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A Cyber-Physical-Social System (CPSS) is an evolving subset of Cyber-Physical Systems (CPS), which involve the interlinking of the cyber, physical, and social domains within a system-of-systems mindset. CPSS is in a growing state, which combines secure digital technologies with physical systems (e.g., sensors and actuators) and incorporates social aspects (e.g., human interactions and behaviors, and societal norms) to facilitate automated and secure services to end-users and organisations. This paper reviews the field of CPSS, especially in the scope of complexity theory and cyber security to determine its impact on CPS and social media's influence activities. The significance of CPSS lies in its potential to provide solutions to complex societal problems that are difficult to address through traditional approaches. With the integration of physical, social, and cyber components, CPSS can realize the full potential of IoT, big data analytics, and machine learning, leading to increased efficiency, improved sustainability and better decision making. CPSS presents exciting opportunities for innovation and advancement in multiple domains, improving the quality of life for people around the world. Research challenges to CPSS include the integration of hard and soft system components within all three domains, in addition to sociological metrics, data security, processing optimization and ethical implications. The findings of this paper note key research trends in the fields of CPSS, and recent novel contributions, followed by identified research gaps and future work.

Poor quality jobs, incorporating job demands, resources and rewards, can impact employees' health and wellbeing inside and outside work. However, jobs' changing nature and employees' increasingly diverse backgrounds mean existing job quality models may not adequately explain individuals' job quality experiences within their individual, organisational and societal contexts. The paper aimed to understand mothers, fathers and childless women and men's gendered, classed and aged experiences of quantitative job demands (including work amount, speed, effort, length and timing) and their resources and rewards, within multilevel contexts. We conducted a qualitative case-study of an Australian organisation, employing a critical feminist grounded theory design. We collected and analysed data from open-ended questionnaire responses from 47 employees and iterative in-depth interviews with 10 employees. Participants' experiences of excessive quantitative demands, whether they could meet such demands, and whether they felt extrinsically or intrinsically resourced and rewarded for doing so, were embedded within ComCo's masculine-neoliberal-capitalist growth imperative, cultures, policies and practices reinforcing growth, and quantitatively extreme and qualitatively conformant ideal worker discourses, as well as participants' organisationally and societally-embedded individual, family and community-level contexts; producing nuanced gendered, classed and aged experiences among mothers, fathers and childless women and men. Although confirming well-established objective job quality dimensions, our research suggests individuals' nuanced and subjective job quality experiences are embedded within individual, family, community, organisational and societal contexts., Competing Interests: Competing InterestsThe authors have no relevant financial or non-financial interests to declare., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The 4-valent human papillomavirus (HPV) vaccine (4vHPV vaccine), Gardasil®, is indicated for the prevention of several HPV-related diseases. The objective was to assess the safety of 4vHPV vaccine administered to males as part of routine care. The study used a US health insurance claims database, and included males, age 9 to 26 years, who initiated 4vHPV between October 2009 and December 2016. General safety outcomes were identified using ICD diagnosis codes associated with emergency room visits and hospitalizations in the claims database in risk periods (Days 1-60 and Days 1-14 following vaccine administration) and self-comparison periods (Days 91-150 and 91-104 for the Days 1-60 and Days 1-14 analysis, respectively). Incidence rates (IRs) and relative rates (RRs) with 95% confidence intervals (CIs) were calculated comparing the risk and self-comparison periods. In this study, 114,035 males initiated 4vHPV vaccine and received 202,737 doses. Using the 60-day time window, 5 outcomes had significantly elevated RRs after accounting for multiple comparisons: ear conditions (RR 1.28, 95% CI 1.03-1.59); otitis media and related conditions (RR 1.65, 95% CI 1.09-2.54); cellulitis and abscess of arm (RR 2.17, 95% CI 1.06-4.72); intracranial injury (RR 1.23, 95% CI 1.01-1.50); and concussion (RR 1.29, 95% CI 1.05-1.59). A higher rate of allergic reactions was noted on the day of 4vHPV vaccine receipt compared to other vaccines (21.07 events per 10,000 doses, 95% CI 18.89-23.44 versus 11.44 per 10,000 doses, 95% CI 9.84-13.22). A higher incidence rate of VTE was observed following vaccination but this association was not significant (RR 2.17, 95% CI 0.35-22.74). The 4vHPV vaccine was associated with same-day allergic reactions as well as ear infections, intracranial injury, cellulitis, and concussion within 2 months after vaccination. While allergic reaction and cellulitis are consistent with the known safety profile of 4vHPV vaccine, the association of the other outcomes were determined by an independent Safety Review Committee to be most likely a result of activities common in adolescent males that coincide with the timing of vaccination and not directly related to vaccination itself. Implications and Contributions : The study results support the general safety of routine immunization with 4vHPV vaccine among males to prevent HPV-related diseases and cancers.

