SARS-CoV-2 rapidly evolves lineage-specific phenotypic differences when passaged repeatedly in immune-naïve mice.

The persistence of SARS-CoV-2 despite the development of vaccines and a degree of herd immunity is partly due to viral evolution reducing vaccine and treatment efficacy. Serial infections of wild-type (WT) SARS-CoV-2 in Balb/c mice yield mouse-adapted strains with greater infectivity and mortality. We investigate if passaging unmodified B.1.351 (Beta) and B.1.617.2 (Delta) 20 times in K18-ACE2 mice, expressing the human ACE2 receptor, in a BSL-3 laboratory without selective pressures, drives human health-relevant evolution and if evolution is lineage-dependent. Late-passage virus causes more severe disease, at organism and lung tissue scales, with late-passage Delta demonstrating antibody resistance and interferon suppression. This resistance co-occurs with a de novo spike S371F mutation, linked with both traits. S371F, an Omicron-characteristic mutation, is co-inherited at times with spike E1182G per Nanopore sequencing, existing in different within-sample viral variants at others. Both S371F and E1182G are linked to mammalian GOLGA7 and ZDHHC5 interactions, which mediate viral-cell entry and antiviral response. This study demonstrates SARS-CoV-2's tendency to evolve with phenotypic consequences, its evolution varying by lineage, and suggests non-dominant quasi-species contribution.

Multidisciplinary Teams for the Management of Infective Endocarditis: A Systematic Review and Meta-analysis.

Background: The management of infective endocarditis (IE) is complex owing to a high burden of morbidity and mortality. Recent guidelines recommend dedicated multidisciplinary teams (MDTs) for the management of IE. The aim of this systematic review and meta-analysis was to evaluate and summarize the effect of MDT management on patient outcomes. Methods: A systematic review was performed and, where feasible, results were meta-analyzed; otherwise, results were summarized narratively. Data extraction and quality assessment were performed in duplicate. Restricted maximum likelihood random effects models were used to calculate unadjusted risk ratios and 95% CIs. Results: Screening of 2343 studies based on title and abstract yielded 60 full-text reviews; 18 studies were summarized narratively, of which 15 were included in a meta-analysis of short-term mortality. Meta-analysis resulted in a risk ratio of 0.61 (95% CI, .47-.78; I2 = 62%) for mortality in favor of a dedicated MDT as compared with usual care. Length of stay was variable, with 55% (10/18) of studies reporting an increased length of stay. Most studies (16/18, 88.9%) reported a decreased time to surgery and an increased rate of surgery (13/18, 73%). No studies reported on patient-reported outcomes. Conclusions: This is the first systematic review and meta-analysis to assess the impact of MDT management on IE. The sum of evidence demonstrated a significant association between MDTs and improved short-term mortality. Further research is needed to evaluate benefits of virtual MDT care, cost-effectiveness, and the impact on patient-reported outcomes and long-term mortality.

Food systems determinants of nutritional health and wellbeing in urban informal settlements: A scoping review in LMICs.

INTRODUCTION: Increasing food and nutritional inequities are apparent in urban settings across Low- and Middle-Income Countries (LMICs), along with nutrition transition towards ultra-processed diets high in fat, sugar, and salt. In urban informal settlements, characterized by insecurity and inadequate housing and infrastructure, food systems dynamics and their nutritional implications are poorly understood. OBJECTIVES: This paper explores the food system determinants of food and nutrition security in urban informal settlements in LMICs with the goal of identifying effective approaches and entry points for policy and program. METHODS: Scoping review. Five databases were screened spanning the period 1995 to 2019. A total of 3748 records were assessed for inclusion based on title and abstract followed by 42 full text reviews. At least two reviewers assessed each record. Twenty-four final publications were included, coded, and synthesized. RESULTS: Factors influencing food security and nutrition in urban informal settlements can be organized into three interconnected levels. Macro-level factors include globalization, climate change, transnational food corporations, international treaties and regulations, global and national policies such as SDGs, insufficient social aid programs, and formalization or privatization. Meso-level factors include gender norms, inadequate infrastructure and services, insufficient transportation, informal food retailers, weak municipal policies, marketing strategies, and (lack of) employment. Micro-level factors comprise gender roles, cultural expectations, income, social networks, coping strategies, and food (in) security. CONCLUSIONS: Greater policy attention should focus at the meso-level, with priority investments in services and infrastructure within urban informal settlements. The role and engagement of the informal sector is an important consideration in improving the immediate food environment. Gender is also crucial. Women and girls have a central role in food provisioning but are more vulnerable to various forms of malnutrition. Future research should include context-specific studies in LMIC cities as well as promoting policy change using a participatory and gender transformative approach.

