK-2) signaling. In bovine aortic endothelial cells, OSS (±3 dyn/cm2) induced JNK activation, which peaked at 1 h, accompanied by an increase in fluorescein isothiocyanate-conjugated JNK fluorescent and MitoSOX Red (specific for mtO2•- production) intensities. Pretreatment with apocynin (NADPH oxidase inhibitor) or N-acetyl cysteine (antioxidant) significantly attenuated OSS-induced JNK activation. Apocynin further reduced OSS-mediated dihydroethidium and MitoSOX Red intensities specific for cytosolic O2•- and mtO2•- production, respectively. As a corollary, transfecting bovine aortic endothelial cells with JNK siRNA (siJNK) and pretreating with SP600125 (JNK inhibitor) significantly attenuated OSS-mediated mtO2•- production. Immunohistochemistry on explants of human coronary arteries further revealed prominent phosphorylated JNK staining in OSS-exposed regions. These findings indicate that OSS induces mtO2•- production via NADPH oxidase and JNK activation relevant for vascular oxidative stress.

A 'critical window of opportunity' has been proposed for the efficacy of ovarian hormone intervention in peri- and post-menopausal women. We sought to address this hypothesis using a long-term ovariectomized non-human primate (NHP) model, the cynomolgus macaque (Macaca fascicularis). In these studies, we assessed the ability of 17β-estradiol and equol to regulate markers of hippocampal bioenergetic capacity. Results indicated that 17β-estradiol treatment significantly increased expression of mitochondrial respiratory chain proteins complex-I and -III in the hippocampus when compared to non-hormone-treated animals. Expression of the TCA cycle protein succinate dehydrogenase α was decreased in animals treated with equol compared to those treated with 17β-estradiol. There were no significant effects of either 17β-estradiol or equol treatment on glycolytic protein expression in the hippocampus, nor were there significant effects of treatment on expression levels of antioxidant enzymes. Similarly, 17β-estradiol and equol treatment had no effect on mitochondrial fission and fusion protein expression. In summary, findings indicate that while 17β-estradiol induced a significant increase in several proteins, the overall profile of bioenergetic system proteins was neutral to slightly positively responsive. The profile of responses with the ERβ-preferring molecule equol was consistent with overall nonresponsiveness. Collectively, the data indicate that long-term ovariectomy is associated with a decline in response to estrogens and estrogen-like compounds. By extension, the data are consistent with a primary tenet of the critical window hypothesis, i.e., that the brains of post-menopausal women ultimately lose their ability to respond positively to estrogenic stimulation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Estrogen therapy can promote cognitive function if initiated within a 'critical window' during the menopausal transition. However, in the absence of a progestogen, estrogens increase endometrial cancer risk which has spurred research into developing estrogenic alternatives that have the beneficial effects of estrogen but which are clinically safer. Soy protein is rich in isoflavones, which are a class of potential estrogenic alternatives. We sought to determine the effects of two diets, one with casein-lactalbumin as the main protein source and the other with soy protein containing isoflavones, on protein markers of hippocampal bioenergetic capacity in adult female cynomolgus macaques (Macaca fascicularis). Further, we assessed the effects of dietary soy isoflavones before or after ovariectomy. Animals receiving soy diet premenopausally then casein/lactalbumin post-ovariectomy had higher relative hippocampal content of glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase subunit e1α. Post-ovariectomy consumption of soy was associated with higher succinate dehydrogenase α levels and lower levels of isocitrate dehydrogenase, both proteins involved in the tricarboxylic acid cycle, significantly decreased expression of the antioxidant enzyme peroxiredoxin-V, and a non-significant trend towards decreased manganese superoxide dismutase expression. None of the diet paradigms significantly affected expression levels of oxidative phosphorylation enzyme complexes, or of mitochondrial fission and fusion proteins. Together, these data suggest that long-term soy diet produces minimal effects on hippocampal expression of proteins involved in bioenergetics, but that switching between a diet containing primarily animal protein and one containing soy isoflavones before and after menopause may result in complex effects on brain chemistry., (Copyright © 2011. Published by Elsevier B.V.)

The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy.

