Factors associated with fractures in HIV-infected persons: which factors matter?

This study aims to determine what factors are associated with increased risk of fracture among patients with HIV, in particular whether an important medication used to treat HIV, tenofovir, is associated with fracture. Our study found that while co-infection with hepatitis C and markers of HIV severity were associated with fracture, tenofovir was not. INTRODUCTION: Growing evidence suggests that tenofovir disoproxil fumarate decreases bone density among patients with HIV, but there are conflicting reports as to whether this decrease in bone density translates to higher fracture risk. We aimed to determine what factors were associated with an increased risk of fracture for patients with HIV, in particular whether tenofovir is associated with elevated fracture risk. METHODS: We conducted a retrospective cohort study at two tertiary care hospitals in Boston, MA, between 2001 and 2012 to determine whether tenofovir use is associated with elevated all-site fracture risk, as compared to other antiretroviral medications. We also examined other potential factors associated with fracture among patients with HIV. RESULTS: We identified 1981 HIV-infected patients who had at some point used tenofovir and 682 patients who had not. The mean age was 43 years, and 72 % were male. The hepatitis C co-infection rate was 28 %, about 40 % had nadir CD4 count <200, and about 40 % had a history of an AIDS-defining illness. We did not find an association between risk of fracture and tenofovir disoproxil fumarate (TDF) (adjusted RR (aRR) 0.8, 95 % CI 0.6-1.1). However, co-infection with hepatitis C did increase risk of fracture (aRR 1.6, 95 % CI 1.1-2.3), as did nadir CD4 count <200 (aRR 3.1, 95 % CI 1.9-5.0) and history of AIDS-defining illness (aRR 1.6, 95 % CI 1.1-2.2). CONCLUSION: There was no association found between fracture and tenofovir use, but there were associations between co-infection with hepatitis C and markers of advanced HIV disease and fracture.

Forecasting the burden of advanced knee osteoarthritis over a 10-year period in a cohort of 60-64 year-old US adults.

OBJECTIVE: To forecast the burden of symptomatic knee osteoarthritis (OA) in the elderly US population over a 10-year horizon. DESIGN: Using a computer simulation model of the natural history and management of knee OA combined with population-based data from the 2008 US Census we projected the 10-year burden of knee OA among persons 60-64 years of age. Knee OA incidence and progression rates were derived from national cohorts and calibrated to published literature. RESULTS: Using national data we estimated that 13% of 14,338,292 adults 60-64 years old have prevalent symptomatic, radiographic knee OA. Among persons surviving the next decade, 20% will have symptomatic advanced (Kellgren-Lawrence [K-L] grade 3) or end-stage (K-L 4) knee OA. Prevalence of advanced knee OA will range from 10% among non-obese to 35% among obese persons. Our estimates show that a more sensitive imaging tool, such as magnetic resonance imaging (MRI), may increase the number of OA cases diagnosed by up to 94% assuming that 50% of all 'pre-radiographic knee OA' (K-L 1) has some evidence of cartilage degeneration seen on MRI. CONCLUSIONS: Projecting new and advanced cases of knee OA among persons aged 60-64 years over the next decade creates a benchmark that can be used to evaluate population-based benefits of future disease-modifying OA drugs that are currently undergoing testing at various stages.

Prevalence and co-infection of Toxoplasma gondii and Neospora caninum in Apodemus sylvaticus in an area relatively free of cats.

The protozoan parasite Toxoplasma gondii is prevalent worldwide and can infect a remarkably wide range of hosts despite felids being the only definitive host. As cats play a major role in transmission to secondary mammalian hosts, the interaction between cats and these hosts should be a major factor determining final prevalence in the secondary host. This study investigates the prevalence of T. gondii in a natural population of Apodemus sylvaticus collected from an area with low cat density (<2·5 cats/km2). A surprisingly high prevalence of 40·78% (95% CI: 34·07%-47·79%) was observed despite this. A comparable level of prevalence was observed in a previously published study using the same approaches where a prevalence of 59% (95% CI: 50·13%-67·87%) was observed in a natural population of Mus domesticus from an area with high cat density (>500 cats/km2). Detection of infected foetuses from pregnant dams in both populations suggests that congenital transmission may enable persistence of infection in the absence of cats. The prevalences of the related parasite, Neospora caninum were found to be low in both populations (A. sylvaticus: 3·39% (95% CI: 0·12%-6·66%); M. domesticus: 3·08% (95% CI: 0·11%-6·05%)). These results suggest that cat density may have a lower than expected effect on final prevalence in these ecosystems.