Microglia, the brain's resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in knowledge by establishing an extensive collection of 97 post-mortem tissues in order to enable quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing waves in microglial density across gestation, infancy, and childhood, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNA-seq and single-cell RNA-seq datasets. This study provides a detailed insight into the spatiotemporal dynamics of microglia across the human lifespan and serves as a foundation for elucidating how microglia contribute to shaping neurodevelopment in humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Santa Fe Gully zone is a marginalized area of Mexico City where nearly 39% of children live with either overweight or obesity. Despite the extensive research on obesogenic behaviors, studies frequently overlook the contexts where such behaviors occur. This qualitative study described individual and familial obesogenic behaviors among children with obesity from Santa Fe Gully, and explained how these behaviors might be contextually shaped. We used a grounded theory approach to investigate the process of development/maintenance of obesity in our sample. Fifteen participants (seven 10-year-olds with overweight or obesity and their parents) participated in nine art-based focus groups, and parents completed individual semi-structured interviews. Data were analyzed using a structured thematic content analysis. Results showed children's weight status was part of their identity, providing children with a familial 'fitting' sense while increasing psychosocial difficulties, leading to emotional overeating as a coping strategy. Parents' use of controlling and low-structured parenting practices reinforced children's emotional overeating and failed to regulate children's dietary and physical activity behaviors. Some low-structured parenting practices were guilt-motivated or fostered by socioeconomic and cultural factors (e.g., limited food access, unhealthy food exposure, community unsafety). Future interventions in Santa Fe Gully aimed at modifying obesogenic behaviors should incorporate systemic and ecological approaches to help participants navigate through contextual obstacles, as their behaviors should be analized considering the context where they occur., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: The quadrivalent human papillomavirus vaccine (4vHPV, GARDASIL® ) , was approved in the US in 2009 for use in males aged 9 to 26 for the prevention of HPV-related genital warts, and in 2010 for the prevention of certain HPV-related anogenital diseases. A regimen was approved in 2016 for those who initiate the vaccine series between the ages of 9 to 14 years. We describe patterns of 4vHPV administration among US males before this modification., Methods: The study used a US health insurance claims database, and included males, age 9 to 26 years, who initiated 4vHPV between 2012 and 2016. Time from first dose to subsequent doses was estimated. Logistic regression identified factors associated with regimen completion., Results: Among 100,786 males who initiated 4vHPV (corresponding to ∼ 13% of male birth cohorts), 50,573 (50.2%) and 25,763 (25.6%) received a second and third dose, respectively. Annual administration was common, with 47% of males receiving 3 doses over 3 years (1 dose per year) as compared to 12% receiving the 3-dose series in the recommended 6-month timeframe. Receipt of 4vHPV was 2.2 (range 1.5 to 2.9) times as likely to occur in summer months compared to other times of the year. Individuals aged 18 to 21 years and those living in Western states or rural regions were less likely to complete the 3-dose regimen., Conclusions: The real-world patterns of 4vHPV vaccination observed, particularly the low uptake and regimen completion, suggest that better strategies are needed for males to improve 4vHPV vaccine use in males., 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 aim of this study was to identify serum ferritin (SF) cut-off points (COPs) in a cohort of healthy full-term normal birth weight infants who had repeated measurements of SF and haemoglobin every 3 months during the first year of life. The study included 746 full-term infants with birth weight ≥2,500 g, having uncomplicated gestations and births. Participants received prophylactic iron supplementation (1 mg/day of iron element) from the first to the 12th month of life and did not develop anaemia during the first year of life. Two statistical methods were considered to identify COPs for low iron stores at 3, 6, 9 and 12 months of age: deviation from mean and cluster analysis. According to the K-means cluster analysis results by age and sex, COPs at 3 and 6 months for girls were 39 and 21 μg/L and for boys 23 and 11 μg/L, respectively. A single COP of 10 μg/L was identified, for girls and boys, at both 9 and 12 months. Given the physiological changes in SF concentration during the first year of life, our study identified dynamic COPs, which differed by sex in the first semester. Adequate SF COPs are necessary to identify low iron stores at an early stage of iron deficiency, which represents one of the most widespread public health problems around the world, particularly in low- and middle-income countries., (© 2021 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Mexico has the highest prevalence globally for children who are overweight. We conducted a qualitative study to understand childhood obesity in Mexico and the complex factors at play. Data were collected at three elementary schools in a low socio-economic area in Mexico City. Semi-structured interviews were conducted with 60 children, 24 parents and 28 teachers. The children interviewed were between the ages of 8 and 12 years old. Interview texts were analysed using NVivo 9 and 10 and thematic discourse analysis was used. Findings revealed how children's choices around nutrition and physical activity were constrained by their environment and discursive constructions., 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.

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522., (© 2018 by The American Society of Hematology.)

Objectives: This study sought to examine predictors of psychological well-being (PWB) among nursing students at an Australian regional university. The study postulated that: stress would have a negative effect on PWB; internal factors such as self-efficacy, resilience and mindfulness would have a positive effect on PWB and, external factors like social support would have a positive effect on PWB., Design: A cross sectional descriptive predictive model was used to test the study hypotheses., Setting and Participants: Convenience sampling was used to recruit participants at an Australian regional university with non-traditional nursing cohorts and where the curriculum is predominantly taught on-line., Methods: Six validated scales (The Perceived Stress Scale; General Self-Efficacy Scale; Connor Davidson Resilience Scale; Multi-Dimensional Scale of Perceived Social Support; Psychological Wellbeing Scale, Mindfulness Awareness Scale) and a demographic inventory were administered as an online survey. A multiple linear regression analysis was performed to assess the internal and external factors to predict the participants' PWB., Results: Of the 1760 invitations distributed, 657 responses were returned; however, because some were found to be significantly incomplete, 538 responses only were used for the data analysis. Demographics illustrated the characteristics of a non-traditional cohort that was female dominated. All three hypotheses were supported. An unexpected finding was that while it might be anticipated that non-traditional cohorts will have stronger coping skills due to life experiences, this should not be assumed. We found that our participants had higher stress scores and lower psychological wellbeing, compared to the younger groups (nursing or health allied) reported in previous studies. It was perhaps due to their difficulties in juggling responsibilities between study, work and family and the nature of studying externally online., Conclusions: This study represents only a snapshot in time but emphasises the need for specific curriculum preparation to promote positive coping strategies. In this way, new graduates may be better prepared to engage with complex, demanding and ever-changing work environments across the globe., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A super-hydrophobic surface has been obtained from nanocomposite materials based on silica nanoparticles and self-assembled monolayers of 1 H ,1 H ,2 H ,2 H -perfluorooctyltriethoxysilane (POTS) using spin coating and chemical vapor deposition methods. Scanning electron microscope images reveal the porous structure of the silica nanoparticles, which can trap small-scale air pockets. An average water contact angle of 163° and bouncing off of incoming water droplets suggest that a super-hydrophobic surface has been obtained based on the silica nanoparticles and POTS coating. The monitored water droplet icing test results show that icing is significantly delayed by silica-based nano-coatings compared with bare substrates and commercial icephobic products. Ice adhesion test results show that the ice adhesion strength is reduced remarkably by silica-based nano-coatings. The bouncing phenomenon of water droplets, the icing delay performance and the lower ice adhesion strength suggest that the super-hydrophobic coatings based on a combination of silica and POTS also show icephobicity. An erosion test rig based on pressurized pneumatic water impinging impact was used to evaluate the durability of the super-hydrophobic/icephobic coatings. The results show that durable coatings have been obtained, although improvement will be needed in future work aiming for applications in aerospace.

