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Over the past decade, numerous approaches have been taken to replace unsustainable chemical syntheses with green biosynthetic alternatives. In a landmark paper, Yim et al. utilised an in silico-to-in vivo workflow to enable the high-level bioproduction of the unnatural small molecule 1,4-butanediol in the bacterium Escherichia coli.

IntroductionOver the past two decades, vaccination programmes for vaccine-preventable diseases (VPDs) have expanded across low- and middle-income countries (LMICs). However, the rise of COVID-19 resulted in global disruption to routine immunisation (RI) activities. Such disruptions could have a detrimental effect on public health, leading to more deaths from VPDs, particularly without mitigation efforts. Hence, as RIs resume, it is important to estimate the effectiveness of different approaches for recovery.MethodsWe apply an impact extrapolation method developed by the Vaccine Impact Modelling Consortium to estimate the impact of COVID-19-related disruptions with different recovery scenarios for ten VPDs across 112 LMICs. We focus on deaths averted due to RIs occurring in the years 2020-2030 and investigate two recovery scenarios relative to a no-COVID-19 scenario. In the recovery scenarios, we assume a 10% COVID-19-related drop in RI coverage in the year 2020. We then linearly interpolate coverage to the year 2030 to investigate two routes to recovery, whereby the immunization agenda (IA2030) targets are reached by 2030 or fall short by 10%.ResultsWe estimate that falling short of the IA2030 targets by 10% leads to 11.26% fewer fully vaccinated persons (FVPs) and 11.34% more deaths over the years 2020-2030 relative to the no-COVID-19 scenario, whereas, reaching the IA2030 targets reduces these proportions to 5% fewer FVPs and 5.22% more deaths. The impact of the disruption varies across the VPDs with diseases where coverage expands drastically in future years facing a smaller detrimental effect.ConclusionOverall, our results show that drops in RI coverage could result in more deaths due to VPDs. As the impact of COVID-19-related disruptions is dependent on the vaccination coverage that is achieved over the coming years, the continued efforts of building up coverage and addressing gaps in immunity are vital in the road to recovery.SUMMARYWhat is already known?The impact of vaccination programmes without COVID-19-related disruption has been assessed by the Vaccine Impact Modelling Consortium.The COVID-19 pandemic has disrupted vaccination programmes resulting in a decline in coverage in the year 2020, the ramifications of this is unclear.What are the new findings?We estimate the impact of disruptions to routine immunisation coverage and different routes to recovery. We compare to a scenario without COVID-19-related disruptions (assuming no drops in immunisation coverage).We estimate that reaching the Immunization Agenda (IA2030) targets leads to 5% fewer FVPs and 5.22% more deaths over the years 2020 to 2030 relative to the scenario with no COVID-19-related disruptions, whereas falling short of the IA2030 targets by 10% leads to 11.26% fewer fully vaccinated persons (FVPs) and 11.34% more deaths.The impact of the disruption varies across the vaccine-preventable diseases with those forecasted to have vast expansions in coverage post-2020 able to recover more.What do the new findings imply?A drop in vaccination coverage results in fewer vaccinated individuals and thus more deaths due to vaccine-preventable diseases. To mitigate this, building up coverage of routine immunisations and addressing immunity gaps with activities such as catch-up campaigns are vital in the road to recovery.

Funder: Juniper Consortium MR/V038613/1, Funder: Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation), Diagnostics for COVID-19 detection are limited in many settings. Syndromic surveillance is often the only means to identify cases but lacks specificity. Rapid antigen testing is inexpensive and easy-to-deploy but can lack sensitivity. We examine how combining these approaches can improve surveillance for guiding interventions in low-income communities in Dhaka, Bangladesh. Rapid-antigen-testing with PCR validation was performed on 1172 symptomatically-identified individuals in their homes. Statistical models were fitted to predict PCR-status using rapid-antigen-test results, syndromic data, and their combination. Under contrasting epidemiological scenarios, the models' predictive and classification performance was evaluated. Models combining rapid-antigen-testing and syndromic data yielded equal-to-better performance to rapid-antigen-test-only models across all scenarios with their best performance in the epidemic growth scenario. These results show that drawing on complementary strengths across rapid diagnostics, improves COVID-19 detection, and reduces false-positive and -negative diagnoses to match local requirements; improvements achievable without additional expense, or changes for patients or practitioners.