Impact of field heterogeneity on the dynamics of the forced Kuramoto model.

We studied the impact of field heterogeneity on entrainment in a system of uniformly interacting phase oscillators. Field heterogeneity is shown to induce dynamical heterogeneity in the system. In effect, the heterogeneous field partitions the system into interacting groups of oscillators that feel the same local field strength and phase. Based on numerical and analytical analysis of the explicit dynamical equations derived from the periodically forced Kuramoto model, we found that the heterogeneous field can disrupt entrainment at different field frequencies when compared to the homogeneous field. This transition occurs when the phase- and frequency-locked synchronization between groups of oscillators is broken at a critical field frequency, causing each group to enter a new dynamical state (disrupted state). Strikingly, it is shown that disrupted dynamics can differ between groups.

Evidence for high levels of vertical transmission in Toxoplasma gondii.

Toxoplasma gondii is a highly ubiquitous and prevalent parasite. Despite the cat being the only definitive host, it is found in almost all geographical areas and warm blooded animals. Three routes of transmission are recognised: ingestion of oocysts shed by the cat, carnivory and congenital transmission. In natural populations, it is difficult to establish the relative importance of these routes. This paper reviews recent work in our laboratory which suggests that congenital transmission may be much more important than previously thought. Using PCR detection of the parasite, studies in sheep show that congenital transmission may occur in as many as 66% of pregnancies. Furthermore, in families of sheep on the same farm, exposed to the same sources of oocysts, significant divergent prevalences of Toxoplasma infection and abortion are found between different families. The data suggest that breeding from infected ewes increases the risk of subsequent abortion and infection in lambs. Congenital transmission rates in a natural population of mice were found to be 75%. Interestingly, congenital transmission rates in humans were measured at 19.8%. The results presented in these studies differ from those of other published studies and suggest that vertical transmission may be much more important than previously thought.

Treatment of mouse mammary tumors using combined hyperthermia and ischemia.

To investigate ischemic potentiation of thermal cell killing, mammary carcinomas transplanted to the legs or tails of C3H mice were treated with hyperthermia using rubber-lined compression cuffs. During treatment, warm water was circulated through the cuffs under pressure so that blood flow to the contained tumor-bearing limbs was interrupted. Ninety min at 41.5, 42.0, or 42.5 degrees and pressures between 60 and 135 mm Hg destroyed about 50% of tumors but damaged the normal tissues. Damage increased with the degree of compression. Intermittent pressure application was therefore adopted (five 18-min periods at 80 to 90 mm Hg alternating with four periods of 5 min at zero pressure). This favored the normal tissues, a high cure rate being maintained (73%) with damage to normal tissue virtually eliminated. The most satisfactory explanation of these results is a selective heat sensitivity, augmented by ischemia, on the part of tumor blood vessels. The success of intermittent treatment is then attributable to progressive impairment of the blood supply to the tumors, preventing the heat dissipation and relief of conditions such as acidity and nutrient deficiency which would otherwise result from periodic restoration of the circulation.

In vitro transendothelial migration of blood T lymphocytes from HIV-infected individuals.

OBJECTIVE: We hypothesized that differential extravasation of circulating CD4+ or CD8+ T lymphocytes contributes to HIV-associated CD8+ lymphocytic alveolitis. Differences in T-cell transendothelial migration may be intrinsic or emerge at sites where vascular endothelium is activated by overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. DESIGN: We used an in vitro model of lymphocyte extravasation to assess transendothelial migration of peripheral blood mononuclear cells (PBMC) from HIV-positive individuals. We assayed bronchoalveolar lavage (BAL) fluid from HIV-positive and normal individuals to determine if increased levels of TNF-alpha and IFN-gamma were present in the lungs of HIV-infected individuals. METHODS: Transendothelial migration was assessed by determining the number and flow cytometric phenotype of PBMC adherent to or migrating across unstimulated or TNF-alpha and IFN-gamma-activated endothelial cell monolayers. We measured BAL fluid cytokine concentrations using standard antigen-capture enzyme-linked immunosorbent assays for TNF-alpha and IFN-gamma. RESULTS: T cells migrating across unactivated endothelial cells were significantly enriched for CD4+ T cells. Cytokine activation of endothelial cells allowed significantly greater transendothelial migration of CD8+ T cells compared to unactivated endothelial cells. TNF-alpha was increased in BAL fluid from HIV-positive individuals relative to controls. CONCLUSIONS: These data suggest that, in HIV-positive individuals, CD4+ T cells are migration competent and blood CD8+ T cells do not have enhanced migration competence relative to CD4+ T cells. CD8+ T cell extravasation is aided by TNF-alpha and IFN-gamma-induced endothelial cells activation.