Background: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab., Patients and Methods: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m(2)) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1., Results: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months., Conclusions: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Qutenza is a high-dose capsaicin patch used to relieve neuropathic pain from postherpetic neuralgia (PHN) and HIV-associated neuropathy (HIV-AN). In clinical studies, some patients had a dramatic response to the capsaicin patch. Our objective was to determine the baseline characteristics of patients who best benefit from capsaicin patch treatment., Methods: We conducted a meta-analysis of 6 completed randomized and controlled Qutenza studies by pooling individual patient data. Sustained response was defined as>50% decrease in the mean pain intensity from baseline to weeks 2 to 12, and Complete Response as an average pain intensity score≤1 during weeks 2 to 12. Logistic regression was used to identify predictors of response and Complete Response, and subgroups of patients who respond best to the capsaicin patch., Results: Baseline pain intensity score (BPIS)≤4 was a predictor of Sustained and Complete Response in PHN and HIV-AN patients; absence of allodynia and presence of hypoesthesia, and a McGill Pain Questionnaire (MPQ) sensory score <22 were predictors of Sustained Response in PHN patients; female sex was a predictor of Sustained and Complete Response in HIV-AN patients. Thus, characteristics associated with the highest chance of responding to the capsaicin patch were, for PHN, BPIS≤4, MPQ sensory score≤22, absence of allodynia, and presence of hypoesthesia; for HIV-AN, they were female sex and BPIS≤4. Patients with these characteristics had a statistically significantly greater chance of responding to the capsaicin patch than other patients., Discussion: We identified subpopulations of PHN and HIV-AN patients likely to benefit from the capsaicin patch.

Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Bortezomib frequently produces severe treatment-related peripheral neuropathy (PN) in Waldenström's macroglobulinemia (WM). Carfilzomib is a neuropathy-sparing proteasome inhibitor. We examined carfilzomib, rituximab, and dexamethasone (CaRD) in symptomatic WM patients naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m(2) (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m(2), on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m(2), and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m(2), on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1% (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88(L265P) or CXCR4(WHIM) mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. CaRD offers a neuropathy-sparing approach for proteasome inhibitor-based therapy in WM. This trial is registered at www.clinicaltrials.gov as #NCT01470196., (© 2014 by The American Society of Hematology.)

Introduction: Qutenza (capsaicin) 8% patch is used to treat various neuropathic indications, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN)., Objectives: We conducted a meta-analysis of Qutenza studies to describe clinical phenomena of effects of Qutenza treatment better, such as onset and duration of pain relief, and the need for retreatments., Methods: The meta-analyses combined individual patient data (1313 participants with PHN and 801 with HIV-AN) from 7 completed randomized, double-blind, controlled studies. Studies had similar designs, and all used the Qutenza patch (8% capsaicin) and a low-dose control patch (0.04% capsaicin). A 30% response was defined as a ≥30% decrease in mean pain intensity score during week 2 to end of follow-up; complete pain relief was defined as an average pain intensity ≤1 during week 2 to end of follow-up. Duration of response was calculated using the data from long-term studies as the time from onset of response to offset of response, retreatment, or end of follow-up (whichever occurred first)., Results: Overall 44% of PHN and 41% of HIV-AN patients had a 30% response, and 11% and 7%, respectively, had complete pain relief 2 to 12 weeks after treatment with Qutenza. The mean (median) onset of response to Qutenza was 3.4 (1) days for PHN and 6.5 (4) days for HIV-AN (delayed due to an initial increase in discomfort). The mean (median) duration of response after 1 Qutenza treatment was 5 (3) months. Of the patients followed-up for 12 months, 40% PHN and 36% HIV-AN patients had a 30% response, and 9% and 10%, respectively, had complete pain relief from week 2 to end of follow-up., Conclusions: Qutenza is effective in a high proportion of patients. In patients who respond to Qutenza, analgesia starts within a few days of treatment and lasts on average 5 months.

Introduction: As part of the Centers for Disease Control and Prevention's monitoring and evaluation activities for influenza vaccines, we examined relationships between influenza vaccination and selected outcomes in the 2009-2010 and 2010-2011 influenza seasons in a claims-based data environment., Methods: We included patients with claims for trivalent influenza vaccine (TIV) and/or 2009 pandemic influenza A H1N1 vaccine (H1N1) during the 2009-2010 and 2010-2011 influenza seasons. Patients were followed for several pre-specified outcomes identified in claims. Seizures and Guillain-Barré Syndrome were selected a priori for medical record confirmation. We estimated incidence rate ratios (IRR) using a self-controlled risk interval (SCRI) or a historical comparison design. Outcomes with elevated IRRs, not selected a priori for medical record review, were further investigated with review of claims histories surrounding the outcome date to determine whether the potential event could be ruled-out or attributed to other causes based on the pattern of medical care., Results: In the 2009-2010 season, no significant increased risks for outcomes following H1N1 vaccination were observed. Following TIV administration, the IRR for peripheral nervous system disorders and neuropathy was slightly elevated (1.07, 95% CI: 1.01-1.13). The IRR for anaphylaxis following TIV was 28.55 (95% CI: 3.57-228.44). After further investigation of claims histories, the majority of potential anaphylaxis cases had additional claims around the time of the event indicating alternate explanatory factors or diagnoses. In the 2010-2011 season following TIV administration, a non-significant elevated IRR for anaphylaxis was observed with no other significant outcome findings., Conclusion: After claims history review, we ultimately found no increased outcome risk following administration of 998,881 TIV and 538,257 H1N1 vaccine doses in the 2009-2010 season, and 1,158,932 TIV doses in the 2010-2011 season., (Published by Elsevier Ltd.)