Background Subsyndromal delirium following surgery in older adults is related to increased lengths of hospital stay and increased admissions to long-term care. Impaired nutrition increases risk for delirium, but its relationship to subsyndromal delirium remains unclear. Purpose This correlational study examined the relationship between nutritional status and subsyndromal delirium in older adults. Methods Assessments for subsyndromal delirium in 53 adults 65 years or older were completed for three consecutive days following joint replacement surgery. Relationships between nutritional status and subsyndromal delirium were analyzed. Level of significance for all tests was set at p ≤ .05. Results Participants' scores from the Mini Nutritional Assessment screen were significantly related (p = .05) to subsyndromal delirium severity after accounting for variability posed by age and cognition status. Conclusion When preoperative risk assessment of older adults indicates nutritional risk, preoperative optimization may improve effectiveness of delirium prevention efforts.

Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have an incidence of at least 1 in 4700 live births and significant morbidity and elevated risk of early death. This report includes a discussion of the types of leukodystrophies; their prevalence, clinical presentation, symptoms, and diagnosis; and current and future treatments. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Diagnosis is based on a combination of history, examination, and radiologic and laboratory findings, including genetic testing. Although there are few cures, there are significant opportunities for care and improvements in patient well-being. Rapid advances in imaging and diagnosis, the emergence of and requirement for timely treatments, and the addition of leukodystrophy screening to newborn screening, make an understanding of the leukodystrophies necessary for pediatricians and other care providers for children.

Peer review, in various forms, is fundamental to research-based fields and scholarly publication. The integrity of the publication process is necessary to advance nursing science and support clinical nursing practice. The peer review process undergirds publication and grant funding. In theory, peer review should occur in a process that is unbiased with results providing a fair assessment of the scientific merit and credibility of the work being reviewed. The purpose of peer review is lost if reviewer comments are unprofessional. Budding nurse scholars may be demoralized and discouraged to revise and resubmit their work after receiving review feedback they perceive unprofessional and lacking constructive recommendations on how to improve their work. This "incivility" in the peer review process may discourage nursing authors from revising and resubmitting their work, thus robbing nursing of potentially meaningful contributions to nursing science. Often beginning doctorate nursing students have little or no experience in having their scholarly works evaluated and receiving feedback via the peer review process. Peer review provides an opportunity to educate emerging nurse scholars on ways to improve their writing skills and ways to receive and respond to constructive, meaningful feedback. This article aims to discuss: 1) peer review process, 2) challenges with peer review, 3) impact of unprofessional peer review comments and incivility in nursing peer review process can have on a budding scientists and nurse scholars, 4) ways the peer review process can be used to educate and empower emerging nurse scholars, 5) implications for nursing scholarship, 6) recommendations to address bias and how to provide supportive and constructive feedback and 7) finally provide readers with available resources where they can learn more about how to conduct a peer review.

BACKGROUND Screening for poststroke depression (PSD) using a valid and reliable tool is recommended for all stroke survivors. This literature review identifies the specificity, sensitivity, and appropriateness of the 9-item Patient Health Questionnaire (PHQ-9) to screen stroke patients for PSD. METHODS Relevant databases were searched using the following selection criteria: (1) peer-reviewed primary research, (2) published from 2012 to 2018 (to evaluate the most recent research using this tool), and (3) examined the specificity and sensitivity of the PHQ-9 for screening stroke survivors for PSD. RESULTS Six studies, with an overall level of evidence grade of "B," representing an overall total sample size of 930 participants (851 given a diagnosis of stroke and 49 given a diagnosis of transient ischemic attacks) met criteria for inclusion in the review. Only 2 studies reported data on all of the components necessary to determine the robustness of this tool to screen for depression in stroke survivors. CONCLUSION Evidence regarding the sensitivity and specificity of the PHQ-9 to screen stroke patients for PSD is inconclusive. Additional research is needed to address the appropriateness of the PHQ-9 as a depression screening tool in this population. Clinicians should validate the results of PHQ-9 screening of ischemic stroke patients for PSD with the Structured Clinical Interview for DSM-5, the standard for diagnosing depression, before initiating treatment of PSD.

