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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.

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.

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).

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.

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.

OBJECTIVES: To describe the variation in household crowding and social mixing patterns in the African meningitis belt and to assess any association with self-reported recent respiratory symptoms. METHODS: In 2010, the African Meningococcal Carriage Consortium (MenAfriCar) conducted cross-sectional surveys in urban and rural areas of seven countries. The number of household members, rooms per household, attendance at social gatherings and meeting places were recorded. Associations with self-reported recent respiratory symptoms were analysed by univariate and multivariate regression models. RESULTS: The geometric mean people per room ranged from 1.9 to 2.8 between Ghana and Ethiopia respectively. Attendance at different types of social gatherings was variable by country, ranging from 0.5 to 1.5 per week. Those who attended 3 or more different types of social gatherings a week (frequent mixers) were more likely to be older, male (OR 1.27, p

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.

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.

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.

This project aimed to improve RNs' recognition of and appropriate responses to failure to rescue situations on a surgical oncology unit. Simulation exercises played a key role in identifying areas of strength, opportunities for improvement, and development of a personalized education plan. In addition, the exercises improved RNs' clinical confidence.

Some bacteria that are common human pathogens produce protein toxins that are potent activators of human T lymphocytes expressing certain types of T-cell receptors. In this study we examined the ability of staphylococcal toxins to stimulate human T lymphocytes that also recognized the myelin autoantigens myelin basic protein and proteolipid protein. T-cell populations responding to myelin basic protein or proteolipid protein were isolated from 4 subjects including 1 individual with multiple sclerosis. All myelin antigen-specific T cells responded in proliferation studies to at least one of the nine superantigenic toxins used in this study. The superantigenic toxins were up to 7 x 10(5)-fold more potent in proliferation assays than the myelin antigens to which the T cells were initially sensitized. In addition, cytotoxic, myelin basic protein-reactive T lymphocytes lysed antigen-presenting cells incubated with superantigenic toxins. These findings demonstrate a mechanism by which some bacterial infections might produce activation of myelin basic protein- and proteolipid protein-reactive T lymphocytes and perhaps contribute to demyelinating disease in humans.

Cytotoxic T cells reactive with myelin basic protein (MBP) may be isolated from most human subjects. Since activated T cells express major histocompatibility complex (MHC) class II antigens, we assessed whether MBP-specific, CD4+ T cells could present MBP or synthetic MBP peptides to themselves and whether this provoked self lysis. We examined two MBP-specific cell lines and eight T cell clones recognizing four different MBP epitopes. All T cell populations presented MBP as well as synthetic peptides to themselves eliciting self lysis of the T cell clones. CD4+ T cell populations recognizing another central nervous system (CNS) protein, proteolipid protein (PLP), or the recall antigen, Candida, did not exhibit this antigen-induced, autocytolytic activity. However, activated, PLP-reactive T cells were susceptible to lysis by cytotoxic MBP-specific T cells in the presence of MBP. These results suggest that antigen-induced self lysis of activated human T cells might limit an autoimmune response within a target organ independent of other immunoregulatory mechanisms.

Serum levels of the cytokines interleukin-1 alpha (IL-I alpha), IL-1 beta, IL-2, IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha) and the soluble IL-2 receptor were measured in chronic progressive multiple sclerosis patients (CPMS) and normal, inflammatory, and noninflammatory disease controls. Serum IL-2 levels displayed the most consistent abnormalities in the group of tests for the CPMS group, and were the only cytokine levels to achieve significance in statistical group analyses. However, several patients with CPMS had normal serum IL-2 levels. An incidental finding was a statistical correlation between serum IL-2 and TNF-alpha levels among all groups tested. This finding was supported on analysis of serial serum samples from CPMS patients. These results suggest a linkage of IL-2 and TNF-alpha production, especially in pathological conditions.

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.