The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Qutenza® is a capsaicin patch used to treat peripheral neuropathic pain, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN). The Qutenza Clinical Trials Database has been assembled to more fully characterize the effects of Qutenza. We conducted a within-subject meta-analysis of Qutenza studies to further define the medication's efficacy profile across studies. The meta-analysis combined individual patient data from randomized, controlled studies of Qutenza in peripheral neuropathic pain (1458 subjects treated with approved doses of Qutenza or control patches; 1120 with PHN and 338 with HIV-AN). These 7 studies had similar designs and were performed with the high-dose 8% capsaicin Qutenza patch and a 0.04% low-dose control patch. The difference between treatment groups for the primary efficacy end point of percentage change from baseline to weeks 2 to 12 on pain intensity score was calculated. Response was defined as a ≥ 30% decrease in mean pain intensity score during weeks 2 to 12. The overall between-group difference in percentage change from baseline in pain intensity was 8.0% (95% confidence interval 4.6, 11.5; P<.001), which statistically significantly favored Qutenza over low-dose control. Qutenza superiority was demonstrated for both PHN and HIV-AN patients for the primary end point and the end point proportion of 30% pain reduction response, and for PHN patients for the end point of proportion of 50% pain reduction response. These results confirm that Qutenza is effective for the treatment of both PHN and HIV-AN compared to low-dose control patch., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Serum immunoglobulin (Ig) M monoclonal protein determined by electrophoresis (sIgM-MP) and total serum IgM (sIgM) by nephelometry are widely used for response assessment in Waldenström macroglobulinemia (WM), although have not been compared for predicting changes in underlying disease burden. We, therefore, compared these serum markers with changes in bone marrow (BM) and extramedullary disease for 73 patients who were rituximab naive and treated with a rituximab-containing regimen. By linear regression analysis, reductions in sIgM-MP and sIgM showed moderate correlation with BM disease involvement (r = 0.4051 and r = 0.4490, respectively), and did not differ from one another as estimators of BM disease response (P = .3745). Neither sIgM-MP nor sIgM showed a strong correlation with BM disease response in patients with low (<1000 mg/dL) or high (>5000 mg/dL) IgM levels and extramedullary disease response. sIgM-MP and sIgM, therefore, are comparable response markers in WM. Development of newer, more accurate surrogate response markers are needed to better delineate treatment outcomes in patients with WM and with low or high IgM levels, and extramedullary disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: Familial disease is common in Waldenström macroglobulinemia (WM). We examined the impact of familial disease status on treatment outcome in WM and observed that familial disease was associated with inferior outcomes. However patients with familial WM receiving a bortezomib-containing regimen showed improved treatment outcomes vs. those receiving non–bortezomib-containing regimens. Bortezomib-containing regimens may therefore represent a more optimal treatment approach for patients with familial WM., Background: We examined the impact of familial predisposition on treatment outcome in 135 patients with Waldenström macroglobulinemia (WM), 26.7% of whom had first- or second-degree relatives with a B-cell lymphoproliferative disorder., Patients and Methods: All patients were rituximab naive and received a rituximab-containing regimen. There were no significant differences in baseline characteristics between cohorts., Results: Overall response (93.9% vs. 75.0%; P = .029) and complete response/very good partial response (CR/VGPR) (23.2% vs. 16.7%; P < .0001), time to progression (TTP) (45.5 vs. 21 months; P = .015) and time to next therapy (TTNT) (50.0 vs. 33.0 months; P = .024) favored patients with sporadic WM. By multivariate analysis, familial predisposition was an independent marker for disease progression (hazard ratio, 0.554). Patients with familial but not sporadic disease exhibited better responses, including CR/VGPR attainment (P = .0006) and a trend for longer progression-free survival (> 33 vs. 20.6 months; P = .08), with bortezomib-containing therapy., Conclusion: The findings convey that familial predisposition is an important determinant of treatment outcome in WM. Prospective studies to confirm these observations are needed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Cardiovascular events are inconclusively associated with duloxetine use in clinical trials and spontaneous reports. This analysis of cardiovascular events in relation to duloxetine use within a large health insurance database provides further data on the association., Methods: This cohort study was conducted within a population with commercial health insurance. Adults with depression who initiated duloxetine were matched to separate cohorts of initiators of venlafaxine, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs), along with untreated patients with depression, and enrollees without depression. The cohorts were followed for cardiovascular events (acute myocardial infarction, sudden death, hypertensive crisis, arrhythmia, and coronary revascularization), which were identified through health insurance claims and confirmed upon review of underlying medical records. Proportional hazards and Poisson regression models were used for comparisons., Results: There were approximately 64,000 person-years of follow-up among all cohorts (including 17,386 person-years among 21,457 duloxetine initiators), yielding 279 cardiovascular events. Relative to duloxetine initiators, those without depression had lower rates of combined events (incidence rate ratio [IRR], 0.51; 95% confidence interval [CI], 0.32-0.81) and coronary revascularizations (IRR, 0.51; 95% CI 0.29-0.89). The IR of each of the cardiovascular outcomes did not differ across the other cohorts, even accounting for time since last duloxetine dispensing., Conclusion: The incidence of cardiovascular events did not differ among duloxetine initiators relative to other antidepressant comparators or those with untreated depression but was higher than those without depression, suggesting that depression itself (or associated morbidities) may affect the risk of cardiovascular events.