Background: The last two decades have seen substantial expansion of childhood vaccination programmes in low and middle income countries (LMICs). Here we quantify the health impact of these programmes by estimating the deaths and disability-adjusted life years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030. Methods: Independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B (HepB), Haemophilus influenzae type b (Hib), human papillomavirus (HPV), Japanese encephalitis (JE), measles, Neisseria meningitidis serogroup A (MenA), Streptococcus pneumoniae, rotavirus, rubella, yellow fever. Using standardized demographic data and vaccine coverage estimates for routine and supplementary immunization activities, the impact of vaccination programmes on deaths and DALYs was determined by comparing model estimates from the no vaccination counterfactual scenario with those from a default coverage scenario. We present results in two forms: deaths/DALYs averted in a particular calendar year, and in a particular annual birth cohort. Findings: We estimate that vaccination will have averted 69 (2⋅5-97⋅5% quantile range 52-88) million deaths between 2000 and 2030 across the 98 countries and ten pathogens considered, 35 (29-45) million of these between 2000-2018. From 2000-2018, this represents a 44% (36-57%) reduction in deaths due to the ten pathogens relative to the no vaccination counterfactual. Most (96% (93-97%)) of this impact is in under-five age mortality, notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 122 (96-147) million deaths will be averted by vaccination, of which 58 (39-75) and 38 (26-52) million are due to measles and Hepatitis B vaccination, respectively. We estimate that recent increases in vaccine coverage and introductions of additional vaccines will result in a 72% (61-79%) reduction in lifetime mortality caused by these 10 pathogens in the 2018 birth cohort. Interpretation: Increases in vaccine coverage and the introduction of new vaccines into LMICs over the last two decades have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained. Funding Statement: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill & Melinda Gates Foundation (BMGF). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMCfunded institutions represented in this paper: Imperial College London, London School of Hygiene & Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Metiers). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: Professor Hallett, Professor Grassly, Dr Cucunuba, Professor Jit, Dr Xiang Li, Dr Mukandavire, Ms Woodruff, Professor Ferguson, Dr Garske); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). In addition, the following funding declarations are noted: Dr Eilertson and Dr Ferrari report grants from BMGF, outside the submitted work. Mr Gamkrelidze, Dr Razavi and Mr Razavi-Shearer report grants from John C Martin Foundation during the conduct of the study; and grants from AbbVie, Gilead, Intercept, Pan American Health Organization, and Association of State and Territorial Health Officials outside the submitted work; all three authors are employees of the Center for Disease Analysis Foundation which had no role in study design, data collection and analysis, interpretation of data, or preparation of the manuscript. Dr Gaythorpe reports personal fees from Wellcome Genome Campus advanced courses and scientific conferences, and grants from MRC during the conduct of the study. Dr Hallett reports grants and personal fees from WHO, Pharos, Avenhir Health, outside the submitted work. Dr Nayagam reports Consultancy work for WHO and Pharos Global Health Advisors, and acknowledges support from NIHR Imperial Biomedical Research Centre (BRC). Dr Trotter reports personal fees from GSK, outside the submitted work. Professor Hallett, Dr Nayagam, Dr Garske, Dr Gaythorpe, Dr Hinsley, Dr Jean, and Professor Ferguson acknowledge joint Centre funding from the UK Medical Research Council and Department for International Development (MR/R015600/1). Development of LSHTM's models for HPV, measles, PCV, Hib and rotavirus was funded by WHO, Gavi and BMGF under several grants, past and current. BMGF supported the development and maintenance of the Lives Saved Tool. Dr Resch and Mr Sy acknowledge other funding from BMGF not related to this work and with no influence on the manuscript or the decision to submit it for publication. Declaration of Interests: This publication is authored by members of the Vaccine Impact Modelling Consortium (VIMC, www.vaccineimpact.org). VIMC is jointly funded by Gavi, the Vaccine Alliance, and by the Bill & Melinda Gates Foundation. The views expressed are those of the authors and not necessarily those of the Consortium or its funders. The funders were given the opportunity to review this paper prior to publication, but the final decision on the content of the publication was taken by the authors. Consortium members received funding from Gavi and BMGF via VIMC during the course of the study (see funding statement above). In addition, the following potential conflicts of interest were disclosed: Dr Eilertson and Dr Ferrari report grants from Bill and Melinda Gates Foundation, outside the submitted work. Dr Gamkrelidze, Dr Razavi and Dr Razavi-Shearer report grants from John C Martin Foundation during the conduct of the study; and grants from AbbVie, Gilead, Intercept, Pan American Health Organization, and Association of State and Territorial Health Officials outside the submitted work. Dr Gaythorpe reports personal fees from Wellcome Genome Campus advanced courses and scientific conferences, and grants from MRC during the conduct of the study. Dr Hallett reports grants and personal fees from WHO, Pharos, Avenhir Health, outside the submitted work. Dr Nayagam reports Consultancy work for WHO and Pharos Global Health Advisors. Dr Trotter reports personal fees from GSK, outside the submitted work. Professor Ferguson reports grants from UK Medical Research Council during the conduct of the study, and grants from NIH NIGMS, UK National Institute of Health Research, Janssen Pharmaceuticals, outside the submitted work. Dr Garske reports grants from Janssen Pharmaceuticals, outside the submitted work. Ethical Approval Statement: Not required.