A connective tissue disease screening questionnaire for population studies.

To develop a technique to screen populations for potential connective tissue disease (CTD), we mailed a 30-item questionnaire to 253 randomly selected patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease (MCTD), or Sjögren's syndrome and to 340 randomly selected control subjects. The response rate after four mailings was 71% for case subjects and 54% for control subjects. Test-retest reliability for detection of any CTD was 0.82. Sensitivity for specific CTDs was 83 to 96% and specificity was 83 to 93%. The positive predictive value for any CTD (assuming an overall prevalence of 1.3%) was 5.5%; negative predictive value was 99.7%. The CTD Screening Questionnaire has high sensitivity and specificity for screening large populations.

Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis.

The purpose of this study was to validate the results of a meta-analysis showing the efficacy of fish oil in rheumatoid arthritis with the results of a re-analysis of the complete primary data set. A Medline search yielded seven published papers. Three additional trials were found by contacting authorities in the field. Inclusion criteria included (1) a double-blind, placebo-controlled study, (2) use of at least one of seven predetermined outcome measures, (3) results reported for both placebo and treatment groups at baseline and follow-up, (4) randomization, and (5) parallel or cross-over design. Papers were scored for quality. Demographic and outcomes variables were collected. For the re-analysis of the primary data, the same variables were abstracted for the 395 individual patients randomized. The meta-analysis demonstrated that dietary fish oil supplementation for 3 months significantly reduced tender joint count (rate difference [RD] [95% CI] = -2.9 [-3.8 to -2.1] [p = 0.001]) and morning stiffness (RD [95% CI] = -25.9 [-44.3 to -7.5] [p < 0.01]) as compared with heterogeneous dietary control oils. The re-analysis of the primary data confirmed a significant reduction in tender joint count (p = 0.001) and in morning stiffness (p < 0.02) in the parallel analysis that ignored interaction terms. The analyses that included an interaction term between site and treatment again confirmed a significant reduction in tender joint count. The results for morning stiffness were similar to the meta-analysis, but did not quite reach statistical significance (p = 0.052-0.083). The relative improvements in the other outcome variables did not reach statistical significance. Use of fish oil improved the number of tender joints and duration of morning stiffness at 3 months as analyzed by both meta- and mega-analysis. The fuller mega-analysis confirmed the results of the meta-analysis. The advantages of mega-analysis were as follows: (1) the ability to analyze the homogeneity of the patient populations, (2) the ability to make clinically sensible adjustments in the form of the comparison, and (3) the ability to examine subsets of the data.

The effect of chemotherapy on occult metastases after surgical removal of a non-immunogenic mouse carcinoma.

A transplantable non-immunogenic murine carcinoma of spontaneous origin, WHT Carcinoma N-C (Hewitt), was used to assess the effectiveness of melphalan (Ml) and/or methotrexate (Mx) for treatment of occult metastatic disease following surgical excision of primary tumors. Early surgical excision alone cured 66% of mice; later excision gave no cures. Maximum sublethal doses of chemotherapy rarely cured mice of metastases but did extend their survival time by up to 66% as compared with mice subjected to excision only. The influence of excision and chemotherapy on the frequency of local recurrence or pulmonary metastasis is discussed. Extrapulmonary metastases were 2.5 times more frequent in long-term than in short-term survivors, independently of treatment.

Lyme disease and preventive behaviors in residents of Nantucket Island, Massachusetts.

BACKGROUND: To determine the age-specific prevalence of Lyme disease and whether preventive behaviors on Nantucket Island correlate with Lyme disease, we surveyed island residents. METHODS: A survey with questions on Lyme disease symptoms, history, and preventive behaviors was mailed to all residents. Respondents were stratified by likelihood of having had Lyme disease. A subsample was selected for examination, and then classified according to the Lyme disease national surveillance case definition. RESULTS: The overall lifetime prevalence of Lyme disease for Nantucket residents was 15% (CI, 10%-19.8%): 19% among females, and 11% among males. The prevalence was highest among age groups 0-16 and 30-49 years. Overall, 86% of the population practiced at least one behavior. The most frequently reported preventive behavior was checking oneself for ticks (80%), followed by wearing protective clothing (53%), avoiding tick areas (34%), and using tick repellent (11%). Younger individuals practiced fewer preventive behaviors than older individuals (p=0.001). Although males reported greater tick exposure than females, females uniformly practiced preventive behaviors more frequently (p=0.001). The practice of preventive behaviors was not associated with a history of Lyme disease, but finding more than 5 ticks per year on oneself was (p=0.001). CONCLUSION: Lyme disease is highly prevalent on Nantucket Island. Young people are particularly at risk and health education should emphasize preventive behaviors less frequently practiced: using tick repellent, avoiding tick areas, and wearing protective clothing.

