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Background: The adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD) in ≥60-years-olds over 1 RSV season. We evaluated efficacy and safety of 1 RSVPreF3 OA dose and of 2 RSVPreF3 OA doses given 1 year apart against RSV-LRTD over 2 RSV seasons post-dose 1., Methods: In this phase 3, blinded trial, ≥60-year-olds were randomized (1:1) to receive RSVPreF3 OA or placebo pre-season 1. RSVPreF3 OA recipients were re-randomized (1:1) to receive a second RSVPreF3 OA dose (RSV_revaccination group) or placebo (RSV_1dose group) pre-season 2; participants who received placebo pre-season 1 received placebo pre-season 2 (placebo group). Efficacy of both vaccine regimens against RSV-LRTD was evaluated over 2 seasons combined (confirmatory secondary objective, success criterion: lower limits of 2-sided CIs around efficacy estimates >20%)., Results: The efficacy analysis comprised 24 967 participants (RSV_1dose: 6227; RSV_revaccination: 6242; placebo: 12 498). Median efficacy follow-up was 17.8 months. Efficacy over 2 seasons of 1 RSVPreF3 OA dose was 67.2% (97.5% CI: 48.2-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.6-92.0%) against severe RSV-LRTD. Efficacy over 2 seasons of a first dose followed by revaccination was 67.1% (97.5% CI: 48.1-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.5-92.0%) against severe RSV-LRTD. Reactogenicity/safety of the revaccination dose were similar to dose 1., Conclusions: One RSVPreF3 OA dose was efficacious against RSV-LRTD over 2 RSV seasons in ≥60-year-olds. Revaccination 1 year post-dose 1 was well tolerated but did not seem to provide additional efficacy benefit in the overall study population., Clinical Trials Registration: ClinicalTrials.gov: NCT04886596., Competing Interests: Potential conflicts of interest . M. G. I. declares that research support from GSK was paid to his previous institution, Northwestern University; he received consulting fees from Adagio Therapeutics, ADMA Biologics, Adamis Pharmaceuticals, AlloVir, Atea, Cidara Therapeutics, Genentech/Roche, Janssen, Shionogi, Takeda, Talaris, and Eurofins Viracor; and payment for participating in data safety monitoring boards or advisory boards from Adamis Pharmaceuticals, AlloVir, National Institutes of Health, CSL Behring, Janssen, Merck, Seqirus, Takeda, and Talaris; all of these ended in December 2022; M. G. I. also receives author royalties from UpToDate, which is ongoing, and serves as Chair of the International Society for Influenza and other Respiratory Virus Diseases Antiviral Group and was Editor-in-Chief of Transplant Infectious Disease. A. P. declares funding from GSK for conducting the trial. A. P. also declares that his institution received grants from Chiesi, AstraZeneca, GSK, Sanofi, and Agenzia Italiana del Farmaco; that he received consulting fees from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Avillion, and ELPEN Pharmaceuticals; payment for participation in advisory boards from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, IQVIA, Avillion, and ELPEN Pharmaceuticals; and honoraria from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharmaceuticals, IQVIA, Avillion, and ELPEN Pharmaceuticals. R. G. F. declares having received payment from GSK for lectures and support for travel related to these activities. J. M. L. reports grants from GSK paid to her institution for the conduct of the trial and from GSK, Pfizer, Merck, Moderna, Sanofi, Inventprise, and VBI Vaccines for other trials; J. M. L. also reports being a board member of Seqirus and participating on a data safety monitoring board or advisory board for Vaxcyte; she is an expert panelist for Canada's Drug and Health Technology Agency for the review of nirsevimab. I. L.-R. declares that her institution received funding from GSK for conducting this trial; from Icosavax, Virometix, Janssen Vaccines, Curevac, Moderna, Osivax, MSD, ICON Genetics, and OSE Immunotherapeutics for other vaccine trials; from Janssen Vaccines and MSD for consulting services; and from Janssen Vaccines for participation on a data safety monitoring board or advisory board. F. M.-T. declares that his institution received payment from GSK for conducting this trial and from Ablynx, Abbott, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, Medimmune, Novavax, Novartis, and GSK for other vaccine trials; F. M.-T. also reports receiving honoraria for lectures from Sanofi, MSD, Moderna, GSK, Biofabri, AstraZeneca, Novavax, Janssen, and Pfizer; payment of travel expenses and meeting fees from Pfizer, MSD, GSK, and Sanofi; and participation on data safety monitoring boards or advisory boards for Pfizer and Biofabri; F. M.-T. is also a member of the World Health Organization’s (WHO's) European Technical Advisory Group of Experts, coordinator of the Spanish Pediatric Clinical Trials Network, and coordinator of the WHO Collaborating Center for Vaccine Safety of Santiago de Compostela. T. F. S. reports honoraria and/or participation on data safety monitoring boards or advisory boards from Alexion, AstraZeneca, Bavarian Nordic, Biogen, Biontech, GSK, Janssen-Cilag, Merck-Serono, Moderna, MSD, Novavax, Pfizer, Roche, Sanofi-Aventis, Seqirus, Synlab, Takeda, and va-Q-tec. R. N. v. Z.-S. reports that his institution received support from Boehringer Ingelheim for the Interstitial Lung Diseases (ILD) registry and that he received consulting fees from GSK and honoraria for lectures from Glenmark, Boehringer Ingelheim, Cipla, and Novartis; R. N. v. Z.-S. also participated on data safety monitoring boards or advisory boards for OnQ SA; he is president of the South African Thoracic Society and co-chair of the International Health Committee of the American Thoracic Society. C. V., N. D., O. G., L. F., M.-P. D., L. K., V. H., A. O., M. V. d. W., and D. D. are employed by GSK and have stock options or shares from GSK. N. D. is co-applicant on a pending patent for vaccination against RSV and has stock options from Haleon. L. F., M.-P. D., A. O., and M. V. d. W. are co-applicants on a pending patent filed by GSK. The other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Older adults with chronic cardiorespiratory or endocrine/metabolic conditions are at increased risk of respiratory syncytial virus (RSV)-related acute respiratory illness (RSV-ARI) and severe respiratory disease. In an ongoing, randomized, placebo-controlled, multicountry, phase 3 trial in ≥60-year-old participants, an AS01E-adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD), severe RSV-LRTD, and RSV-ARI. We evaluated efficacy and immunogenicity among participants with coexisting cardiorespiratory or endocrine/metabolic conditions that increase the risk of severe RSV disease ("conditions of interest")., Methods: Medically stable ≥60-year-old participants received 1 dose of RSVPreF3 OA or placebo. Efficacy against first RSV-LRTD and RSV-ARI episodes was assessed in subgroups with/without coexisting cardiorespiratory or endocrine/metabolic conditions of interest. Immunogenicity was analyzed post hoc in these subgroups., Results: In total, 12 467 participants received RSVPreF3 OA and 12 499 received placebo. Of these, 39.6% (RSVPreF3 OA) and 38.9% (placebo) had ≥1 coexisting condition of interest. The median efficacy follow-up was 6.7 months. Efficacy against RSV-LRTD was high in participants with ≥1 condition of interest (94.6%), ≥1 cardiorespiratory (92.1%), ≥1 endocrine/metabolic (100%), and ≥2 conditions of interest (92.0%). Efficacy against RSV-ARI was 81.0% in participants with ≥1 condition of interest (88.1% for cardiorespiratory, 79.4% for endocrine/metabolic conditions) and 88.0% in participants with ≥2 conditions of interest. Postvaccination neutralizing titers were at least as high in participants with ≥1 condition of interest as in those without., Conclusions: RSVPreF3 OA was efficacious against RSV-LRTD and RSV-ARI in older adults with coexisting medical conditions associated with an increased risk of severe RSV disease., Clinical Trials Registration: ClinicalTrials.gov: NCT04886596., Competing Interests: Potential conflicts of interest. R. G. F. declares having received payment from GSK as a speaker for promotional programs and support for travel related to these activities. R. A. I. declares that his institution received a grant from GSK for conducting the trial. K. S. declares that her institution received funding from GSK for conducting the trial and that she is a member of the independent data monitoring committee for the AReSVi-006 trial (without receiving payment). D. G. L. and A. P. declare funding from GSK for conducting the trial. A. P. declares that his institution received grants from Chiesi, AstraZeneca, GSK, Sanofi, and Agenzia Italiana del Farmaco; that he received consulting fees from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Avillion, and ELPEN Pharmaceuticals; payment for participation in data safety monitoring boards or advisory boards from Chiesi, AstraZeneca, GSK, MSD, Novartis, Sanofi, IQVIA, Avillion, and ELPEN Pharmaceuticals; and honoraria from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharmaceuticals, IQVIA, Avillion, and ELPEN Pharmaceuticals. M. G. I. declares that his institution received funding from GSK for RSV vaccine trials; he also received author royalties from UpToDate, consulting fees from Adagio Therapeutics, ADMA Biologics, AlloVir, Atea, Cidara Therapeutics, Genentech/Roche, Janssen, Shionogi, Takeda, and Eurofins Viracor, and payment for participating in data safety monitoring boards or advisory boards from Adamis Pharmaceuticals, AlloVir, CSL Behring, Janssen, Merck, Seqirus, Takeda, and Talaris. L. F., M. P. D., C. M., M. V. d. W., L. K., and V. H. are employed by GSK; L. F., M. P. D., C. M., M. V. d. W., V. H., and L. K. have stock options or shares from GSK. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Data on respiratory syncytial virus (RSV) disease burden in adults remain scarce. We assessed the burden of confirmed RSV-acute respiratory infections (cRSV-ARIs) in community-dwelling (CD) adults and those in long-term care facilities (LTCFs)., Methods: In this prospective cohort study covering 2 RSV seasons (October 2019-March 2020 and October 2020-June 2021), RSV-ARIs were identified through active surveillance, in medically stable CD-adults ≥50 years (Europe) or adults ≥65 years in LTCFs (Europe and the United States). RSV infection was confirmed by polymerase chain reaction from combined nasal and throat swabs., Results: Of 1981 adults enrolled, 1251 adults in CD and 664 LTCFs (season 1) and 1223 adults in CD and 494 LTCFs (season 2) were included in the analyses. During season 1, overall incidence rates ([IRs] cases/1000 person-years) and attack rates (ARs) for cRSV-ARIs were 37.25 (95% confidence interval [CI], 22.62-61.35) and 1.84% in adults in CD and 47.85 (CI, 22.58-101.4) and 2.26% in adults in LTCFs. Complications occurred for 17.4% (CD) and 13.3% (LTCFs) of cRSV-ARIs. One cRSV-ARI occurred in season 2 (IR = 2.91 [CI, 0.40-20.97]; AR = 0.20%), without complications. No cRSV-ARIs led to hospitalization or death. Viral pathogens were codetected in ≤17.4% of cRSV-ARIs., Conclusions: RSV is an important cause of disease burden in adults in CD and LTCFs. Despite the observed low severity of cRSV-ARI, our results support the need for RSV prevention strategies among adults ≥50 years old., Competing Interests: Potential conflicts of interest. RD, SD, J-YP, and DL are employees of the GSK group of companies. SD, J-YP, and DL hold shares in the GSK group of companies as part of their employee remuneration. JMRT declares lectures for Pfizer and attending meetings for GSK and Pfizer. IL-R declares funding from GSK, ICOSAVAX, and Virometix to her institution for conducting RSV clinical trials and participation on Janssen advisory boards for RSV vaccines. CV reports grant/research support from GSK to her institution for the conduct of the current study and is currently an employee of the GSK group of companies. KS, JSTB, and LLH declares research funding received by their institution from GSK. RGF declares lectures for GSK. SM works as a freelance consultant on behalf of the GSK group of companies. All other authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Life expectancy (LE) differences within and between states by race/ethnicity have not been examined., Objective: To estimate LE for selected race/ethnicity groups in states from 1990 to 2019., Design: Cross-sectional time-series analysis., Setting: United States., Participants: Deidentified death records and Census data were used to construct regression models with smoothed time series of mortality from 1990 to 2019., Measurements: LE at birth, by sex and year, for subgroups of people reporting Hispanic, non-Hispanic Black, or non-Hispanic White race/ethnicity., Results: Disparities in LE across states were 8.0 years for females and 12.2 years for males in 1990 and 7.9 years for females and 7.8 years for males in 2019. When race/ethnicity groups were accounted for, disparities across states were 20.7 years for females and 24.5 years for males in 1990, decreasing to 18.5 years for females and 23.7 years for males in 2019. Disparities across states increased within each race/ethnicity group between 1990 and 2019, with the largest increase for non-Hispanic White males and the smallest for Hispanic females. The disparity between race/ethnicity groups within states decreased for most of the 23 states with estimates for all 3 groups but increased for females in 7 states and males in 5 states., Limitation: Because of small sample size, LE was not estimated for 37 of 153 state-race/ethnicity groups., Conclusion: Disparity in LE across states was greater when race/ethnicity groups were considered. Disparities across all state-race/ethnicity groups in general have decreased over the past 3 decades. Within each race/ethnicity group, disparities across states have increased. Although racial/ethnic disparities decreased in most of the 23 states for which LE was estimated for all 3 groups, they increased for females in 7 states and males in 5 states., Primary Funding Source: National Heart, Lung, and Blood Institute.