Background: Foot ulcers are a serious complication associated with diabetes peripheral neuropathy (DPN). Diabetes foot complications associated with increased ulcer risk include: 1) decreases in plantar soft-tissue thickness, 2) increases in plantar tissue stiffness, and 3) increases in forefoot (FF) to rearfoot (RF) loading. Aim: The purpose of this study was to determine whether patients with DPN demonstrate higher forefoot to rearfoot pressures during barefoot walking compared to diabetes patients without peripheral neuropathy (DWPN) and prediabetes patients without peripheral neuropathy (PWPN). Methods: Eight PWPN, twenty-six DWPN and fourteen DPN patients participated in the study. Barefoot walking trials were performed while wearing Medilogic® pressure-measuring insoles. Peak plantar pressure (PPP) and peak pressure gradient (PPG) were measured on the right foot for the FF and RF regions. FF to RF PPP and PPG ratios were then calculated and normalized to body mass. Walking velocity was used as a co-variate for ANCOVAs. A priori statistical significance was set at α=0.05. Results: No significant interactions were observed for Group*Region for PPP (F(2, 89)=1.454, p=0.239) and PPG (F(2, 89)=0.579, p=0.563). Main effects of region revealed significantly higher FF to RF loading in both PPP (F(1, 89)=6.67, p=0.011) and PPG (F(1, 89)=4.02, p=0.048) measures driven by DWPN and DPN patients. No significant differences were observed between groups for FF to RF PPP (F(2, 44)=2.624, p=0.084) or PPG (F(2, 44)=1.331, p=0.275) ratios. Conclusion: Our findings suggest DWPN and DPN patients demonstrate a pattern of loading related to elevated foot ulcer risk. However, no significant difference was observed between groups for FF to RF PPP and PPG ratios. Inclusion of a more robust sample size will allow better testing of our hypothesis. Disclosure K. Izuora: None. M. Trabia: None. J. DeBerardinis: None. D.E. Lidstone: None. M. Varre: None. A.L. Trotter: None. J.S. Dufek: None.

Posttraumatic stress disorder (PTSD) can be a very debilitating condition. Effective approaches to prevent and treat PTSD are important areas of basic science research. Pregabalin (PGB), a gabapentinoid derivative of γ-aminobutyric acid, possesses the potential to positively affect neurobehavioral changes associated with PTSD. Using a rodent model of PTSD, the aims of this study were to determine the effects of PGB as a possible prevention for the development of PTSD-like symptoms and its use as a possible treatment. A prospective, experimental, between groups design was used in conjunction with a three-day restraint/shock PTSD stress model. Sixty rats were randomly assigned between two groups, non-stressed and stressed (PTSD). Each of the main two groups was then randomly assigned into six experimental groups: control vehicle, control PGB, control naïve, PTSD vehicle, PTSD Pre-PGB (prophylactic), PTSD Post-PGB (non-prophylactic). The neurobehavioral components of PTSD were evaluated using the elevated plus maze (EPM), Morris water maze (MWM), and forced swim test (FST). Pregabalin administered 24 hours before the initial PTSD event or for 10 days following the last PTSD stress event did not statistically improve mean open arm exploration on the EPM, spatial memory, and learning in the MWM or behavioral despair measured by the FST (p > 0.05).

Duchenne muscular dystrophy (DMD/Duchenne) is one of the ten most severe and common pediatric genetic diseases and affects an estimated 1 in every 5000 male births. While Duchenne is a 100% fatal disease, the clinical community has demonstrated that immediate identification and early clinical interventions can add years, even decades to an individual's life span. In anticipation of the changing therapeutic landscape for the Duchenne community, Parent Project Muscular Dystrophy established a newborn screening (NBS) initiative. This initiative included a Bioethics and Legal Issues Workgroup to consider the bioethics and legal issues of NBS for Duchenne. The workgroup's discussion focused only on Duchenne NBS and met through conference calls over a one-year period of time seeking consensus on various identified issues. This article reports on the findings and recommendations from that workgroup.

Once an intervention has been found to be effective, it is important to examine the processes and factors within the program that led to its success. The current study examined survivors' reflections on the Community Advocacy Project, an empirically supported intervention for women with abusive partners. The study examined the service delivery processes that survivors affirmed or identified as core components of the intervention. Qualitative analysis of interviews with 51 survivors indicated that 3 main service delivery elements contributed to positive outcomes: orientation to the whole person, unconditional validation and acceptance, and an orientation to information provision and action. These overarching themes are described and implications for domestic violence services and dissemination are discussed. Language: en

Family health history collection and genetic testing are core elements for the successful translation of genomics into primary care practice. Yet, little is known about how pediatric providers implement these elements in practice. We surveyed the membership of the American Academy of Pediatrics regarding family health history (FHH) collection and genetic testing in the primary care setting. Three hundred forty-nine (349) responses were analyzed with the initial response rate of 43.3%. Four principal findings were noted—(1) family health history is still recognized as a critical part of the medical evaluation; (2) perceived obstacles for FHH are time in obtaining the FHH and concerns about the family’s knowledge of their FHH; (3) a 3-generation family history is out of the scope of routine care and alternate methods should be considered; (4) most primary care providers (PCPs) do not feel comfortable ordering, interpreting, and counseling regarding current genetic testing. Expanded genetic/genomic education at multiple levels (undergraduate medical education, graduate medical education, and maintenance of certification) is clearly indicated to allow PCPs to integrate these vital elements into a current evaluation (acute care or health maintenance) in the primary care setting.