Predictors of blood loss during total hip replacement surgery.

OBJECTIVE: To determine total blood loss and transfusion requirements during primary total hip replacement (THR) surgery; and, to identify predictors of increased blood loss. METHODS: This was a prospective cohort study of 295 consecutive patients undergoing primary THR at a 700-bed teaching hospital in Boston, Massachusetts. The main outcome measures were the total blood loss, which was defined (in units) as the initial hematocrit minus final hematocrit divided by 3 plus the number of units transfused, and the number of autologous and homologous units of blood transfused. RESULTS: The mean total blood loss was 3.6 units, and the mean total units transfused was 2.1. Univariate predictors of greater total blood loss (at P < 0.05) included being male, receiving general anesthesia, and higher American Society of Anesthesiologists (ASA) class. In multiple linear regression models which controlled for demographic and clinical variables (age, race, marital status, education, smoking history, obesity, underlying disease, payor status, cemented prosthesis, comorbidity, and season of operation), being male, receiving general anesthesia, and having an ASA score of 3 predicted greater total blood loss. CONCLUSION: Preoperative characteristics can help determine which patients should donate either more or less than the customary 2 units of blood.

Pitfalls of using patient recall to derive preoperative status in outcome studies of total knee arthroplasty.

BACKGROUND: It is essential to adjust for the level of preoperative pain and functional status when measuring the outcome of total knee arthroplasty. Some study designs rely on postoperative patient recall to derive preoperative status. In this study, we compared prospectively collected preoperative data with data derived from patient recall of preoperative status three months after total knee arthroplasty. METHODS: Patients were recruited as part of a prospective observational study of the outcome of primary total knee arthroplasty for osteoarthritis at four centers in the United States, six centers in the United Kingdom, and two centers in Australia. Independent research assistants recruited patients and collected data with use of a uniform documentation system preoperatively and three months postoperatively. Preoperative data included the findings of a clinical history and physical examination, demographic information, socioeconomic status, and scores from two health-status instruments: the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Medical Outcomes Study Short Form-36 Health Survey (SF-36). Postoperative data included the WOMAC and SF-36 scores and patient recall of preoperative status on selected items from these health-status measures. RESULTS: A total of 862 patients were recruited, and recall data were available for 770 patients (89%). The mean age was seventy years (range, thirty-eight to ninety years), and 59% of the patients were women. Comparisons of prospective and recall data on individual pain and function items showed poor-to-fair agreement (weighted kappa, 0.20 to 0.41). Patients recalled significantly more pain than they had reported preoperatively (p < 0.001), but there were random recollection errors for the function items. There was only moderate correlation between the prospective and recalled summary scores for pain (Spearman r = 0.53) and function (Spearman r = 0.48). In addition, 61% of the recalled pain scores and 50% of the recalled function scores differed from the prospective scores by more than 10 points (10% of the total range). CONCLUSIONS: Patients' recall of preoperative pain and functional status three months after total knee arthroplasty demonstrated only moderate agreement with what the patients had reported prospectively. Researchers who use recall data to derive preoperative status must recognize these limitations when drawing conclusions about the effectiveness of total knee arthroplasty.

Validity and responsiveness of the Knee Society Clinical Rating System in comparison with the SF-36 and WOMAC.