Summary: In patients in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study with and without a prior vertebral or hip fracture, the incidence of nonvertebral fractures was lower with >6 months of teriparatide treatment than during the first 6 months., Introduction: Clinical evidence on the effect of teriparatide in patients with prior fracture is limited. In the DANCE observational study, the incidence of nonvertebral fragility fractures (NVFX) decreased significantly in patients receiving teriparatide for >6 months (6-24 months) versus >0 to ≤6 months (reference period)., Methods: We performed a post hoc analysis to assess the effect of teriparatide 20 μg/day in patients who entered DANCE with prior vertebral or hip fractures. The incidence of patients experiencing a NVFX for four 6-month intervals during and after treatment was compared with the reference period., Results: Overall, 4085 patients received ≥1 dose of teriparatide. Of 3720 with sufficient data for efficacy analysis, 692 had prior vertebral fracture, including 179 with previous kyphoplasty/vertebroplasty; 290 had prior hip fracture. These patients were older, and those with prior vertebral fractures had more comorbid conditions at baseline than those without prior vertebral fractures. The incidence of patients experiencing NVFX declined over time in all patient groups. The fracture incidence rate declined 49 and 46%, respectively, in patients with and without prior vertebral fracture and was 63 and 46% lower in patients with previous kyphoplasty/vertebroplasty and without prior vertebral fracture. NVFX declined 43 and 48% in patients with and without prior hip fracture. The reduced incidence over time was consistent in the subgroups (all interaction p values >0.05). Patients with prior fracture were more likely to experience serious adverse events., Conclusion: The incidence of NVFX decreased over time in patients receiving teriparatide in DANCE regardless of prior fracture status.