Telerehabilitation during the COVID-19 pandemic, what are the determinants of satisfaction for chronic diseases? a retrospective study.

Background: During the Covid-19 health crisis, telerehabilitation provided a solution to ensure the continuity of care. Since then, it has been offered as an alternative to face-to-face rehabilitation in chronic conditions. Data measuring satisfaction are essential to adapt and increase the effectiveness of this type of programme. Aim and scope: This research focused on determining the most significant determinants of participant satisfaction in a telerehabilitation programme. Methods: We conducted a retrospective study by analysing the satisfaction questionnaire used from the start of the programme. Result: Two hundred and ten (210) participants completed the programme; 180 questionnaires were filled in and 175 analyzed of which 70 with chronic low back pain (CLBP), 59 for multiple sclerosis (MS) and 22 with parkinson's disease (PD). Satisfaction was high for all participants (scoring out of 10, mean = 8.22 sd = 1.53), but the determinants reported for the three main conditions involved in the programme differed. Main determinant was "benefice" for CLBP (p = 1.23e-05), "home exercises adapted" for MS (p = 0.000679) and "interest in staying at home" for PD (p = 1.84e-05). Conclusion: Depending on the context of the condition/disease, the drivers of satisfaction were not identical. Knowledge of these determinants will allow us to further improve the programme. However, some unresolved questions remain regarding the place of therapists, their role and the skills required for a successful telerehabilitation programme. Further studies are required to understand the impact.

The Three W's of Acetaminophen In Children: Who, Why, and Which Administration Mode.

Acetaminophen is one of the oldest medications commonly administered in children. Its efficacy in treating fever and pain is well accepted among clinicians. However, the available evidence supporting the use of acetaminophen's different modes of administration remains relatively scarce and poorly known. This short report summarizes the available evidence and provides a framework to guide clinicians regarding a rational use of acetaminophen in children.

Evaluation of a Digitally Guided Self-Rehabilitation Device Coupled With Telerehabilitation Monitoring in Patients With Parkinson Disease (TELEP@RK): Open, Prospective Observational Study.

BACKGROUND: Parkinson disease is a neurodegenerative disease causing a progressive loss of autonomy. This requires long-term rehabilitation care. Currently, new technologies are being developed for use in daily life, and there is a progressive implementation of telerehabilitation. OBJECTIVE: The aim of this study (the TELEP@RK study) is to evaluate the uses of a digital self-rehabilitation device in patients with Parkinson disease and their independent physiotherapists on the scale of a health territory. METHODS: A total of 10 independent physiotherapists and 31 patients with Parkinson disease were followed for 1 year to evaluate the use of a telerehabilitation tool (digital tablet and inertial sensor) via questionnaires of the Unified Theory of Acceptance and Use of Technology (UTAUT). The questionnaires were submitted to participants at 0, 2, and 12 months from the start of follow-up. The averages of the scores of the different determinants and constructs of the UTAUT questionnaires were compared at the different follow-up times. RESULTS: Among professionals, the averages of the various determinants were generally high at the beginning of the study with an average (out of 5) performance expectancy of 4.19, effort expectancy of 3.88, social influence of 3.95, facilitating conditions of 4, and intention to use of 3.97. These averages decreased over time. CONCLUSIONS: Acceptability, acceptance, and appropriation of the tool were very high among the physiotherapists as well as the patients, despite the tool's lack of evolution during the study. In the current health care context, these results allow us to envision a new organization of the care pathway for patients with chronic diseases, with the increased use of new technologies associated with telecare.

Evaluation of the Morbidity of Routine Cystoscopy Performed Intraoperatively During Total Laparoscopic Hysterectomies.