The SACHDNC provides advice and recommendations tothe Secretary of the federal Department of Health and HumanServices (HHS) on matters concerning screening infants andchildren for inherited disorders. The SACHDNC’s charge is toadvise and guide the Secretary, HHS, regarding the most ap-propriate application of childhood and universal newbornscreening tests, technologies, policies, guidelines, and programsfor effectively reducing morbidity and mortality in newbornsand children. In addition, SACHDNC is charged to make sys-tematic evidence-based and peer-reviewed recommendationsthat include the heritable disorders, which have the potential toaffect public health significantly, for which all newborns shouldbe screened, including secondary conditions that may be iden-tified as a result of the laboratory methods used for screening.As of September 2010, SACHDNC has considered nominationsfor screening newborns for nine conditions. Formal reviews bythe Evidence Review Workgroup were conducted on six con-ditions; the remaining were considered not ready for evidencereviews. Two conditions were recommended to be added to theSACHDNC’s Recommended Uniform Screening Panel: SevereCombined Immunodeficiency (SCID) and Critical CongenitalCyanotic Heart Disease. The Secretary, HHS, accepted theaddition of SCID to the panel; the Secretary’s decision forCritical Congenital Cyanotic Heart Disease is pending.Newborn screening is an essential preventive public healthprogram that provides early identification of rare genetic, met-abolic, hormonal, and functional disorders among infants andfollow-up care for those affected. Without treatment, thescreened-for disorders can result in devastating health conse-quences and in some cases, death.

The Secretary's Advisory Committee on Heritable Disorders in Newborns and Children is charged with evaluating conditions nominated for addition to the uniform screening panel and consequently making recommendations to the secretary of the US Department of Health and Human Services. This report describes the framework by which the committee approaches its task. Key decision nodes include initial review of every nomination to determine whether conditions are amenable for systematic evidence review, review of systematic evidence reviews conducted by the committee's external review group, and deliberation and formal recommendation for addition or exclusion to the uniform panel. Data analyzed include the accuracy and specificity of screening and diagnostic tests for nominated disorders, the extent of predicted health benefits, harms impact on disease course, and cost from early diagnosis and treatment. The committee process is guided by approaches used by similar entities, but more flexible criteria are sometimes needed to accommodate data limitations stemming from the rarity of many of these conditions. Possible outcomes of committee review range from recommendation to add a nominated condition to the uniform panel; provide feedback on specific gaps in evidence that must be addressed before making a decision; or rejection of a nomination (e.g., because of identified harms). The committee's structured evidence-based assessment of nominated conditions supports a consistently rigorous, iterative and transparent approach to its making recommendations regarding broad population-based screening programs for rare conditions in infants and children.

The use of molecular genetic tests for heritable conditions is expected to increase in medical settings, where genetic knowledge is often limited. As part of a project to improve the clarity of genetic test result reports to minimize misunderstandings that could compromise patient care, we sought input about format and content from practicing primary care clinicians. In facilitated workgroup discussions, clinicians from pediatric, obstetrics-gynecology, and family practice provided their perspectives about molecular genetic testing with a focus on the laboratory reporting of test results. Common principles for enhancing the readability and comprehension of test result reports were derived from these discussions. These principles address the presentation of patient- and test-specific information, the test result interpretation, and guidance for future steps. Model test result reports for DNA-based cystic fibrosis testing are presented that were developed based on workgroup discussions, previous studies, and professional guidelines. The format of these model test reports, which are applicable to a variety of molecular genetic tests, should be useful for communicating essential information from the laboratory to health care professionals.

Myelin proteolipid protein (PLP) is a prime candidate autoantigen for multiple sclerosis. In order to define potential immunodominant epitopes, T cell lines (TCL) from the peripheral blood of HLA-DR 15(2) MS patients were established which responded to the intact molecule of PLP. These TCL were then tested in individual proliferation assays with a variety of PLP peptides spanning most of the PLP molecule. Multiple peptides were recognized by TCL from the MS population, with more than one peptide often recognized by lines from the same individual. Three immunodominant peptides were identified which were recognized by the majority of MS patients. Estimated frequency analyses were then performed on the peripheral blood of HLA-DR15(2)-positive MS and control subjects using TCL initiated by the three immunodominant peptides, 40-60, 95-117, and 185-206. TCL from HLA-DR15 MS subjects recognized peptide 95-117 significantly more often than TCL from control subjects.