The family history is a critical element in pediatric medicine and represents the gateway to the molecular age of medicine for both pediatric clinicians and their patients. The pediatric clinician has several opportunities to obtain a family history and multiple clinical and educational uses for that information. Available methods include paper and digital forms, classical pedigrees, online programs, and focused family history at the time of a new diagnosis or problem. Numerous barriers impede the application of family history information to primary pediatric practice. The most common barrier is the limited amount of time the typical primary care encounter allows for its collection. The family history can be used in many facets of pediatric practice: (1) as a diagnostic tool and guide to testing and evaluation; (2) to identify patterns of inheritance; and (3) as a patient-education tool. The most exciting future use of family history is as a tool for public health and preventive medicine. More accurately identifying children at risk for common chronic conditions such as diabetes, asthma, and cardiovascular disease could change the primary care clinician's approach to pediatric medicine.

The Maternal and Child Health Bureau commissioned the American College of Medical Genetics to outline a process of standardization of outcomes and guidelines for state newborn screening programs and to define responsibilities for collecting and evaluating outcome data, including a recommended uniform panel of conditions to include in state newborn screening programs. The expert panel identified 29 conditions for which screening should be mandated. An additional 25 conditions were identified because they are part of the differential diagnosis of a condition in the core panel, they are clinically significant and revealed with screening technology but lack an efficacious treatment, or they represent incidental findings for which there is potential clinical significance. The process of identification is described, and recommendations are provided.

The prevalence of Neisseria meningitidis carriage is highest in teenagers and lowest in young children. In contrast, invasive meningococcal disease is most common in young children with a smaller secondary peak in teenagers. Data on carriage and disease were analysed to quantify the risks of infection and disease by age and serogroup. The forces of infection for serogroups B, C, other meningococci and Neisseria lactamica were modelled together with the risk of disease given infection for serogroups B and C, using maximum likelihood to fit the models to the available data. The risk of meningococcal disease given infection declines steeply through childhood and is higher for serogroup C than for serogroup B. The secondary peak in disease in teenagers appears to be explained mostly by increased transmission although there is a suggestion that other factors may also contribute. These analyses provide important insights and may be used to guide further data collection and modelling studies.

Background: Although dentists are ideally placed to deliver smoking cessation advice and assistance to their patients, smoking cessation interventions are not often incorporated as a routine part of dental care. Research is needed to identify factors that facilitate and inhibit dentists' capacities to deliver smoking cessation advice. Methods: An initial focus group discussion was conducted in Melbourne with 10 dentists. Six Victorian country dentists were interviewed in depth by telephone. Following this qualitative data collection, a random sample of 250 dentists (response rate of 57 per cent) was interviewed by telephone. Dentists were asked about their perceived role, current practices, knowledge of resources and services and opinions on training in relation to smoking cessation. Results: Dentists are willing to ask and advise patients about smoking, but are less inclined to assist patients to quit or arrange follow-up. Dentists are more likely to implement one-off, opportunistic interventions rather than take a systematic preventive approach. Dentists are interested in attending further education and say they require training to be relevant to the context of their day-today running of the dental practice. Conclusions: Training should aim to legitimize the dentist's role in smoking cessation and provide strategies and resources so that dentists can practise interventions as part of their day-to-day work.

The incidence of invasive Haemophilus influenzae type b (Hib) disease in the UK fell rapidly following the introduction of routine vaccination in 1992 and the implementation of a catch-up campaign in children under 4 years old in 1992-93. However, since 1999 the number of cases of Hib has been increasing, and in 2002 there were 134 cases in 0-4 year olds (266 in all ages). While still much less than the prevaccine burden of disease (over 800 cases a year in 0-4 year olds), this increase in incidence is worrying and has sparked a range of detailed investigations. In February 2003, the Department of Health announced a second catch-up campaign offering all children between 6 months and 4 years a further dose of Hib vaccine. The epidemiology of Hib disease in England and Wales between 1990 and 2002 is reviewed here to provide a context for this public health response.

Longitudinal carriage studies of colonizing bacteria such as Neisseria meningitidis can provide important insights into the transmission dynamics of these organisms. Carriage is detected by culturing from a nasopharyngeal swab, but the sensitivity of this technique is low and varies between studies. This paper applies a statistical method for estimating the sensitivity of swabbing, infection rate, recovery rate and initial prevalence of carriage to three longitudinal carriage studies of N. meningitidis. These parameters and 95% confidence intervals were estimated using maximum likelihood techniques. The sensitivity of swabbing was estimated to be 60–83% and this should be taken into account when interpreting carriage studies. The estimates of force of infection and recovery rates seem to be consistent with estimates from more traditional methods. Differences in the parameter estimates between datasets may be due to differences in study design. This method could be used to assist in the design of future carriage studies.