STUDY OBJECTIVES: The primary objective is to determine the rate of morbid events (urinary tract infection, hematuria, urinary retention, false positive, incidental finding) associated with routine cystoscopies performed intraoperatively during total laparoscopic hysterectomies (TLH). The secondary objectives are 1) to determine the rate of urinary complications during TLHs in our centers and 2) to determine the detection rate of urinary complications using cystoscopy during TLHs. METHOD: Descriptive retrospective multicenter study. The study took place in Obstetrics & Gynecology departments of 2 university centers in Montreal. Patients underwent a routine cystoscopy during their TLH for a benign reason in our centers. Five hundred thirty-one charts from January 1, 2012 to January 31, 2018 were reviewed. RESULTS: The morbidity rate of routine cystoscopies during TLHs is 4.19% (22/524 cases) in our centers. Our urinary complication rate is 2.45% (13/531 cases). Of these 13 complications, 4 were detected by cystoscopy. CONCLUSION: The usefulness of routine cystoscopies performed intraoperatively during TLHs is questionable due to the number of morbid events and the low rate of urinary trauma in our centers. However, it is hard to establish a direct causality link between certain morbid events and cystoscopy. More studies should be conducted on this subject.

A small number of early introductions seeded widespread transmission of SARS-CoV-2 in Québec, Canada.

BACKGROUND: Québec was the Canadian province most impacted by COVID-19, with 401,462 cases as of September 24th, 2021, and 11,347 deaths due mostly to a very severe first pandemic wave. In April 2020, we assembled the Coronavirus Sequencing in Québec (CoVSeQ) consortium to sequence SARS-CoV-2 genomes in Québec to track viral introduction events and transmission within the province. METHODS: Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec. We report 2921 high-quality SARS-CoV-2 genomes in the context of > 12,000 publicly available genomes sampled globally over the first pandemic wave (up to June 1st, 2020). By combining phylogenetic and phylodynamic analyses with epidemiological data, we quantify the number of introduction events into Québec, identify their origins, and characterize the spatiotemporal spread of the virus. RESULTS: Conservatively, we estimated approximately 600 independent introduction events, the majority of which happened from spring break until 2 weeks after the Canadian border closed for non-essential travel. Subsequent mass repatriations did not generate large transmission lineages (> 50 sequenced cases), likely due to mandatory quarantine measures in place at the time. Consistent with common spring break and "snowbird" destinations, most of the introductions were inferred to have originated from Europe via the Americas. Once introduced into Québec, viral lineage sizes were overdispersed, with a few lineages giving rise to most infections. Consistent with founder effects, the earliest lineages to arrive tended to spread most successfully. Fewer than 100 viral introductions arrived during spring break, of which 7-12 led to the largest transmission lineages of the first wave (accounting for 52-75% of all sequenced infections). These successful transmission lineages dispersed widely across the province. Transmission lineage size was greatly reduced after March 11th, when a quarantine order for returning travellers was enacted. While this suggests the effectiveness of early public health measures, the biggest transmission lineages had already been ignited prior to this order. CONCLUSIONS: Combined, our results reinforce how, in the absence of tight travel restrictions or quarantine measures, fewer than 100 viral introductions in a week can ensure the establishment of extended transmission chains.

Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU.

BACKGROUND: Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection. METHODS: Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy. INTERVENTIONS: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg daily in two doses and azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. SECONDARY OUTCOMES: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90. DISCUSSION: Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival. TRIAL REGISTRATION: Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).

SPCA1 governs the stability of TMEM165 in Hailey-Hailey disease.

TMEM165 is a Golgi protein whose deficiency causes a Congenital Disorder of Glycosylation (CDG). We have demonstrated that Mn2+ supplementation could suppress the glycosylation defects observed in TMEM165-deficient cells and that TMEM165 was a Mn2+-sensitive protein. In the Golgi, the other transmembrane protein capable to regulate Mn2+/Ca2+ homeostasis is SPCA1, encoded by the ATP2C1 gene. A loss of one copy of the ATP2C1 gene leads to Hailey-Hailey Disease (HHD), an acantholytic skin disorder in Humans. Our latest results suggest an unexpected functional link between SPCA1 and TMEM165. In order to clarify this link in case of partial SPCA1 deficiency, HHD fibroblasts were used to assess TMEM165 expression, subcellular localization and Mn2+-induced degradation. No differences were observed regarding TMEM165 expression and localization in HHD patients' fibroblasts compared to control fibroblasts. Nevertheless, we demonstrated both for fibroblasts and keratinocytes that TMEM165 expression is more sensitive to MnCl2 exposure in HHD cells than in control cells. We linked, using ICP-MS and GPP130 as a Golgi Mn2+ sensor, this higher Mn2+-induced sensitivity to a cytosolic Mn accumulation in MnCl2 supplemented HHD fibroblasts. Altogether, these results link the function of SPCA1 to the stability of TMEM165 in a pathological context of Hailey-Hailey disease.