Previous studies have suggested that patient care may be compromised as a consequence of poor communication between clinicians and laboratory professionals in cases in which molecular genetic test results are reported. To understand better the contributing factors to such compromised care, we investigated both pre- and postanalytical processes using cystic fibrosis mutation analysis as our model. We found that although the majority of test requisition forms requested patient/family information that was necessary for the proper interpretation of test results, in many cases, these data were not provided by the individuals filling out the forms. We found instances in which result reports for simulated diagnostic testing described individuals as carriers where only a single mutation was found with no comment pertaining to a diagnosis of cystic fibrosis. Similarly, reports based on simulated scenarios for carrier testing were problematic when no mutations were identified, and the patient's race/ethnicity and family history were not discussed in reference to residual risk of disease. Remarkably, a pilot survey of obstetrician-gynecologists revealed that office staff, including secretaries, often helped order genetic tests and reported test results to patients, raising questions about what efforts are undertaken to ensure personnel competency. These findings are reviewed in light of what efforts should be taken to improve the quality of test-ordering and result-reporting practices.

We previously reported elevations of interleukin 2 (IL-2) in the serum of patients with chronic progressive MS. Using gel chromatography, protein A sepharose affinity chromatography, and ELISAs for IL-2 and the IL-2 soluble receptor, we now demonstrate that this cytokine is bound to serum proteins. These serum proteins include antibodies to IL-2, soluble IL-2 receptors, and high-molecular-weight proteins. Using a CTLL cell assay, a serum fraction corresponding to IgG antibodies to IL-2 inhibited the activity of this cytokine. Thus, we present evidence for potential immunomodulation of a pivotal cytokine in MS by serum proteins.

Achondroplasia is the most common condition associated with disproportionate short stature. Substantial information is available concerning the natural history and anticipatory health supervision needs in children with this dwarfing disorder. Most children with achondroplasia have delayed motor milestones, problems with persistent or recurrent middle-ear dysfunction, and bowing of the lower legs. Less often, infants and children may have serious health consequences related to hydrocephalus, craniocervical junction compression, upper-airway obstruction, or thoracolumbar kyphosis. Anticipatory care should be directed at identifying children who are at high risk and intervening to prevent serious sequelae. This report is designed to help the pediatrician care for children with achondroplasia and their families.

Much interest has surrounded the use of conjugate vaccines in recent years, with the development of vaccines against disease caused by Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae. These vaccines offer the potential for safe and effective disease control, but some questions remain, particularly regarding the duration and mechanisms of protection and the longer-term impact of vaccination on carriage. In this paper, the authors use data on immunization with serogroup C meningococcal conjugate vaccines in England and Wales to develop and apply a mathematical model to investigate the direct and indirect (herd immunity) effects of a conjugate vaccine program. A realistic, age-structured, dynamic model was developed and parameterized and was fitted to epidemiologic data from England and Wales. The effects of a range of vaccine strategies, including hypothetical scenarios, were investigated. The basic reproduction number was estimated to be 1.36. Catch-up vaccination targeting teenagers generated substantial herd immunity and was important in controlling disease rapidly. The results were sensitive to changes in the assumptions regarding the method of vaccine action, particularly duration of protection and efficacy of vaccination against carriage acquisition. This model can be used to help predict the potential impact of vaccine strategies both in the United Kingdom and elsewhere.

A community sample of two hundred pregnant women reported on their experiences of psychological abuse, depressive symptoms, and emotional support. Findings indicated that prenatal depressive symptoms mediated the relationship between prenatal severity of psychological abuse and postpartum depressive symptoms. In addition, prenatal emotional support moderated the relationship between the severity of prenatal psychological abuse and prenatal depressive symptoms. Emotional support, therefore, was considered to act as a buffer for psychological abuse severity, as high levels of emotional support were associated with lower levels of depressive symptoms under conditions of more severe psychological abuse. These results were over and above the effects of the physical violence that these women experienced. Implications for research and practice are discussed.