This Letter describes an investigation of interfacial melting in ice-bearing granular flows. It is proposed that energy associated with granular collisions causes melting at an ice particle's surface, which can thus occur at temperatures well below freezing. A laboratory experiment has been designed that allows quantification of this process and its effect on the dynamics of a granular shear flow of ice spheres. This experiment employs a rotating drum, half filled with ice particles, situated in a temperature controlled laboratory. Capillary forces between the wetted melted particle surfaces lead to the clumping of particles and enhanced flow speeds, in turn leading to further melting. Dimensional analysis defines a parameter space for further experimentation., (© 2011 American Physical Society)

Elevated hepatic enzyme levels and hepatic injuries have been associated with duloxetine use in clinical trials and spontaneous reports, but the association of duloxetine with a broad spectrum of hepatic outcomes has not been assessed observationally. This cohort study of adult duloxetine initiators between 2004 and 2006 based on the Ingenix Research Data Mart involved 6 matched comparator cohorts, including 4 antidepressant initiator groups (venlafaxine, nefazodone, selective serotonin reuptake inhibitors, and tricyclic antidepressants), depressed but untreated patients, and individuals without depression. The cohorts were followed up for hepatic events, and proportional hazards regression compared duloxetine initiators with comparator cohorts, whereas Poisson regression compared duloxetine usage categories to account for changed therapy during follow-up. Approximately 64,000 person-years among 21,457 duloxetine initiators and comparator cohorts yielded 51 hepatic outcome events. Venlafaxine initiators (incidence rate ratio [IRR] = 0.34; 95% confidence interval [CI], 0.12-0.95) and the cohort without depression (IRR = 0.30; 95% CI, 0.10-0.93) had lower incidences of combined hepatic events than duloxetine initiators, whereas no other differences in hepatic events were observed for duloxetine initiators relative to selective serotonin reuptake inhibitors, tricyclic antidepressants, and untreated depressed patients. In as-treated analyses, relative to nonuse, current (IRR = 4.30; 95% CI, 1.45-12.81) and recent (IRR = 5.93; 95% CI, 1.63-21.55) duloxetine use was associated with greater incidence of less severe hepatic outcomes but not hepatic-related death and potential acute hepatic failure. Although duloxetine does not seem to increase the risk of hepatic-related death or acute hepatic failure, it may be associated with an increased risk of certain less severe hepatic events.

This study examined the outcome of 248 Waldenstrom macroglobulinaemia (WM) rituximab-naïve patients who responded to a rituximab-containing regimen. Eighty-six patients (35%) subsequently received maintenance rituximab (M-Rituximab). No differences in baseline characteristics, and post-induction categorical responses between cohorts were observed. The median rituximab infusions during induction was 6 for both cohorts; and 8 over a 2-year period for patients receiving M-Rituximab. Categorical responses improved in 16/162 (10%) of observed, and 36/86 (41·8%) of M-Rituximab patients respectively, following induction therapy (P < 0·0001). Both progression-free (56·3 vs. 28·6 months; P = 0·0001) and overall survival (Not reached versus 116 months; P = 0·0095) were longer in patients who received M-Rituximab. Improved progression-free survival was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P ≤ 0·0001). Best serum IgM response was lower (P < 0·0001), and haematocrit higher (P = 0·001) for patients receiving M-Rituximab. Among patients receiving M-Rituximab, an increased number of infectious events were observed, but were mainly ≤ grade 2 (P = 0·008). The findings of this observational study suggest improved clinical outcomes following M-Rituximab in WM patients who respond to induction with a rituximab-containing regimen. Prospective studies aimed at clarifying the role of M-Rituximab therapy in WM patients are needed to confirm these findings., (© 2011 Blackwell Publishing Ltd.)

The incorporation of rituximab into various regimens has improved depth of response in Waldenstrom macroglobulinaemia (WM), though the impact of achieving better responses remains to be determined. We examined response depth on progression-free survival (PFS) in 159 rituximab-naïve WM patients who received rituximab-based therapy. The median follow-up was 33·5 months, and categorical responses were as follows: complete response (CR, 8·8%); very good partial response (VGPR, 13·2%); partial response (50%); minor response (18·9%); Non-Responders (8·8%). Sequencing for polymorphic variants of FCGR2A, FCGR2B, and FCGR3A was performed, and impact on response depth determined. Achievement of better categorical responses was incrementally associated with improved PFS (P < 0·0001). No separation was observed between CR and VGPR, and attainment of at least a VGPR was associated with improved time-to-progression. Neither age, serum IgM, haematocrit, platelet count, serum β(2) microglobulin, WM International Prognostic Scoring System score, and treatment group predicted for CR/VGPR. Polymorphisms at FCGR3A-48 and -158 were associated with improved categorical responses, particularly attainment of CR/VGPR (P ≤ 0·03). The attainment of CR/VGPR was associated with significantly longer PFS in rituximab-naïve WM patients undergoing rituximab-based therapy, and was predicted by polymorphisms in FCGR3A., (© 2011 Blackwell Publishing Ltd.)

A Bayesian methodology was developed based on a latent change-point model to evaluate the performance of milk ELISA and fecal culture tests for longitudinal Johne's disease diagnostic data. The situation of no perfect reference test was considered; that is, no "gold standard." A change-point process with a Weibull survival hazard function was used to model the progression of the hidden disease status. The model adjusted for the fixed effects of covariate variables and random effects of subject on the diagnostic testing procedure. Markov chain Monte Carlo methods were used to compute the posterior estimates of the model parameters that provide the basis for inference concerning the accuracy of the diagnostic procedure. Based on the Bayesian approach, the posterior probability distribution of the change-point onset time can be obtained and used as a criterion for infection diagnosis. An application is presented to an analysis of ELISA and fecal culture test outcomes in the diagnostic testing of paratuberculosis (Johne's disease) for a Danish longitudinal study from January 2000 to March 2003. The posterior probability criterion based on the Bayesian model with 4 repeated observations has an area under the receiver operating characteristic curve (AUC) of 0.984, and is superior to the raw ELISA (AUC=0.911) and fecal culture (sensitivity=0.358, specificity=0.980) tests for Johne's disease diagnosis., (Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

As learning paradigms shift to student-centred active learning, development of effective skills in locating and retrieving information using electronic sources is integral to promoting lifelong learning. Recency of information that is evidence based is a critical factor in a dynamic field such as health. A changing demographic is evident among nursing students with greater numbers of mature age students who may not possess the computer skills often assumed with school leavers, and whose study preference is mostly by external mode. Development of interdisciplinary partnerships between faculties and librarians can provide the attributes and innovation of new and improved ways to better support student learning, whether or not students attend on campus. The Health Online Tutorial, an online database searching tool developed through a collaborative, interdisciplinary partnership at Charles Darwin University is one such example.