Objectives: A history of prior fracture is one of the strongest predictors of a future fragility fracture. In FREEDOM, denosumab significantly reduced the risk of new vertebral, non-vertebral, and hip fractures. We carried out a post-hoc analysis of FREEDOM to characterize the efficacy of denosumab in preventing secondary fragility fractures in subjects with a prior fracture., Methods: A total of 7808 women aged 60-90 years with a bone mineral density T-score of less than - 2.5 but not less than - 4.0 at either the lumbar spine or total hip were randomized to subcutaneous denosumab 60 mg or placebo every 6 months for 36 months. The anti-fracture efficacy of denosumab was analyzed by prior fracture status, to assess secondary fragility fracture, and by subject age, prior fracture site and history of prior osteoporosis medication use., Results: A prior fragility fracture was reported for 45% of the overall study population. Compared with placebo, denosumab significantly reduced the risk of a secondary fragility fracture by 39% (incidence, 17.3% vs. 10.5%; p < 0.0001). Similar results were observed regardless of age or prior fracture site. In the overall population, denosumab significantly reduced the risk of a fragility fracture by 40% (13.3% vs. 8.0%; p < 0.0001), with similar results observed regardless of history of prior osteoporotic medication use., Conclusions: Denosumab reduced the risk of fragility fractures to a similar degree in all risk subgroups examined, including those with prior fragility fractures. Identifying and treating high-risk individuals could help to close the current care gap in secondary fracture prevention.