Several annual mesoscale convective complex (MCC) summaries have been compiled since Maddox strictly defined their criteria in 1980. These previous studies have largely been independent of each other and therefore have not established the extended spatial and temporal patterns associated with these large, quasi-circular, and, typically, severe convective systems. This deficiency is primarily due to the difficulty of archiving enough satellite imagery to accurately record each MCC based on Maddox’s criteria. Consequently, this study utilizes results from each of the MCC summaries compiled between 1978 and 1999 for the United States in order to develop a more complete climatology, or description of long-term means and interannual variation, of these storms. Within the 22-yr period, MCC summaries were compiled for a total of 15 yr. These 15 yr of MCC data are employed to establish estimated tracks for all MCCs documented and, thereafter, are utilized to determine MCC populations on a monthly, seasonal, annual, and multiyear basis. Subsequent to developing an extended climatology of MCCs, the study ascertains the spatial and temporal patterns of MCC rainfall and determines the precipitation contributions made by MCCs over the central and eastern United States. Results indicate that during the warm season, significant portions of the Great Plains receive, on average, between 8% and 18% of their total precipitation from MCC rainfall. However, there is large yearly and even monthly variability in the location and frequency of MCC events that leads to highly variable precipitation contributions.

It was previously shown that BALB/c mice were susceptible to experimental autoimmune encephalomyelitis induced by immunization with proteolipid protein (PLP). To determine the encephalitogenic epitopes of PLP in BALB/c mice, mice were immunized with successively smaller pools of 20-mer peptides spanning the PLP molecule from amino acid 30 to amino acid 206. Immunization with PLP(180-199) resulted in clinical EAE in 9/15 mice (mean max clinical score of 3.3), and immunization with PLP(185-206) induced clinical EAE in 7/21 BALB/c mice (mean maximum score of 3.7). No relapses in disease were observed. No EAE was observed in BALB/c mice immunized with PLP(185-199) (n=15), PLP(178-191) (n=13) or other regions of PLP (n=15). Passive transfer of PLP(180-199)-primed lymph node cells into nai;ve BALB/c mice resulted in EAE (2/2 mice, max score of 4.0). One-micron toluidine blue stained sections from the spinal cord of EAE-affected BALB/c mice revealed features typical of EAE in other strains, including mononuclear cell infiltration, myelin loss, and axonal loss.

(SJL/J × PL/J)F 1 mice immunized with myelin basic protein (MBP) develop an autoimmune demyelinating disease termed relapsing experimental allergic encephalomyelitis (rEAE). The acute stage of disease is mediated by CD4 + T cells specific for MBP amino acids 1–9. To determine the immunologic bases for disease relapse, host sensitization to additional autoantigens of the central nervous system was measured. Results indicate that most animals develop T cell reactivity to endogenous myelin proteolipid protein (PLP) during rEAE. However, PLP-specific immunity does not appear to accound for expression of relapse episodes of demyelination. relapse episodes of demyelination.

Smoking during pregnancy is a significant public health issue, and studies of the effectiveness of interventions to reduce maternal smoking require accurate measurement of smoking status. This study addresses some key issues in improvement of the effectiveness and efficiency of chemical validation of smoking status using a simplified high-pressure liquid chromatography urine cotinine method. Urine samples were collected from pregnant women enrolled in a smoking cessation trial and from non-pregnant volunteers exposed to environmental tobacco smoke (ETS). Analysis of ETS samples produced a maximum cotinine of 28 µg/ mmol creatinine, which was established as the cut-off point for this method. This method is a relatively fast and inexpensive technique with which to analyse large batches of cotinine samples and can reliably measure smoking status.

There is much evidence to implicate B cells, plasma cells, and their products in the pathogenesis of MS. Despite unequivocal evidence that the animal model for MS, EAE, is initiated by myelin-specific T cells, there is accumulating evidence of a role for B cells, plasma cells, and their products in EAE pathogenesis. The role(s) played by B cells, plasma cells, and antibodies in CNS inflammatory demyelinating diseases are likely to be multifactorial and complex, involving distinct and perhaps opposing roles for B cells versus antibody.

Although many types of diagnostic and carrier testing for genetic disorders have been available for decades, the use of molecular methods is a relatively recent phenomenon. Such testing has expanded the range of disorders that can be diagnosed and has enhanced the ability of clinicians to provide accurate prognostic information and institute appropriate health supervision measures. However, the proper application of these tests may be difficult because of their scientific complexity and the potential for negative, sometimes unexpected, consequences for many patients. The purposes of this subject review are to provide background information on molecular genetic tests, to describe specific testing modalities, and to discuss some of the benefits and risks specific to the pediatric population. It is likely that pediatricians will use these testing methods increasingly for their patients and will need to evaluate critically their diagnostic and prognostic implications.