Comparative study of psychometric properties of three assessment tools for degenerative rotator cuff disease.

OBJECTIVE:: To compare psychometric properties of Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, Shoulder Pain and Disability Index (SPADI) and Constant-Murley scale, in patients with degenerative rotator cuff disease (DRCD). DESIGN:: Longitudinal cohort. SETTING:: One French university hospital. METHODS:: The scales were applied twice at one-week interval before physiotherapy and once after physiotherapy two months later. The perceived improvement after treatment was self-assessed on a numerical scale (0-4). The test-retest reliability of the DASH, SPADI and Constant-Murley scales was assessed before treatment by the intraclass correlation coefficient (ICC). The responsiveness was assessed by the paired t-test ( P < 0.05) and standardized mean difference (SMD). The correlation between the percentage of variation in scale scores and the self-assessed improvement score after treatment was measured by the Spearman coefficient. RESULTS:: Fifty-three patients were included. Twenty-six only were available for reliability. The test-retest reliability was very good for the DASH (ICC = 0.97), SPADI (0.95) and Constant-Murley (0.92). The scale score was improved after treatment for each scale ( P < 0.05). The SMD was moderate for the DASH (0.56) and SPADI (0.56) scales, and small for the Constant-Murley (0.44). The correlation between the percentage of variation in scores and self-assessed improvement score after treatment was high, moderate and not significant for the SPADI (0.59, P < 0.0001), DASH (0.42, P < 0.01) and Constant-Murley scales, respectively. CONCLUSION:: The test-retest reliability of the DASH, SPADI and Constant-Murley scales is very good for patients with DRCD. The highest responsiveness was achieved with the SPADI.

Recurrent somatic BRAF insertion (p.V504_R506dup): a tumor marker and a potential therapeutic target in pilocytic astrocytoma.

Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated RAS/RAF/MEK/ERK signaling. In this study, we report the identification of a novel recurrent BRAF insertion (p.V504_R506dup) in five PA cases harboring exclusively this somatic tandem duplication. This recurrent alteration leads to an addition of three amino acids in the kinase domain of BRAF and has functional impact on activating MAPK phosphorylation. Importantly, we show that this mutation confers resistance to RAF inhibitors without changing effectiveness while downstream MEK inhibitors remain effective. Our results further emphasize the importance of BRAF alterations in PA and the need to characterize them in a given tumor as this can affect therapeutic strategies and their potential use as tumor marker in molecular diagnostics.

Digital health, gender and health equity: invisible imperatives.

A growing body of evidence shows the use of digital technologies in health-referred to as eHealth, mHealth or 'digital health'-is improving and saving lives in low- and middle-income countries. Despite this prevalent and persistent narrative, very few studies examine its effects on health equity, gender and power dynamics. This journal supplement addresses these invisible imperatives by going beyond traditional measures of coverage, efficacy and cost-effectiveness associated with digital health interventions, to unpack different experiences of health workers and beneficiaries. The collection of papers presents findings from a cohort of implementation research projects in Africa, Asia, Latin America and the Middle East, and two commentaries offer observations from learning-oriented evaluative activities across the entire cohort. The story emerging from this cohort is comprised of three themes: (i) digital health can positively influence health equity; (ii) gender and power analyses are essential; and (iii) digital health can be used to strengthen upward and downward accountability. These findings, at the individual project level and at the level of the cohort, provide encouraging recommendations on how to approach the design, implementation and evaluation of digital health interventions to address the Sustainable Development Goals agenda of leaving no one behind.

Home-based Neuromuscular Electrical Stimulation as an Add-on to Pulmonary Rehabilitation Does Not Provide Further Benefits in Patients With Chronic Obstructive Pulmonary Disease: A Multicenter Randomized Trial.