The UK was the first country to introduce meningococcal serogroup C conjugate vaccination. The vaccine was incorporated into the routine infant immunisation schedule and was offered to all under 18 year olds in a catch-up campaign. The vaccine has been well accepted in infants receiving routine vaccination, with coverage around 89%. Coverage in older children targeted in the catch-up campaign was above 85% up to the age of 14, and was lowest (43%) in 15-17 year olds not in education. The winter of 2000-01 was the first meningococcal season following the offer of the vaccination to all children and adolescents. The incidence of serogroup C disease in the targeted age groups fell by 80%, and the number of deaths in laboratory confirmed cases in 0-19 year olds decreased from 78 to 8 between 1998-99 and 2000-01. The incidence of serogroup B disease in all age groups was slightly higher in 2000-01 than previous years, and there was an increase in the incidence of serogroup C disease in those aged over 20 during the study period, leading to the extension of the vaccination campaign to 20-24 year olds.

In 1999 a new conjugate vaccine for serogroup C meningococcal disease was licensed for use in the UK. In order for an appropriate vaccination strategy to be developed the burden of serogroup C disease in England and Wales needed to be established. This was done using data from an enhanced surveillance scheme alongside routine laboratory reports and a total of 5,052 cases of serogroup C disease in England and Wales between 1993 and 1998 were estimated. Among these, an estimated 398 died and 1,767 were admitted to intensive care units (ITUs). The greatest burden of disease was in young children and teenagers. The current literature identified four studies reporting sequelae following serogroup C meningococcal disease. These provided estimates of sequelae in the range of 6.5% and 45% and presented some evidence of higher levels than occur following serogroup B meningococcal disease. This information was provided to the Joint Committee on Vaccination and Immunisation to inform policy to implement a serogroup C conjugate vaccination programme in the UK. The vaccination programme has since been justified by the dramatic reduction in serogroup C meningococcal cases.

To compare the ocular comorbidities, visual outcomes, and surgical complications between a series of functionally monocular patients who had phacoemulsification and intraocular lens (IOL) implantation and a control group of age- and sex-matched binocular patients.Jules Stein Eye Institute and the Department of Ophthalmology, UCLA School of Medicine, Los Angeles, California, USA.The records of a consecutive series of 100 functionally monocular patients who had phacoemulsification and IOL implantation were reviewed. The records of a control group of binocularly sighted patients who were matched to the monocular patients by age, sex, and date of surgery were also reviewed.Thirteen patients in the monocular group were monocular because of surgical complications. The remaining patients (87%) were monocular from medical conditions. Monocular patients had significantly more ocular comorbidity than binocular control patients (P.0001). Age-related macular degeneration, diabetic retinopathy, and open-angle glaucoma were the most common reasons for monocular status and the most common ocular comorbidities in study eyes. The median preoperative best corrected visual acuity (BCVA) was 20/50 in the monocular group and 20/40 in the binocular group. The median postoperative BCVA was 20/25 and 20/20, respectively. A final BCVA of 20/40 or worse was the result of preexisting macular pathology or glaucoma in every instance. Surgical complications (P =.096) and the number of postoperative procedures (P =.724) were similar between the 2 groups.Ocular comorbidity was significantly more prevalent in the eyes of monocular patients. Monocular and binocular patients experienced a 3-line improvement in BCVA after cataract surgery; however, the final median acuity was 20/25 in the monocular group and 20/20 in the binocular group. The 2 groups had a similar complication rate.