Objective Conjunctivodacryocystorhinostomy (CDCR) with Jones tube placement as described by Jones has traditionally been performed as an “open” or external procedure by means of medial canthal incision. Application of endoscopic technique for CDCR with Jones tube placement has not been well described in the peer-reviewed literature. Design Retrospective nonrandomized comparative trial. Participants Ten patients with epiphora secondary to canalicular stenosis. Methods A total of 13 consecutive CDCR with Jones tube procedures were reviewed. Five procedures (performed predominantly in the early study period) were done by means of a traditional external approach with a medial canthal incision. Eight procedures were performed with an intranasal endoscopic approach and instrumentation with Jones tube placement under direct endoscopic visualization. Main outcome measures Total operative time, estimated blood lost, intraoperative, and postoperative complications and need for secondary surgery were evaluated. Results All procedures were successfully completed with no intraoperative complications. Average operative time was 59 minutes in the endoscopic group and 74 minutes in the external group. Average blood loss was 3.5 ml and 4.4 ml in the endoscopic and external groups, respectively. Postoperative adjustment of tube size or position (performed as an office procedure with topical/local anesthesia) was common: five of eight endoscopic and three of five external approach. Two patients in the endoscopic group required secondary surgery for anatomic reasons. Ultimately, all cases in both groups demonstrated patent, retained Jones tubes and relief of epiphora. Conclusion Endoscopic technique appears to be a reasonable approach for CDCR with Jones tube placement. Operative time and blood loss were comparable in the two groups, with the endoscopic group being slightly lower for each variable. Endoscopic Jones tube placement can be accomplished with readily available instrumentation. In this series, we did not find it necessary to use laser, radiofrequency, or monopolar devices for intranasal hemostasis.

Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unresponsiveness to CNS Ags and ameliorates murine relapsing experimental autoimmune encephalomyelitis (REAE). However, a recent clinical trial in which multiple sclerosis patients were treated with repeated doses of oral myelin was unsuccessful in reducing disease exacerbations. Therefore, we directly compared the tolerizing capacity of myelin vs MBP during REAE in B10.PL mice. Oral administration of high doses of myelin, either before disease induction or during REAE, did not provide protection from disease or decrease in vitro T cell responses. In contrast, repeated oral administration of high doses of MBP suppressed established disease and MBP-specific T cell proliferation and cytokine responses. The frequency of IL-2-, IFN-γ-, and IL-5-secreting MBP-specific T cells declined with MBP feeding, implicating anergy and/or deletion as the mechanism(s) of oral tolerance after high Ag doses. We have previously shown that the dosage and timing of Ag administration are critical parameters in oral tolerance induction. Studies presented here demonstrate that Ag homogeneity is also important, i.e., homogeneous Ag (MBP) is more effective at inducing oral tolerance than heterogeneous Ag (myelin).

Although multiple sclerosis (MS) patients and healthy individuals have similar frequencies of myelin basic protein (MBP)-specific T cells, the activation state of these cells has not been well characterized. Therefore, we investigated the dependence of MBP-reactive T cells on CD28-mediated costimulation in MS patients, healthy controls, and stroke patients. MBP-reactive T cells from healthy controls and stroke patients failed to proliferate efficiently when costimulation was blocked using anti-CD28, consistent with a naive T cell response. In contrast, MBP-specific T cell proliferation was not inhibited, or was only partially inhibited when CD28-mediated costimulation was blocked in MS patients. Blockade of CD28 failed to inhibit tetanus toxoid-specific T cell proliferation in both the controls and MS patients, demonstrating that memory cells are not dependent on CD28-mediated costimulation. Limiting dilution analysis indicated that the frequency of MBP-reactive T cells was significantly decreased in healthy controls compared with MS patients when CD28-mediated costimulation was blocked. These data suggest that MBP-reactive T cells are more likely to have been activated in vivo and/or differentiated into memory T cells in MS patients compared with controls, indicating that these cells may be participating in the pathogenesis of MS.

Mutation of the hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene in a T-cell is believed to be an indication that the T-cell has been activated and has proliferated in vivo. HPRT mutant T-cell lines were generated from peripheral blood mononuclear cells from patients with MS and control subjects. More lines were isolated from the MS patients than from the control subjects. Using stringent criteria for recognition, none of the lines from MS-affected or control subjects recognized intact myelin basic protein (MBP) or myelin proteolipid protein (PLP) molecules. Using stringent criteria, two of the 10 MS patients harbored mutant lines each recognizing distinct PLP peptides (PLP peptide 40–60 recognized by 3 lines from one patient and PLP peptide 178–191 recognized by 2 lines from the other patient). A single line recognizing PLP peptide 89–106 was derived from 1 of 7 normal controls. HPRT mutant lines recognizing multiple epitopes of PLP which spanned much of the molecule could be isolated from MS patients, and to a lesser extent, normal subjects.