An earlier age at onset of Parkinson's disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopathic PD was assessed by looking at age at disease onset. The effects of heritable genetic risk factors, which may also influence age at onset, was minimized by including only sporadic cases of PD with no family history of the disease (n=58). Independent samples Student t-test revealed that subjects with occupational exposure to metals and/or pesticides (n=36) were significantly (p=0.013) younger than unexposed controls (n=22). These subjects were then divided into three groups [high (n=18), low (n=18), and unexposed (n=22)] to ascertain if duration of exposure further influenced age at onset of PD. One-way ANOVA revealed that subjects in the high exposure group were significantly (p=0.0121) younger (mean age: 50.33 years) than unexposed subjects (mean age: 60.45 years). Subjects were also stratified by exposure type (metals vs. pesticides). These results suggest that chronic exposure to metals and pesticides is associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect.

We describe a new antifouling surface coating, based on aggregation of a short amphiphilic four-armed PEG-dopamine polymer into particles and on surface binding by catechol chemistry. An unbroken and smooth polymeric coating layer with an average thickness of approximately 4 μm was formed on top of titanium oxide surfaces by a single step reaction. Coatings conferred excellent resistance to protein adhesion. Cell attachment was completely prevented for at least eight weeks, although the membranes themselves did not appear to be intrinsically cytotoxic. When linear PEG or four-armed PEG of higher molecular weight were used, the resulting coatings were inferior in thickness and in preventing protein adhesion. This coating method has potential applicability for biomedical devices susceptible to fouling after implantation.

In the estrogen-regulated RANK ligand (RANKL)/RANK/osteoprotegerin (OPG) pathway, estrogen deficiency favors osteoclast maturation, leading to increased bone resorption compared with bone formation. Treatment of low bone mineral density (BMD) should be based on fracture risk, assessed using the WHO Fracture Risk Algorithm (FRAX(R)). Criteria for treatment are 10-year overall fracture risk ≥ 20% or 10-year hip fracture risk ≥ 3%. Vitamin D supplementation at levels higher than those traditionally recommended may be appropriate for healthy menopausal women. Multiple strategies are needed to effectively manage osteoporosis in postmenopausal women.

Biomaterial-associated infection (BAI) is a major problem in modern medicine, and is often caused by Staphylococcus epidermidis. We aimed to raise monoclonal antibodies (mAbs) against major surface protein antigens of S. epidermidis, and to assess their possible protective activity in experimental BAI. Mice were vaccinated with a cell wall protein preparation of S. epidermidis. A highly immunodominant antigen was identified as Accumulation-associated protein (Aap). mAbs against Aap and against surface-exposed lipoteichoic acid (LTA) were used for passive immunization of mice in experimental biomaterial-associated infection. Neither anti-Aap nor anti-LTA mAbs showed protection. Either with or without antibodies, tissue surrounding the implants was more often culture positive than the implants themselves, but bacterial adherence to the implants was significantly increased in mice injected with anti-LTA. In vitro, anti-Aap and anti-LTA did show binding to S. epidermidis, but no opsonic activity was observed. We conclude that antibodies against S. epidermidis LTA or Aap showed no opsonic activity and did not protect mice against BAI. Moreover, the increase in binding to implanted biomaterial suggests that passive immunization may increase the risk for BAI.

Objective: To determine functionality and acceptability of a new teriparatide (Forteo, Eli Lilly and Company, Indianapolis, IN, USA) delivery device by patients with osteoporosis., Research Design and Methods: This was an eight week, single-arm, multicenter, open-label clinical trial. Patients received teriparatide 20 microg/day by subcutaneous injection using a new delivery device. Men and postmenopausal women with osteoporosis at high risk for fracture were stratified to Current User (n = 92) or Not Current User (n = 107) groups. Current Users had used the original delivery device for > or =8 weeks, including uninterrupted use for four weeks before enrollment., Clinical Trial Registration: ClinicalTrials.gov, NCT00577863., Main Outcome Measures: The primary objective was to detect common complaints (> or =3% for all patients) regarding the functionality and acceptability of the new device. Complaints were categorized as functional (e.g., malfunction), nonfunctional (e.g., size), or user manual. Secondary objectives included questionnaire assessment of preference of the new versus original device, features of the new delivery device, and analysis of adverse events., Results: A total of 31 patients (16%) reported 47 complaints (four functional, 27 nonfunctional, and 16 user manual). There were two common complaints: device size (4.0%) and lack of information on alcohol swabs (3.5%). Overall, patients agreed that the new device was easy to use (99.5%), easy to learn to use (99%), easy to attach a needle (97%), easy to hold while injecting (95%), and that it reduced their reluctance to take injections (90%). Most Current Users (92%) preferred the new delivery device over the original device. Adverse events reported by > or =2% of patients were upper respiratory infection (3.5%), urinary tract infection (2%), influenza (2%), and headache (2%). Limitations include the one-arm study design and the short (eight week) duration of the study., Conclusions: Patients found the new teriparatide delivery device easy to use and Current Users preferred the new delivery device over the original device.