The natural course of disease in multiple sclerosis varies. Multiple sclerosis that is clinically apparent but causes minimal disability over time has been labeled benign multiple sclerosis. The ability to predict the subsequent clinical course of multiple sclerosis on the basis of clinical and other supportive data at presentation would be invaluable. In this article we report our findings based on a retrospective analysis of 1800 patients diagnosed as having multiple sclerosis, of which 44 patients met our inclusion criteria. There was a suggestion that a low or absent number of oligoclonal bands in the cerebrospinal fluid at the time of diagnosis predicts a better prognosis. However, quantification of oligoclonal bands in cerebrospinal fluid remains an insensitive prognostic indicator and must not be used to influence decisions regarding therapeutic options.

Acute aphasia is rare in multiple sclerosis. We describe 3 patients with multiple sclerosis who had acute exacerbations presenting as aphasias. One patient had a mixed transcortical aphasia, 1 had a transcortical motor aphasia, and 1 had a Broca aphasia. Magnetic resonance imaging scans of the brain with contrast enhancement revealed new white matter lesions in the left hemisphere in all 3 patients. Two of the 3 patients had a good response to treatment with methylprednisolone sodium succinate. Arch Neurol. 2000;57:1207-1209

The proliferative response of mononuclear cells from MS patients and normal control subjects to intact and delipidated myelin membranes was examined. The mean frequency of recognition in both groups of human subjects was greater for delipidated myelin than for intact myelin. Human T cell lines established using intact or delipidated myelin as the antigen were highly heterogeneous in response, and were each able to recognize myelin basic protein and myelin proteolipid protein peptides. However, there was no difference in the frequency of recognition of either form of myelin membrane when MS patients were compared to control subjects. Our results suggest that the presentation of delipidated forms of membrane proteins might enhance the response to myelin antigens in vivo, and be relevant to demyelinating diseases.

We tested for serum antibodies to glycosaminoglycans (GAGs), including heparan sulfate, in patients with Guillain–Barre syndrome (GBS) and other disorders. We used ELISA methods that optimize immunoglobulin binding to carbohydrate antigens to measure serum antibodies to heparan sulfate GAGs in GBS, and control neuromuscular and immune disorders. We found serum IgM or IgG antibodies to heparan sulfate GAGs in 34% of patients with GBS. Serum IgM binding to heparan sulfate GAGs was also found in some chronic demyelinating polyneuropathies, with the highest frequency (33%) in patients with IgM anti-MAG M-proteins. Antibodies to heparan sulfate GAGs were rare (1%) in control serums from patients with other disorders. This result is the first demonstration of high titer serum antibodies to a specific antigen in a substantial group of, and with some specificity for, patients with the classically described GBS syndrome of acute-onset, motor–sensory polyneuropathy with demyelinating features.

Research into the pathogenesis of multiple sclerosis (MS) has focused on myelin antigens as potential targets of autoimmune attack. Proteolipid protein (PLP) is the most abundant myelin protein comprising more than 50% of central nervous system myelin. Although PLP is a hydrophobic membrane protein which has made it difficult to study, the use of synthetic peptides based on the PLP sequence provides an alternative method for studying the immunological properties of PLP. Using peripheral blood lymphocytes from MS patients, long-term TCL established in the presence of PLP reacted weakly to PLP in proliferation assays; however, these same lines were much more reactive to synthetic peptides of PLP. Thus, we established short-term T cell lines (TCL) from the peripheral blood lymphocytes (PBL) of MS patients in the presence of five separate synthetic PLP peptides. In 6/7 MS patients, proliferative responses were elicited most often to PLP 40-60 compared to four other PLP peptides (PLP 89-106, 103-120, 125-143, and 139-154) (Pelfrey et al., 1993). Interestingly, however, the magnitude of the proliferative response was greatest in response to PLP 89-106. Characterization of PLP 89-106-responsive TCL from several MS patients, indicated that TCL proliferating to the peptide also lysed PLP 89-106 pulsed autologous targets. The majority of cytolytic PLP 89-106 TCL were CD4+ and MHC class II restricted and the predominant restriction elements were those most commonly found in MS patients. These findings suggest that the use of synthetic peptides represents a viable alternative approach to the study of PLP reactivity in humans. We report here that MS PBL recognize several PLP peptides, with the predominant responses to PLP 40-60 and PLP 89-106. Since these cells have both helper (CD4+) and cytolytic capabilities, it is possible that they may play a role in the pathogenesis or progression of MS.