OBJECTIVE: To assess the additional effect of a home-based neuromuscular electrical stimulation (NMES) program as an add-on to pulmonary rehabilitation (PR), on functional capacity in subjects with chronic obstructive pulmonary disease (COPD). DESIGN: Single-blind, multicenter randomized trial. SETTING: Three PR centers. PARTICIPANTS: Subjects with severe to very severe COPD (N=73; median forced expiratory volume in 1 second, 1L (25th-75th percentile, 0.8-1.4L) referred for PR. Twenty-two subjects discontinued the study, but only 1 dropout was related to the intervention (leg discomfort). INTERVENTION: Subjects were randomly assigned to either PR plus quadricipital home-based NMES (35Hz, 30min, 5 time per week) or PR without NMES for 8 weeks. MAIN OUTCOME MEASURE: The 6-minute walk test (6MWT) was used to assess functional capacity. RESULTS: Eighty-two percent of the scheduled NMES sessions were performed. In the whole sample, there were significant increases in the distance walked during the 6MWT (P<.01), peak oxygen consumption (P=.02), maximal workload (P<.01), modified Medical Research Council dyspnea scale (P<.01), and Saint George's Respiratory Questionnaire total score (P=.01). There was no significant difference in the magnitude of change for any outcome between groups. CONCLUSIONS: Home-based NMES as an add-on to PR did not result in further improvements in subjects with severe to very severe COPD; moreover, it may have been a burden for some patients.

The change-makers of West Africa.

West Africa was the focus of global attention during the Ebola virus disease outbreak, when systemic health system weaknesses compounded a serious emergency and complicated response efforts. Following the crisis, calls were made to strengthen health systems, but investments to date have fallen short of delivering the support needed to build strong health systems able to prevent and manage future outbreaks.In part, this reality serves to highlight the shortcomings of the solutions being repeatedly prioritised by external funders and experts, solutions that often fail to consider the wealth of West African evidence and actors actively working to strengthen the leadership and health systems needed to drive and sustainably improve national health outcomes. Unfortunately, this knowledge and experience are rarely heard in the global arena.This journal supplement is a contribution, although small, to changing this practice by putting the perspectives, experiences and knowledge of West Africans on the table. It presents findings from a series of research and capacity development projects in West Africa funded by the International Development Research Centre's Maternal and Child Health programme (formerly Governance for Equity in Health Systems).The evidence presented here centres around two key themes. First, the theme that context matters. The evidence shows how context can change the shape of externally imposed interventions or policies resulting in unintended outcomes. At the same time, it highlights evidence showing how innovative local actors are developing their own approaches, usually low-cost and embedded in the context, to bring about change. Second, the collection of articles discusses the critical need to overcome the existing fragmentation of expertise, knowledge and actors, and to build strong working relationships amongst all actors so they can effectively work together to identify priority issues that can realistically be addressed given the available windows of opportunity.Vibrant West African-led collaborations amongst researchers, decision-makers and civil society, which are effectively supported by national, regional and global funding, need to foster, strengthen and use locally-generated evidence to ensure that efforts to strengthen health systems and improve regional health outcomes are successful. The solutions are clearly not to be found in the 'travelling models' of standardised interventions.

Predictive factors for successful sacral nerve stimulation in the treatment of fecal incontinence: lessons from a comprehensive treatment assessment.

BACKGROUND: Sacral nerve stimulation has a place in the treatment algorithm for fecal incontinence, but the predictive factors of its midterm and long-term success are unknown. OBJECTIVE: The purpose of this study was to investigate the effect of a 3-year sacral nerve stimulation treatment of fecal continence and to identify specific predictive factors from the pretreatment and per-treatment assessments for the midterm success of sacral nerve stimulation. DESIGN: A cohort analysis of consecutive patients treated with sacral nerve stimulation for fecal incontinence over a period of 3 years was performed. SETTINGS: This study was conducted at an academic colorectal unit in a tertiary care center. PATIENTS: Sixty patients were available for the assessment of 3-year outcomes. MAIN OUTCOME MEASURES: Clinical outcome (including Cleveland Clinic score) and anorectal physiological data were collected prospectively before and after treatment. RESULTS: At the 3-year follow-up, 33 of the 60 implanted patients had an improved outcome as defined by a ≥30% improvement in the Cleveland Clinic score from baseline (37.1% on intention to treat and 55.0% per protocol), whereas 22 had an unsuccessful outcome as defined by a <30% improvement in the Cleveland Clinic score from baseline (24.7% on intention to treat and 36.7% per protocol), of whom 7 had their device explanted or switched off permanently before the 3-year assessment, and 3 were lost at follow-up. At 3 years, we failed to identify any factors that could predict the 3-year clinical outcome of sacral nerve stimulation based on preimplantation and postimplantation assessments. LIMITATIONS: This study involved a relatively small number of patients. There was a lack of consistency in the tool used to evaluate the efficacy of the test and permanent stimulations. CONCLUSIONS: Based on per-protocol assessments, 55% of the patients had improved outcomes at the 3-year follow-up. No predictor was identified by the pretreatment and posttreatment assessments (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A133).