Biomaterial-associated infections (BAI), which are predominantly caused by Staphylococcus epidermidis, are a significant problem in modern medicine. Biofilm formation is considered the pivotal element in the pathogenesis, but in previous mouse studies we retrieved S. epidermidis from peri-implant tissue. To assess the kinetics and generality of tissue colonization, we investigated BAI using two S. epidermidis strains, two biomaterials, and two mouse strains. With small inocula all implants were culture negative, whereas surrounding tissues were positive. When higher doses were used, tissues were culture positive more often than implants, with higher numbers of CFU. This was true for the different biomaterials tested, for both S. epidermidis strains, at different times, and for both mouse strains. S. epidermidis colocalized with host cells at a distance that was >10 cell layers from the biomaterial-tissue interface. We concluded that in mouse experimental BAI S. epidermidis peri-implant tissue colonization is more important than biofilm formation.

A large number of bacterial species have been identified in fetal membranes after preterm labour (PTL) associated with intrauterine infection by microbiological culture. In this study, we have investigated a molecular and bioinformatic approach to organism identification which surmounts the need for specific and diverse microbiological culture conditions required by conventional methods. Samples of fetal membranes were taken from 37 preterm infants, and 6 normal term controls delivered by caesarean section, in which bacteria had been detected by in situ hybridization of 16S ribosomal RNA using a generic probe. Degenerate primers were designed to amplify bacterial 16S ribosomal DNA by PCR and used to amplify bacterial DNA from human fetal membranes. Amplicons were cloned, sequenced and bacteria were identified bioinformatically by comparison of sequences with known bacterial DNA genomes. In situ hybridization using an organism specific probe was then used to confirm the presence of the commonest identified organism in tissue samples. Bacterial DNA amplified from 15/43 samples, all from preterm deliveries, and the bioinformatic approach identified organisms in all cases. Multiple bacteria were identified including Mycoplasma hominis, Pasturella multocida, Pseudomonas PH1, Escherichia coli and Prevotella bivia. The commonest organism Fusobacterium nucleatum was found in 9/15 (60%) of samples. Ten of the 12 samples obtained after prolonged membrane rupture were positive for bacterial DNA, and 7 of these (70%) contained DNA from F. nucleatum. Bacteria from fetal membranes may be identified by molecular and bioinformatic methods. Further work is warranted to investigate the apparent linkage between F. nucleatum, fetal membrane rupture and preterm delivery.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study., ((c) 2005 Movement Disorder Society.)

Objective: To investigate the effects of a physical therapy (PT) program in groups of people with Parkinson's disease (PD)., Design: Randomized controlled trial with a crossover design., Setting: Two outpatient rehabilitation clinics in Boston and Amsterdam, respectively., Participants: Sixty-eight subjects diagnosed with typical, idiopathic PD, Hoehn and Yahr stage II or III, and stable medication use., Intervention: Group A received PT and medication therapy (MT) for the first 6 weeks, followed by MT only for the second 6 weeks. Group B received only MT for the first 6 weeks and PT and MT for the second 6 weeks., Main Outcome Measures: The Sickness Impact Profile (SIP-68), the mobility portion of the SIP-68, the Unified Parkinson's Disease Rating Scale (UPDRS), and comfortable walking speed (CWS) at baseline, 6-week, 12-week, and 3-month follow-up., Results: At 6 weeks, differences between groups were significant for the SIP mobility ( P =.015; effect size [ES]=.55), for CWS ( P =.012; ES=.49), for the activities of daily living (ADL) section of the UPDRS ( P =.014; ES=.45), and for the total UPDRS ( P =.007; ES=.56). The total SIP and the mentation and motor sections of the UPDRS did not differ significantly between groups. Significant differences were found at 3 months compared with baseline for CWS, the UPDRS ADL, and total scores., Conclusions: People with PD derive benefits in the short term from PT group treatment, in addition to their MT, for quality of life related to mobility, CWS, and ADLs; long-term benefits were found in CWS, UPDRS ADL, and total scores but varied between groups.

Streptococcus agalactiae (Group B streptococcus) is an important cause of disease in infants, pregnant women, the elderly and in immunosuppressed adults. An effective vaccine is likely to prevent the majority of infant disease (both early and late onset), as well as Group B streptococcus-related stillbirths and prematurity, to avoid the current real and theoretical limitations of intrapartum antibiotic prophylaxis, and to be cost effective. The optimal time to administer such a vaccine would be in the third trimester of pregnancy. The main limitations on the production of a Group B streptococcus vaccine are not technical or scientific, but regulatory and legal. A number of candidates including capsular conjugate vaccines using traditional carrier proteins such as tetanus toxoid and mutant diphtheria toxin CRM197, as well as Group B streptococcus-specific proteins such as C5a peptidase, protein vaccines using one or more Group B streptococcus surface proteins and mucosal vaccines, have the potential to be successful vaccines. The capsular conjugate vaccines using tetanus and CRM197 carrier proteins are the most advanced candidates, having already completed Phase II human studies including use in the target population of pregnant women (tetanus toxoid conjugate), however, no definitive protein conjugates have yet been trialed. However, unless the regulatory environment is changed specifically to allow the development of a Group B streptococcus vaccine, it is unlikely that one will ever reach the market.