The lymphokine production of two T-cell clones, which both recognize epitopes within the encephalitogenic 139–151 sequence of myelin proteolipid protein, was examined after stimulation with immobilized antibodies to the CD3 moiety of the T-cell-receptor complex. Clone A1 produced interleukin (IL)-2 and interferon (IFN)-γ, but no IL-4, while clone D5 produced IL-4, but no IL-2 or IFN-γ. A1 therefore belongs to the T-helper type 1 (Th1) subset, while D5 is a Th2 clone. In addition, the Th1 clone induced severe experimental allergic encephalomyelitis (EAE), while the Th2 clone did not induce any signs of EAE. Synthetic peptides were used to demonstrate that these clones recognized slightly different epitopes within the 139–151 sequence. Histidine 139 was shown to be optimal for the stimulation of the Th2 clone, while the presence of this residue inhibited the stimulation of the Th1 clone. Th2 cells specific for an encephalitogenic peptide may be important in the regulation of encephalitogenic Th1 cells.

Research into the pathogenesis of multiple sclerosis (MS) has focused on myelin antigens as potential targets of autoimmune attack. Proteolipid protein (PLP), which makes up more than 50% of central nervous system myelin, is a hydrophobic membrane protein with many properties that historically have made it difficult to study. The use of synthetic peptides based on the PLP sequence provides an alternative method for studying the immunological properties of PLP. Using peripheral blood lymphocytes from MS patients, long-term TCL established in the presence of PLP reacted weakly to PLP in proliferation assays; however, these same lines were much more reactive to synthetic peptides of PLP. Thus, we established short-term T cell lines (TCL) from the peripheral blood lymphocytes (PBL) of MS patients in the presence of five separate synthetic PLP peptides. In six out of seven MS patients, proliferative responses were elicited most often to PLP 40-60 compared to four other PLP peptides (PLP 89-106, 103-120, 125-143, and 139-154). Characterization of PLP 40-60-responsive TCL from a single MS patient, MS1, indicated that six out of seven TCL proliferating to the peptide also lysed PLP 40-60 pulsed autologous targets. All cytolytic PLP 40-60 TCL were CD4+ and MHC class II restricted and further analysis of MS1 TCL showed that the PLP 40-60 TCL were restricted by DR4 whereas the MBP TCL from MS1 were restricted by DR6. These findings suggest that difficulties in examining the immune response to PLP have been due to the poor response generated in vitro using the whole molecule and that the use of synthetic peptides may represent an alternative approach to the study of PLP. These results also suggest that MS PBL recognize several PLP peptides, with the predominant response to PLP 40-60. Since these cells phenotypically resemble T cells known to mediate experimental autoimmune encephalomyelitis, it is possible that they may play a role in the pathogenesis of MS.

Although chronic inflammatory demyelinating polyneuropathy (CIDP) is presumed to be an autoimmune disorder, no neural antigen has been recognized as an immune target. We found that serum IgM from a patient with CIDP and an IgM paraprotein reacted with a 53-kd protein by Western blot analysis. Amino acid sequence analysis identified this protein as beta-tubulin. We then studied sera from 70 CIDP patients, 35 Guillain-Barre syndrome (GBS) patients, and 483 disease (amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, diabetes, and other polyneuropathies) and normal controls for selective high-titer anti-beta-tubulin using ELISA methodology. Forty-two percent (30/70) of patients with CIDP had selective high titer IgM reactivity against beta-tubulin; 23% (16/70) had selective high-titer IgG reactivity against beta-tubulin. Overall, 57% of CIDP patients, 20% of GBS patients, and 2% of control patients had selective, high serum IgM or IgG anti-beta-tubulin reactivity. Selective high-titer serum anti-beta-tubulin antibodies occur in a majority of patients with CIDP but are rare in other chronic neuropathies or CNS disorders.