A fatal complication of ultrasound-guided abdominal paracentesis.

Ultrasound-guided abdominal paracentesis is a procedure that is frequently performed by radiologists for both diagnostic and therapeutic purposes. This procedure has been shown to be safe with few complications. We report the case of a patient who underwent an ultrasound-guided therapeutic abdominal paracentesis for refractory ascites complicated by intraperitoneal hemorrhage leading to death. This case suggests that ultrasound-guided paracentesis may need to become a more standardized procedure and that in the event of hemorrhage, alternative treatment options such as embolization or surgical intervention should be utilized when manual compression fails.

The fallacy of coverage: uncovering disparities to improve immunization rates through evidence. Results from the Canadian International Immunization Initiative Phase 2 - Operational Research Grants.

Immunization can and does save lives. However, the presence of vaccines does not easily translate into every child being vaccinated, and this is what the studies in this journal supplement reveal. From South Asia to West Africa,the evidence presented here reveals what we are calling the fallacy of coverage, going beyond uncovering the real vaccination rates to providing evidence on the reasons for the lack of effective coverage.The evidence for the fallacy of coverage is part of an operational research program entitled the Canadian International Immunization Initiative Phase 2 (CIII2). Through a competitive peer review process, six research grants were awarded to increase access to and enhance immunization services. This journal supplement provides a forum for the presentation of the results of five of the six studies.The story of the fallacy of coverage is made up of five theme areas of evidence - timeliness of immunization, social and gender inequities, vaccine efficacy, understanding demand side issues to tailor interventions, and national data sets masking actual district level coverage rates - that reveal the discrepancies in immunization coverage rates and the reasons behind these discrepancies. As part of the story, and to turn around the fallacy of coverage, the studies also provide proof of effective and locally relevant solutions.Policies and funding, while keeping an eye on future diseases, clearly need to maintain and increase support to address existing vaccine-preventable diseases to increase coverage such that by 2015 we can achieve 90% national vaccination coverage and reach the MDG of reducing mortality rates among children under five by two-thirds.The results from the operational research grants of the CIII2 offer some answers on how to reach this goal by demonstrating how locally generated evidence can inform immunization strategies to ensure that children who need to get vaccinated will get vaccinated, and vaccinated on time.

Common variants of the glial cell-derived neurotrophic factor gene do not influence kidney size of the healthy newborn.

Glial cell-derived neurotrophic factor (GDNF) plays an important role in renal development, serving as a trophic factor for outgrowth of the ureteric bud and its continued arborisation. Our previous studies have shown that common variants of the human paired-box 2 (PAX2) gene (a transcriptional activator of GDNF) and rearranged during transfection (RET) gene (encoding the cognate receptor for GDNF) are associated with a subtle reduction in the kidney size of newborns. Since heterozygosity for a mutant GDNF allele causes mild renal hypoplasia and modest hypertension in mice, we considered the possibility that common variants of the GDNF gene might also contribute to renal hypoplasia in humans. We studied the relationship between newborn renal size or umbilical cord cystatin C and 19 common GDNF gene variants [minor allele frequency (MAF) >5%], three single nucleotide polymorphisms (SNPs) related to a putative PAX binding site and one rare SNP (rs36119840 A/G) which changes an amino acid (R93W), based on data from the haplotype map of the human genome (HapMap). However, none of these 23 SNPs was associated with reduced newborn kidney size or function. Among the 163 Caucasians in our cohort, none had the R93W allele.