Intrauterine infection has been frequently linked with preterm labor before 30 wk of human pregnancy. Many different species of organisms have been detected, leading to the suggestion that infection-induced preterm labor is a generic inflammatory response to organisms rather than a specific response to a limited number of pathogens. The detection of organisms by microbiological culture is a laborious and unreliable process, so the aim of this study was to harness modern molecular techniques to detect organisms in tissues from human pregnancy. A DNA probe specific for conserved regions of bacterial 16S ribosomal RNA sequence was designed and labeled with fluorescein for fluorescence in situ hybridization. Organisms were detected in the great majority (>80%) of fetal membranes after prolonged premature rupture of the fetal membranes and after preterm labor, which was consistent with previous data. Organisms were also detected in fetal membranes after preterm delivery without labor and in term deliveries (with or without labour). Inflammatory cells were found frequently in the amnion or chorion of preterm fetal membranes but not in term tissues. Our primary finding is that fluorescence in situ hybridization is an appropriate method to detect organisms in human fetal membranes. In addition, our data show that bacteria may be present in fetal membranes without necessarily causing an inflammatory response, so the mere presence of bacteria may not be sufficient to cause preterm labor.

Objective: To identify a haplotype influencing onset age for Parkinson's disease (PD) in the PARK3 region on chromosome 2p13., Methods: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families., Results: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP-rs2421095, rs1876487, rs1561244-revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005)., Conclusions: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Using an alkaline phosphatase-based genetic screening method, we identified a number of proteins that are potentially located on the outer surface of Group B streptococcus (Streptococcus agalactiae). In an enzyme-linked immunosorbent assay, antisera raised against two of the proteins, the streptococcal yutD homologue and a subunit of an ABC transporter, recognised clinically important serotypes of Group B streptococcus. In a neonatal rat model, purified IgG from the sera conferred significant levels of protection against a lethal challenge infection. The proteins identified show potential as protein subunit candidates for vaccines against Group B streptococcal disease in neonates.

The attenuation and immunogenicity of two novel Salmonella vaccine strains, Salmonella enterica serovar Typhi (Ty2 Delta aroC Delta ssaV, designated ZH9) and S. enterica serovar Typhimurium (TML Delta aroC Delta ssaV, designated WT05), were evaluated after their oral administration to volunteers as single escalating doses of 10(7), 10(8), or 10(9) CFU. ZH9 was well tolerated, not detected in blood, nor persistently excreted in stool. Six of nine volunteers elicited anti-serovar Typhi lipopolysaccharide (LPS) immunoglobulin A (IgA) antibody-secreting cell (ASC) responses, with three of three vaccinees receiving 10(8) and two of three receiving 10(9) CFU which elicited high-titer LPS-specific serum IgG. WT05 was also well tolerated with no diarrhea, although the administration of 10(8) and 10(9) CFU resulted in shedding in stools for up to 23 days. Only volunteers immunized with 10(9) CFU of WT05 mounted detectable serovar Typhimurium LPS-specific ASC responses and serum antibody responses were variable. These data indicate that mutations in type III secretion systems may provide a route to the development of live vaccines in humans and highlight significant differences in the potential use of serovars Typhimurium and Typhi.

Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.

The role of genetics in Parkinson disease (PD) continues to be an area of considerable interest and controversy. We collected information involving the nuclear families of 948 consecutively ascertained PD index cases from the University of Virginia (UVA) Health System, the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson (RWJ) School of Medicine, and Boston University (BU) School of Medicine. We performed a segregation analysis to assess evidence for the presence of a Mendelian pattern of familial transmission. The proportion of male (60.4%) and female (39.6%) cases, the mean age of onset (57.7 years), and the proportion of affected fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were similar across the three sites. While most of the index cases were male, modestly more of the reported affected relatives were female. These analyses support the presence of a rare major Mendelian gene for PD in both the age-of-onset and susceptibility model. The age-of-onset model provides evidence for a gene that influences age-dependent penetrance of PD, influencing age of onset rather than susceptibility. We also found evidence for a Mendelian gene influencing susceptibility to the disease. It is not evident whether these two analyses are modeling the same gene or different genes with different effects on PD. The finding of significant genes influencing penetrance for PD raises the question of whether these may interact with environmental factors or other genes to increase the risk for PD. Such gene environment interactions, involving reduced penetrance in PD, may explain the low concordance rates among monozygotic twins for this disease., (Copyright 2002 Wiley-Liss, Inc.)

To identify the major outer surface proteins of Streptococcus agalactiae (group B streptococcus), a proteomic analysis was undertaken. An extract of the outer surface proteins was separated by two-dimensional electrophoresis. The visualized spots were identified through a combination of peptide sequencing and reverse genetic methodologies. Of the 30 major spots identified as S. agalactiae specific, 27 have been identified. Six of these proteins, previously unidentified in S. agalactiae, were sequenced and cloned. These were ornithine carbamoyltransferase, phosphoglycerate kinase, nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase, purine nucleoside phosphorylase, enolase, and glucose-6-phosphate isomerase. Using a gram-positive expression system, we have overexpressed two of these proteins in an in vitro system. These recombinant, purified proteins were used to raise antisera. The identification of these proteins as residing on the outer surface was confirmed by the ability of the antisera to react against whole, live bacteria. Further, in a neonatal-animal model system, we demonstrate that some of these sera are protective against lethal doses of bacteria. These studies demonstrate the successful application of proteomics as a technique for identifying vaccine candidates.

Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD., Methods: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed., Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%)., Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

It is well known that Abraham Lincoln took a medicine called "blue mass" or "blue pill," commonly prescribed in the 19th century. What is now hardly known is that the main ingredient of blue mass was finely dispersed elemental mercury. As his friends understood, mercury was often prescribed for melancholy or "hypochondriasis," a condition Lincoln famously endured. Mercury in the form of the blue pill is a potential neurotoxin, which we have demonstrated by recreating and testing the recipe. We present the testimony of many of Lincoln's contemporaries to suggest that Lincoln suffered the neurobehavioural consequences of mercury intoxication but, perhaps crucial to history, before the main years of his presidency; he was astute enough to recognize the effects and stop the medication soon after his inauguration.

Recent progress in microbial genome sequencing, along with functional genomics technologies based on gene expression, proteomics and genetics have facilitated the identification of significant numbers of Gram-positive virulence genes. These genes represent a novel and heterogeneous class of targets for antimicrobial drug development. This review will concentrate of the contribution of two functional genomics technologies, in vivo expression technology (IVET) based on gene expression and signature-tagged mutagenesis (STM), a genetics based technology to the identification of virulence genes in Gram-positive pathogens.

Coagulase negative staphylococci are the commonest blood culture isolate from infants on neonatal intensive care units. The differentiation of contaminants from isolates representing true infection remains a significant clinical problem. Data from two neonatal intensive care units were collected prospectively in order to find those parameters, which best correlated with actual sepsis. Each case was assessed using clinical parameters to categorise infants into infection and contaminant groups. Logistic regression was then performed to find significant correlates. Three correlates were found, namely the presence of a long line (P = 0.001), abnormal white cell count (P = 0.037) and abnormal white cell morphology (P = 0.027). Abnormal white cell morphology was assessed by two experienced hematologists. More than half the isolates were probable contaminants and true infection may occur in the absence of a long line in this patient group.

Signature-tagged mutagenesis is a functional genomics technique that identifies microbial genes required for infection within an animal host, or within host cells. The application of this technique to a range of microbial pathogens has resulted in the identification of novel virulence determinants in each screen performed to date, so that cumulatively several hundred genes have been ascribed a role in virulence.

Objective: To assess the safety and the effect on standardized clinical rating measures of transplanted embryonic porcine ventral mesencephalic (VM) tissue in advanced PD., Methods: Twelve patients with idiopathic PD underwent unilateral implantation of embryonic porcine VM tissue; six received cyclosporine immunosuppression and six received tissue treated with a monoclonal antibody directed against major histocompatibility complex class I. Patients were followed for 12 months and assessed by clinical examination, MRI, and 18F-levodopa PET. Porcine endogenous retrovirus testing was conducted by PCR-based method on peripheral blood mononuclear cells., Results: Cell implantation occurred without serious adverse events in all patients. Cultures were negative for bacterial and unknown viral contamination. No porcine endogenous retrovirus DNA sequences were found. MRI demonstrated cannula tracts within the putamen and caudate, with minimal or no edema and no mass effect at the transplant sites. In the medication-off state, total Unified Parkinson's Disease Rating Scale scores improved 19% (p = 0.01). Three patients improved over 30%. There were two patients with improved gait. 18F-levodopa PET failed to show changes on the transplanted side., Conclusions: Unilateral transplantation of porcine embryonic VM cells into PD patients was well tolerated with no evidence of transmission of porcine endogenous retrovirus. Changes in standardized clinical PD rating measures were variable, similar to the results of the first trials of unilateral human embryonic allografts that transplanted small amounts of tissue.

Controversy persists about the etiology of Parkinson's disease (PD). Pesticides, herbicides, well-water consumption, head injury, and a family history of PD have been reported as risk factors for PD. The purpose of this study was to (1) investigate the impact of environmental factors on PD risk (2) estimate the chronology, frequency, and duration of those exposures associated with PD; and (3) investigate the effects of family history on PD risk. One-hundred and forty PD cases were recruited from Boston University Medical Center. The control group was composed of 147 friends and in-laws of PD patients. Environmental, medical, and family history data were obtained by structured interview from each participant for events recalled prior to PD onset for cases, or corresponding censoring age for controls (mean age = 56 years of age for each group). A traditional stratified analysis, adjusting for birth cohort and sex, was employed. Four factors were associated with increased risk for PD: (1) head injury (OR=6.23, confidence interval [CI]: 2.58-15.07); (2) family history of PD (OR=6.08, CI: 2.35-15. 58); (3) family history of tremor (OR=3.97, CI: 1.17-13.50); and (4) history of depression (OR=3.01, CI: 1.32-6.88). A mean latency of 36. 5 (SE=2.81) years passed between the age of first reported head injury and PD onset. A mean latency of 22 (SE=2.66) years passed between the onset of the first reported symptoms of depression and onset of PD. Years of education, smoking, and well-water intake were inversely associated with PD risk. PD was not associated with exposure to pesticides or herbicides. These findings support the role of both environmental and genetic factors in the etiology in PD. The results are consistent with a multifactorial model. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:742-749, 1999., (Copyright 1999 Wiley-Liss, Inc.)