Background: We have previously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic Alzheimer's (3xTgAD) mouse model. Herein, we sought to determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD., Methods: Both nonTg and 3xTgAD female mice at 3, 6, 9, and 12 months of age were sacrificed and mitochondrial bioenergetic profile as well as oxidative stress markers were analyzed., Results: In both nonTg and 3xTgAD mice, reproductive senescence paralleled a significant decline in PDH, and Complex IV cytochrome c oxidase activity and mitochondrial respiration. During the reproductive senescence transition, both nonTg and 3xTgAD mice exhibited greater individual variability in bioenergetic parameters suggestive of divergent bioenergetic phenotypes. Following transition through reproductive senescence, enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism were significantly increased and variability in cytochrome c oxidase (Complex IV) collapsed to cluster at a approximately 40% decline in both the nonTg and 3xTgAD brain which was indicative of alternative fuel generation with concomitant decline in ATP generation., Conclusions: These data indicate that reproductive senescence in the normal nonTg female brain parallels the shift to ketogenic/fatty acid substrate phenotype with concomitant decline in mitochondrial function and exacerbation of bioenergetic deficits in the 3xTgAD brain., General Significance: These findings provide a plausible mechanism for increased life-time risk of AD in postmenopausal women and suggest an optimal window of opportunity to prevent or delay decline in bioenergetics during reproductive senescence., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Disposable technology is being used more each year in the biotechnology industry. Disposable bioreactors allow one to avoid expenses associated with cleaning, assembly and operations, as well as equipment validation. The WAVE bioreactor is well established for Chinese Hamster Ovary (CHO) production, however, it has not yet been thoroughly tested for E. coli production because of the high oxygen demand and temperature maintenance requirements of that platform. The objective of this study is to establish a robust process to generate inoculum for E. coli production fermentations in a WAVE bioreactor. We opted not to evaluate the WAVE system for production cultures because of the high cell densities required in our current E. coli production processes. Instead, the WAVE bioreactor 20/50 system was evaluated at laboratory scale (10-L) to generate inoculum with target optical densities (OD(550)) of 15 within 7-9 h (pre-established target for stainless steel fermentors). The maximum settings for rock rate (40 rpm) and angle (10.5) were used to maximize mass transfer. The gas feed was also supplemented with additional oxygen to meet the high respiratory demand of the culture. The results showed that the growth profiles for the inoculum cultures were similar to those obtained from conventional stainless steel fermentors. These inoculum cultures were subsequently inoculated into 10-L working volume stainless steel fermentors to evaluate the inocula performance of two different production systems during recombinant protein production. The results of these production cultures using WAVE inocula showed that the growth and recombinant protein production was comparable to the control data set. Furthermore, an economic analysis showed that the WAVE system would require less capital investment for installation and operating expenses would be less than traditional stainless steel systems., ((c) 2010 American Institute of Chemical Engineers)

Objective: This study qualitatively assesses the coping strategies of parents who care for a child with cancer., Method: Semi-structured interviews were conducted with 28 French and English families who had had a child diagnosed with cancer in the last ten years in two Eastern Canadian provinces. Interviews were transcribed verbatim and coded with a focus on parental coping strategies., Results: Using coping behaviors as described and categorized in the Family Adjustment and Adaptation Response (FAAR) model as a foundation, we found that families used a variety of appraisal-, emotion-, and problem-focused coping. Appraisal-focused coping strategies involved trying to stay "positive" and "making positive comparisons." Problem-focused coping involved behaviors such as being an advocate for the child and seeking information. The majority of parents, however, described using emotion-focused coping behaviors such as trying to avoid "feeling too much" by hiding difficult emotions and "escaping" from problems. Others used more positive emotion-focused coping behaviors such as humor, seeking support (informal or formal), or writing diaries. A small group of parents used ineffective coping strategies (alcohol abuse, misdirected anger) that added to family stress. These ineffective strategies have led to a modification of the FAAR model indicating that not all coping behaviors are beneficial to family adjustment in crisis. Overall, many parents felt that their coping strategies were effective; however, a few described having a complete "coping breakdown"., Significance of Results: Parents used a range of coping strategies of which emotion-focused coping was the most prominent. We have enhanced the FAAR model by including additional coping behaviors as well as a description of how some coping behaviors add to the daily stressors for parents dealing with a child's illness. Professional health care providers need to understand the variability of the coping behaviors in order to appropriately assist parents to avoid coping breakdowns.

Objective: To examine the career prevalence of abusive encounters for family physicians in Canada., Design: A 7-page cross-sectional mailed survey in English and French., Setting: Canada., Participants: A total of 3802 randomly selected practising family physicians who were members of the College of Family Physicians of Canada., Main Outcome Measures: Demographic characteristics of survey participants, career prevalence of abusive encounters, and perpetrators of abuse., Main Findings: Twenty percent (20.4%) of the surveys (n = 774) were returned. Of the respondents, 44% were men and 56% were women. Most were in private practice in urban settings. The average number of years in practice was 15. The career prevalence of abusive encounters was divided into "minor," "major," and "severe" incidents. Of all the respondents, 98% had experienced at least 1 incident of minor abuse, 75% had experienced at least 1 incident of major abuse, and 39% had experienced at least 1 incident of severe abuse. Using chi(2) analysis, a number of demographic variables were found to be significantly associated with abuse including the physician's race and sex. Patients were the most common perpetrators of abuse. Ninety percent of family physicians surveyed reported that they had been abused by patients, while 70% reported that they had been abused by family members of patients., Conclusion: Approximately 2 in 5 family physicians surveyed were subjected to a considerable amount of severe abuse during practice. Abuse in the office setting might have grave consequences for the health and well-being of the victimized physicians and might hinder service retention where the risk of abuse is greatest.

Objective. The goal of this study was to examine the monthly incidence rates of abusive encounters for family physicians in Canada. Methods. A 7-page cross-sectional survey. Results. Of the entire study sample (N = 720), 29% of the physicians reported having experienced an abusive event in the last month by a patient or patient family member. Abusive incidents were classified as minor, major, or severe. Of the physician participants who reported having been abused, all reported having experienced a minor event, 26% a major, and 8% a severe event. Of the physicians who experienced an abusive event, 55% were not aware of any policies to protect them, 76% did not seek help, and 64% did not report the abusive event. Conclusion. Family physicians are subjected to significant amounts of abuse in their day-to-day practices. Few physicians are aware of workplace policies that could protect them, and fewer report abusive encounters. Physicians would benefit from increased awareness of institutional policies that can protect them against abusive patients and their families and from the development of a national policy.