This paper discusses as study of mentoring and its relationship to nursing academics' scholarly productivity. A hermeneutic phenomenological approach was used to explore participants' experiences of mentoring and scholarship. Although all participants were well aware of the need to increase levels of scholarship, few had experienced the role modelling, guidance and leadership to assist them in meeting the expectations of the tertiary environment. While quality mentoring was viewed as a productive facilitator to improving levels of scholarly productivity, a supportive work environment with strong academic leadership was also considered an essential element in developing scholarship. Mentoring alone was considered unlikely to ameliorate any institutional issues, but rather, comprised one of a number of strategies. The picture that emerged from the study illustrates a discipline in transition in which a culture of mentoring is not well established, one that requires change not only within the discipline, but within tertiary institutions., (© 2010 Blackwell Publishing Asia Pty Ltd.)

Objective: To estimate the incidence rate (IR) of progressive multifocal leukoencephalopathy (PML) in patients without HIV., Methods: Within a large US health insurer database between January 2000 and June 2008, we conducted a retrospective observational study. We identified people with autoimmune diseases, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or history of bone marrow or solid organ transplantation, and a general population cohort. We developed a PML case-finding algorithm and validated PML diagnoses in medical charts., Results: There were 138,469 patients with autoimmune diseases, 25,706 with NHL or CLL, and 8,778 with transplants. Among 699 people who met screening criteria for potential PML, 89 had a claim diagnosis of PML (International Classification of Diseases-9 046.3). Medical records were sought for 24 patients without HIV, and 6 had confirmed PML upon review of medical records. The PML IR was 2.4 (95% confidence interval [CI] 0.06-13.18) in the systemic lupus erythematosus cohort and 10.8 (95% CI 0.27-60.39) in the autoimmune vasculitis cohort per 100,000 person-years. In the NHL and CLL cohorts, the IR was 8.3 (95% CI 1.71-24.24) and 11.1 (0.28-61.74) per 100,000 person-years. The IR among patients with bone marrow transplantation was 35.4 per 100,000 person-years (95% CI 0.90-197.29). There were no cases of PML among patients with rheumatoid arthritis (95% CI 0.0-2.24), multiple sclerosis (95% CI 0.0-5.24), Sjögren disease (95% CI 0.0-21.84), or solid organ transplantation (95% CI 0.0-26.81)., Conclusions: In this large population-based investigation of PML with thorough case finding and a known source population, the IR of medical record-confirmed PML was rare in non-HIV patient cohorts.

Objective: To compare mothers' assessments of nutritional status with anthropometric measures and gain further insights into mothers' reasons for their judgment., Design: Each mother was asked to assess the nutritional status of her child and 2 other children and to compare all 3. Rates for "hits" and "misses" between mothers' assessment and physical anthropometry were analyzed using the binomial test. The rationale for the mothers' assessments was explored through open-ended questions., Setting: A rural clinic in an indigenous area of Mexico., Participants: 31 mothers of children 1-5 years of age., Main Outcome Measures: Physical anthropometry and mothers' assessments., Results: A significant proportion (P

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.

Since the adoption of rituximab, the importance of doxorubicin and vincristine as treatment components remains to be clarified in Waldenström's macroglobulinemia (WM). We therefore examined the outcomes of symptomatic patients with WM who received CHOP-R (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab; n = 23), CVP-R (cyclophosphamide/vincristine/ prednisone plus rituximab; n = 16), or CP-R (cyclophosphamide/prednisone plus rituximab; n = 19) at our institution. Baseline characteristics for all 3 cohorts were similar for age, previous therapies, bone marrow involvement, hematocrit, platelet count, and serum beta2-microglobulin, though serum immunoglobulin M levels were higher in patients treated with CHOP-R (P < or= .015). The overall response rates (ORR) and complete response (CR) rates to therapy were as follows: CHOP-R (ORR, 96%; CR, 17%); CVP-R (ORR 88%; CR 12%); CP-R (ORR, 95%; CR, 0%); P = not significant. Adverse events attributed to therapy showed a higher incidence for neutropenic fever and treatment-related neuropathy for CHOP-R and CVP-R versus CPR (P < .03). The results of this study demonstrate comparable responses among patients with WM receiving CHOP-R, CVP-R, or CP-R, though a significantly higher incidence of treatment-related neuropathy and febrile neutropenia was observed among patients treated with CVP-R and CHOP-R versus CP-R. The use of CP-R might provide analogous treatment responses to more intense cyclophosphamide-based regimens while minimizing treatment-related complications in patients with WM.

This article describes the utilization of humidified high-flow oxygen therapy systems, which can comfortably deliver optimal humidified high-flow oxygen therapy, via nasal cannulae, at flow rates of up to 40 litres per minute to adult patients, in hospital or at home. The oxygen is saturated with water vapour at body temperature allowing flow to be well tolerated. First, to set the scene, three clinical scenarios are presented of patients nursed in intensive care, who suffered severe respiratory distress. Respiratory failure is explained, and the need for oxygen therapy set out. Alternative oxygen delivery devices and systems are then outlined, and an example of a high-flow system introduced. Set-up of the system is explained and the need for decontamination propounded. Finally, the benefits of the humidified high-flow oxygen system are exemplified, with particular reference to the critically ill patients presented here.

Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.

Background: In Mexico, as in other developing countries, micronutrient deficiencies are common in infants between 6 and 24 months of age and are an important public health problem. The objective of this study was to determine the prevalence of anemia and of iron, folic acid, and zinc deficiencies in Mexican children under 2 years of age who use the health care services provided by the Mexican Institute for Social Security (IMSS)., Methods: A nationwide survey was conducted with a representative sample of children younger than 2 years of age, beneficiaries, and users of health care services provided by IMSS through its regular regimen (located in urban populations) and its Oportunidades program (services offered in rural areas). A subsample of 4,955 clinically healthy children was studied to determine their micronutrient status. A venous blood sample was drawn to determine hemoglobin, serum ferritin, percent of transferrin saturation, zinc, and folic acid. Descriptive statistics include point estimates and 95% confidence intervals for the sample and projections for the larger population from which the sample was drawn., Results: Twenty percent of children younger than 2 years of age had anemia, and 27.8% (rural) to 32.6% (urban) had iron deficiency; more than 50% of anemia was not associated with low ferritin concentrations. Iron stores were more depleted as age increased. Low serum zinc and folic acid deficiencies were 28% and 10%, respectively, in the urban areas, and 13% and 8%, respectively, in rural areas. The prevalence of simultaneous iron and zinc deficiencies was 9.2% and 2.7% in urban and rural areas. Children with anemia have higher percentages of folic acid deficiency than children with normal iron status., Conclusion: Iron and zinc deficiencies constitute the principal micronutrient deficiencies in Mexican children younger than 2 years old who use the health care services provided by IMSS. Anemia not associated with low ferritin values was more prevalent than iron-deficiency anemia. The presence of micronutrient deficiencies at this early age calls for effective preventive public nutrition programs to address them.

Deep vein thrombosis (DVT) is a major health problem, which affects 1 in 1000 people in the general population each year. It may be asymptomatic or cause swelling and pain, and can lead to potentially fatal complications. Immobilisation following bone surgery significantly increases the risk of DVT, and prevention is a salient goal for nursing. This article reviews the pathogenesis of DVT, and therapeutic venous thromboembolic prophylaxis in the prevention of DVT following orthopaedic surgery. Best nursing practice is outlined from management of the Arteriovenous (A-V) Impulse System(R), the advent of which has had a positive impact on the incidence of DVT following orthopaedic surgery but requires further research to substantiate its effectiveness and determine patient acceptability.

Objective: To describe the physical growth in weight and height of children less than two years of age cared for the Mexican Institute of Social Security (IMSS)., Material and Method: A population-based National Survey, which was also regional representative, was carried out in Ordinary Regime (RO) and the IMSS-Oportunidades Program (IO). In two years (2000-2002) the study gathered data on 17,502 children from the RO and 9872 from IO. The measures of weight and length were made by nurses, according to WHO criteria. Growth is reported as weight and length for each month of age and gender, in tables and percentile curves derived from quintile regressions, using a third degree polynomial to smooth out the lines., Results: The trends of the means of weight and height in the first two years of life in children cared by Instituto Mexicano del Seguro Social show a pattern similar to those described in healthy children in other populations. However, the values are lower than those obtained in developed countries., Conclusions: Children's growth at two years of age at the Instituto Mexicano del Seguro Social shows a curve that is lower than that of the reference population recommended by the World Health Organization as an international standard.

Establishing a healthy diet during the toddler years is important for both short- and long-term health. During the second year of life the toddler gains independence and seeks a degree of dietary autonomy. Dietary habits adopted at this time are important because they will be taken forward into later childhood and adult life. Part 2 of this two-part review explores the relationship between the diets of toddlers and short- and long-term health, focusing particularly on obesity, dental health and constipation. Meals plans are included. This paper follows on from Part 1 (Journal of Family Health Care 2007; 17(5): 167-170) which reviewed the risks of micronutrient deficiencies.

The toddler diet in the U.K. changed considerably during the 25 years between the last two national dietary surveys, and these and other reports suggest that the nutritional intake of many toddlers does not comply with national recommendations. This is a concern for parents and health care workers because both deficiencies and excesses in nutrition are associated with increased risk of diseases, such as iron deficiency anaemia, rickets, dental caries and diseases related to obesity. Paradoxically, a decrease in energy intake has been accompanied by a rise in obesity, while a parallel fall in vitamin and mineral intake has been seen in tandem with an increase in diseases associated with nutritional deficiency. Establishing good dietary habi in early childhood is therefore important for short-term health. Dietary patterns at this time may be crucial to later behaviour and, if carried through to adulthood, may affect long-term health. In particular, deficiencies of micronutrients such as iron, zinc and vitamin D are a cause for con cern. Childhood diseases such as rickets, which affects bone development and was thought to have been eradicated, have re-emerged in recent years and the prevalence of iron deficiency anaemia has increased, particularly among migrant populations among migrant populations. Part 1 of this review considers the relationship between current toddler diet and micronutrient deficiencies, focusing on the impact of deficiency on both short- and longterm health. In Part 2 (to be published in Journal of Family Health Care 2007; 17[6]), the authors will consider effects on health of nutritional imbalance resulting from overconsumption of energy and nutrients.

This study describes the incorrect use of child restraints among car drivers with young children and examines factors that may influence their misuse. A cross-sectional survey was undertaken in supermarket car parks with car drivers travelling with children under the age of 8 years. The main measure was errors in child restraint use. Short interviews were conducted with 1113 drivers with a close inspection of the child restraints used in the vehicles. Only 4% of children were unrestrained but 64% of drivers made at least one error in restraint use. Most respondents thought using a restraint was easy, but 65% of these drivers made at least one error. Child restraints are used, but many are incorrectly fitted and/or have the child incorrectly placed in them. Correct use is a moderately complex task. Restraint systems need to be designed to minimize the opportunity for error and maximize safety.