A new portable tremometer allows determination of tremor intensities at different tremor frequencies. Based on past studies, two tremor frequency windows of similar size were chosen at 3.0-6.5 Hz and 6.6-10.0 Hz to reflect major tremor intensities in Parkinson's disease and mercury vapor poisoning, respectively. In 81 healthy controls, total tremor intensity was higher for the preferred hand and depended on age. Ten patients treated for Parkinson's disease showed substantially increased tremor intensity, especially within the low-frequency window. This pattern was also apparent in 14 patients with de novo Parkinson's disease whose overall tremor intensity was only mildly elevated. In contrast, ten patients with essential tremor had peak frequencies in both windows, and some patients had increased tremor on one side only. Sixty-three Brazilian gold traders exposed to mercury vapor showed increased tremor predominantly in the high-frequency window. Three of the gold traders had a narrower tremor peak at frequencies of 7-8 Hz. While the urine-mercury concentration was significantly associated with the current number of burning sessions per week, it did not correlate with tremor intensities. However, eight traders had a urinary mercury excretion level above 50 microg and at the same time a greatly increased average tremor intensity within the high-frequency window. These patterns were statistically significant for relative tremor intensities, but were less clear when total intensities were used. These observations suggest that the relative distribution of tremor intensities in specific frequency bands may be a valuable supplement to current diagnostic methods for subjects with mercury vapor exposure.

The role of environmental and occupational exposures to neurotoxicants in the pathogenesis of neurodegenerative disease has not been fully elucidated. Recent published research on whether genetic polymorphisms contribute to individual susceptibility to develop neurodegenerative diseases such as Parkinson's disease have been equivocal at best. This review relates putative mechanisms of neurotoxicant-induced cell damage to polymorphisms in the genes that encode for the enzymes involved in the metabolism of neurotoxicants. The effects that genetically induced alterations in enzyme functioning have on neurotoxicant metabolism and how this relates to the risk of neurotoxic effects among exposed individuals are reviewed. A pragmatic approach to future research in the area of neurodegenerative disease is developed on the basis of the interrelationship between known routes of neurotoxicant metabolism and human genetics.

The reduction or loss of cytochrome P450 enzyme activity as a result of mutations in the CYP2D6 gene has been suggested as a risk factor for Parkinson's disease (PD). Conflicting results among reported studies of the prevalence of mutations among patients with PD suggested a more comprehensive genotyping and an analysis of the interactions with other suspected risk factors and family history. We determined the frequency of seven CYP2D6 mutations among 109 patients with PD and 110 control subjects. Family history of PD, age of onset, exposure to pesticides or herbicides, and well-water consumption were obtained for all cases. There was no significant difference in frequency between patients with PD and control subjects for any mutant allele and no significant association with family history, onset age, or environmental exposures. We sought to increase the power of our study by combining reports from the literature, choosing allele frequencies as the most informative measure. Although we found variability in reported allele frequencies for control subjects that made a meta-analysis problematic, summing all reports demonstrated no difference in CYP2D6 mutation frequency between patients with PD and control subjects. This comprehensive study of CYP2D6 mutations demonstrates that other genes or shared environmental exposures account for the familial risk of PD.

This paper describes symptoms and findings in a 57-year-old painter who had been exposed to various organic solvents for over 30 years. He began to work as a painter at 16 years of age, frequently working in poorly ventilated areas; he used solvents to remove paint from the skin of his arms and hands at the end of each work shift. The patient and his family noticed impaired short-term memory function and changes in affect in his early forties, which progressed until after he stopped working and was thus no longer exposed to paints and solvents. After the patient's exposures had ended, serial neuropsychological testing revealed persistent cognitive deficits without evidence of further progression, and improvement in some domains. Magnetic resonance imaging revealed global and symmetrical volume loss, involving more white than gray matter. The findings in this patient are consistent with chronic toxic encephalopathy and are differentiated from other dementing processes such as Alzheimer's disease, multi-infarct (vascular) dementia, and alcoholic dementia. Previous descriptions in the literature of persistent neurobehavioral effects associated with chronic exposure to organic solvents corroborate the findings in this case.

This article provides the neurologist with simple methods that can be applied to all clinical neurologic evaluations, regardless of the future potential for litigation. This article defines the appropriate application and interpretation of conventional neurologic, neurophysiologic, neuropsychological, and biochemical diagnostic tests that are sensitive to neurotoxic exposures. This article also provides the neurologist with guidance in the preparation of clinical findings and tips on the recognition and use of supportive literature that is often required for admissibility of evidence at a deposition or testimony.

Most publications on the subject of group B streptococcus since December 1996 have concentrated on supporting and to some degree extending our existing knowledge of the epidemiology of group B streptococcus and of intrapartum antimicrobial prophylaxis, which is the only approach available for reducing the incidence of group B streptococcal infection. Of greatest importance clinically are the reviews and studies on intrapartum antimicrobial prophylaxis, which continue to show that this is a worthwhile intervention as it significantly reduces the incidence of early onset group B streptococcal sepsis. The best approach to the detection of carriage is also covered, as is the changing epidemiology as a result of the implementation of intrapartum antimicrobial prophylaxis in some centres. Finally, the prospect of a vaccine is discussed.

The group B streptococcus is the commonest cause of bacterial infection in the newborn. In an attempt to prevent these infections, various vaccines are in development, most of which contain at least one of the capsular carbohydrates of the bacterium. We present new detailed data on the natural human antibody response to the type III capsular carbohydrate as we believe it is important to ascertain equivalent data for any new candidate vaccine in order to predict efficacy. We demonstrate that naturally occurring IgG is opsonically active in a complement-dependent manner, that fractions of differing avidity isolated from single donors have broadly similar opsonic activity, that the clonotypes from four individuals are restricted in number to a maximum of 15, and that binding kinetics ascertained using a resonant mirror biosensor show that specific antibodies have a moderately high affinity (mean Kd = 1.1e-8 M)., (Copyright 1998 Academic Press.)