We performed a longitudinal analysis of serum interleukin-2 (IL-2) and soluble IL-2 (sIL-2R) concentrations in 60 patients with relapsing-remitting (R-R) multiple sclerosis (MS) as well as in 33 age- and sex-matched normal controls. Overall, we found that serum IL-2 levels remained low (less than 10 U/ml) and did not change appreciably over time; however, marked fluctuations in sIL-2R levels were observed in both the patient and control groups. Using patients as their own controls, we calculated an interrelapse (disease stable) mean sIL-2R concentration as a baseline for comparison with relapse values; sIL-2R levels greater than the 90th percentile of the Student's t distribution of stable values were defined as "peaks." There were a total of 27 sIL-2R peaks, eight (30%) of which correlated with clinical relapses but were potentially predictive of only 18% (8/45) of all the recorded clinical relapses. There was no difference in disease severity (Expanded Disability Status Scale) score between peak-correlated and noncorrelated relapses. Our data suggest that despite reports of elevated levels of IL-2 and sIL-2R in MS, neither may be a useful marker for predicting clinical disease activity in R-R MS.

Serum levels of immunoreactive interleukin-2 (IL-2) were determined at monthly intervals from a group of placebo- and drug-treated chronic progressive multiple sclerosis patients before and during a cyclosporine A therapeutic trial. Significantly elevated levels of the lymphokine in active patients confirmed earlier studies. The magnitude of the initial levels varied inversely with the duration of disease and predicted subsequent worsening in chronic progressive patients. In addition, the occurrence of periodic bursts of serum IL-2 was noted. Although in some patients there appeared to be a sudden drop in serum IL-2 levels with the onset of cyclosporine A medication, no effect of this drug was noted on group analysis.

We studied a series of 64 patients with sensory +/- motor peripheral neuropathies by comparing clinical and physiologic features to serum antibody reactivity against compounds containing sulfated carbohydrate moieties. We determined antibody reactivity by an enzyme-linked immunosorbent assay (ELISA) using purified glycolipids and glycoproteins as antigens, and we used high-performance thin-layer chromatography and Western blotting to test the specificity of results. Twelve patients with high titers of IgM antibodies directed against the myelin-associated glycoprotein (MAG) had sensory-motor polyneuropathies with physiologic evidence of demyelination. IgM antibody reactivity to MAG was associated with an IgM serum M protein in five patients. Eight other patients, most with sensory greater than motor polyneuropathies, had high titers of antibody reactivity to sulfatide but not of IgM to MAG. Two had an associated IgM paraprotein. None of the patients with selective serum antisulfatide activity had predominantly demyelinating features on physiologic testing. We conclude that (1) high ELISA titers of antibodies to MAG may be more common than previously suspected in patients with chronic demyelinating sensory-motor neuropathies, and (2) the presence of high titers of antisulfatide antibodies in serum may provide clues to the pathogenesis of otherwise idiopathic, axonal, predominantly sensory neuropathies.

A retrospective analysis of quantitative and qualitative immunoglobulin G (IgG) results from 253 children who were either medically and neurologically normal or highly unlikely to have abnormalities of CSF IgG is reported. Normal values in this reference population vary with age for CSF/albumin IgG ratio and CSF/serum IgG index and are significantly different from the adult reference values. The rate of false positivity is lower for quantitative values than for qualitative IgG determinations (oligoclonal bands).

Studies were performed on lymphocytes from patients with multiple sclerosis before and after thymectomy (group I) and before and after thymectomy and azathioprine therapy (group II), and from matched control patients with multiple sclerosis, control patients with other neurological diseases, and healthy control subjects. Following treatment the percentage of T gamma cells in both group I and group II patients decreased from above the mean normal control levels to below this level; OKT8+ cell numbers in group I became lower than in any of the control groups; the percentage of concanavalin A-induced suppressor activity, which was initially normal, fell in group II and suggestively but not significantly in group I; and total blood lymphocytes in group I decreased from normal to below control levels. Other tests showed no significant changes with therapy. No significant difference in changes in clinical status were observed after one year in the treated patients compared with matched controls.

• We reviewed 317 patients with multiple sclerosis (MS) and found that the incidence of clinically significant pain, excluding headache and paresthesia, was 28.8%. Successful treatment requires recognition of the pathophysiology of the pain syndromes encountered in MS. Antidepressant drugs have been of particular value in the treatment of chronic pain in these patients.