Based on health insurance claims from a large U.S. health insurer, the authors identified 44 progressive multifocal leukoencephalopathy (PML) cases from 2002 through 2004 and described their characteristics, including antecedent diagnoses and treatments as well as survival. Immunosuppressive conditions such as HIV/AIDS, rather than potentially immunosuppressive treatments, were the main antecedents of PML. A lower mortality was observed among PML patients whose antecedent diagnosis was HIV/AIDS, the majority of whom received highly active antiretroviral therapy.

Paratuberculosis (Johne's disease) is a significant animal health problem. Evaluation of diagnostic tests for Johne's disease has been difficult due to lack of a gold standard test. In recent years, there has been interest in receiver operating characteristic (ROC) curve estimation without any gold standard test. Typically, either Bayesian or maximum likelihood methods are proposed. Although these methods overcome the lack of a gold standard test in ROC curve estimation, little work has been done to incorporate covariates in the analysis. In this paper, we propose a method for estimation of ROC curves based on statistical models to adjust for covariate effects when the true disease states of test animals are unknown. The covariates may be correlated with the disease process or with the diagnostic testing procedure, or both. We propose a 2-part Bayesian model: first, a logistic regression model for disease prevalence is used to fit the covariates; second, a linear model is used to fit the covariates to the distribution of test scores. We used Markov chain Monte Carlo methods to compute the posterior estimates of the sensitivities and specificities that provide the groundwork for inference concerning the diagnostic procedure's accuracy. We applied the methodology to milk ELISA scores from several dairy-cow herds for the diagnostic testing of paratuberculosis. We found that both milk yield and its interaction with age had significant effects on the disease process whereas only milk yield was significant on the testing procedure.

This article aims to address the potential shortfall in care provision offered by general practitioners (GPs) resulting from pending retirement and the retention and recruitment crisis. An educational module was developed that offered both theory and practise to unqualified general practice assistants. The module content was determined following discussion with local GPs. A small qualitative study of six students was carried out to review efficacy of participants in their new role. Using a grounded theory approach, participant and supervisor views of course content and delivery, role preparation diversity were analysed and compared. Tape-recorded interviews were conducted and analysis carried out employing the constant comparative method. Data were coded and emergent themes categorized. Overall, participants agreed that the module had strengthened their knowledge, added new skills, heightened their job satisfaction, added significant diversity to their role and enhanced their employability potential. Five participants communicated that they were more confident in performing clinical skills and advising health improvement techniques. Supervisors also reported that participants displayed a more competent and professional approach to health care, which was complementary to the role of the GP and practice nurse. Ultimately this allowed both GP and practice nurse to focus on dealing with chronic illness targets, as required in the new directive (Scottish Executive, 2004).

Objective: To describe how local research ethics committees (LRECs) consider and apply research ethics in the evaluation of biomedical research proposals., Design: A qualitative study was conducted using purposeful sampling, focus groups and a grounded theory approach to generate data and to analyse the work of the LRECs., Setting and Participants: 11 LRECs of the Mexican Institute of Social Security (IMSS)., Results: LRECs considered ethics to be implicit in all types of research, but that ethics reviews were only necessary for projects that included the direct participation of human beings. The LRECs appeared to understand the importance of consent, as in the completion of a consent form, but did not emphasise the importance of the process of acquiring 'informed' consent. The committees considered their main roles or functions to be: (a) to improve the methodological quality of research and to verify - if applicable - the ethical aspects; (b) to encourage personnel to undergo research training; (c) to follow-up research to oversee the adherence to norms and compliance with a specified research timetable., Conclusions: This study provides a valuable insight into how these LRECs understand the ethical review process. The emphasis of the committees was on rules, regulations, improving research methodology and research training, rather than a focus on efforts to protect the rights and well being of research subjects. The results encourage further normative and descriptive lines of investigation concerning education and the development of LRECs.

Indigenous children in school shelters in Mexico suffer from anemia in spite of food that is subsidized, prepared, and served to them. Economically and biomedically centered strategies to reduce anemia have achieved only partial and short-term success. An interdisciplinary team investigated the food security system of the school shelters and collected data through interviews and participant observation. The analysis revealed that the children's nutrition depends on a frail chain of events in which a single link's failure can lead to nutritional insecurity. The authors conclude that the social actors involved in the process are mainly considering the economic aspects of nutrition, but anemia persists as a social construction of the faulty relationship between the institution that runs the shelters and the indigenous culture. The authors make suggestions for an intervention that empowers the community by involving it actively in solving the problem.

Objectives: The study explored the maternal beliefs and practices related to pregnancy, breastfeeding, and infant feeding among women living in several regions in Mexico. We hypothesized that, despite the culinary diversity within Mexico, there would be similar patterns in the types of flavors and foods eaten by mothers and fed to infants., Design: A structured interview was conducted through personal interviews with mothers during routine visits to their local family medical units. The units were located in four regions in Mexico that represent the diversity of culinary practices characteristic of the country., Subjects: A random sample of 101 women whose infants ranged in age from 6 days to 9 months., Results: Although the vast majority of mothers knew of its benefits and nursed their infants, breastfeeding during the first week of life was not exclusive; approximately one third of the infants were also fed teas, water, and/or formula. The feeding of teas continued throughout infancy in three of the regions, but the flavor of the tea differed. There were also regional similarities in the foods chosen and avoided during pregnancy and lactation and the type of first foods offered to the infants., Conclusions: The similarities in the types of foods fed to infants and eaten more of by mothers during pregnancy suggest that these cultural and regional practices contribute to the development of strong preferences for regional cuisines. The foods eaten by the mother during pregnancy and lactation form the basis of the child's weaning patterns.

Purpose: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab., Patients and Methods: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known., Results: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms., Conclusion: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.

Objective: To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 micro g daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA., Materials and Methods: Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models., Results: SS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of