BACKGROUND: The aim of this study was to validate the Knee Society Clinical Rating System (knee and function scores) and to compare its responsiveness with that of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Medical Outcomes Study Short Form-36 (SF-36). METHODS: Patients were recruited as part of a prospective observational study of the outcomes of primary total knee arthroplasty for the treatment of osteoarthritis in four centers in the United States, six centers in the United Kingdom, and two centers in Australia. Independent research assistants at each site collected the Knee Society clinical data. The WOMAC, SF-36, patient satisfaction, and demographic data were obtained with self-administered questionnaires. RESULTS: A total of 862 eligible patients were recruited, and complete preoperative and twelve-month data were available for 697 (80.9%) of them. The mean age was seventy years (range, thirty-eight to ninety years), and the majority of the patients (58.9%) were women. Low correlations were found among the items of both the knee and the function score at both assessment times. The Knee Society pain and function scores had moderate-to-strong correlations with the corresponding pain and function domains of the WOMAC and SF-36 (r = 0.31 to 0.72). Measurement of the standardized response mean showed the Knee Society knee score to be more responsive (standardized response mean, 2.2) than the WOMAC (standardized response means, 2.0 for pain and 1.4 for function) and the SF-36 (standardized response means, 1.0 for bodily pain and 1.1 for physical functioning). The Knee Society function score was the least responsive measure (standardized response mean, 0.8). Correlation of changes in scores at twelve months with patient reports of satisfaction and improvement in health status showed the WOMAC and SF-36 to be more responsive than the Knee Society scores. CONCLUSIONS: There is a poor correlation among the items of the Knee Society Clinical Rating System, but the rating system has adequate convergent construct validity. The WOMAC and SF-36 are more responsive measures of outcome of total knee arthroplasty. As they are less labor-intensive for researchers to use and as use of these instruments removes observer bias from the study design, they are preferable for knee arthroplasty outcome studies.

Use of condoms as contraceptive and disease preventive measures among residents of Jos, northern Nigeria.

The effectiveness, acceptability and protective aspects of condoms as both contraceptive and disease control measures was evaluated in 168 male residents of Jos in Nigeria. They were aged between 15 and 40 years and were attending the Family Planning Clinic of the Jos University Teaching Hospital. The results showed that the majority (87.5%) of our patients were in the 21 to 30 years age group and most of the clients had used condoms for between 1 to 5 years. A good number of our clients (40.5%) used condom because it protects them against venereal disease while others felt it was safe and effective. The Family Planning Clinic was the main source of knowledge of the condom among our clients (42.9%), and the condom was rated as good or excellent by 137 (81.5%) clients. The only side effect of condom usage which featured prominently among our clients was reduced sexual excitement. The results were compared with studies carried out elsewhere. It was concluded that the condom could be an acceptable and effective form of contraception in this population. The users must, however, be highly motivated so as to use it during every act of coitus for optimal efficacy.

PIP: The effectiveness, acceptability, and protective aspects of condoms as both contraceptive and disease control measures was evaluated in 168 male residents of Jos in Nigeria. They were between 15-40 years of age and attended the Family Planning Clinic of the Jos University Teaching Hospital. The results showed that the majority (87.5%) of these patients were between 21-30 years of age and most had used condoms for between 1-5 years. A good number (40.5%) used condoms because of the protection against venereal disease while many others felt it was safe and effective. The Family Planning Clinic was the main source of knowledge concerning the condom (42.9%) and the condom was rated as good or excellent by 137 clients (81.5%). The only side effect seen with the condom was reduced sexual excitement: this was a predominant manifestation. Results were compared with studies carried out elsewhere. It was concluded that the condom should be an acceptable and effective form of contraception in this population. The users must, however, be highly motivated to use it during every act of coitus for optimal efficacy.

Spongy degeneration of the central nervous system (Van Bogaert-Bertrand disease): report of a case in a Saudi family.

Spongy degeneration of the central nervous system in infancy (Van Bogaert-Bertrand disease) is a disorder usually thought to occur in Ashkenazi Jewish infants. We report a case occurring in an Arab infant of consanguineous parents.

Features of the geriatric EEG: age-dependent incidence of POSTS.

Positive occipital sharp transients of sleep (POSTS) are well recognized as a normal electroencephalographic phenomenon in young to middle-aged persons, but little comment has been made concerning their occurrence in geriatric age groups. This study encompassing 365 electroencephalograms, showing POSTS among patients aged 22 to 86 years, demonstrates that the presence of POSTS is not an age limited occurrence, but extends over a wide age range into the later decades of life. Though the incidence of POSTS declined with advancing age, the diminution was not striking until after age 70. POSTS appeared only in normal and mildly abnormal EEGs. POSTS did not occur in markedly abnormal EEGs, and thus they resemble other features of normal sleep including sleep spindles and K-complexes.

The effect of environmental temperature on the rate of healing of fractures in tail vertebrae of mice.

The effect of the environmental temperature on the healing of fractures was assessed in vertebrae of tails of young albino mice. It was found that fractures in animals kept at 33 degrees Celsius healed very rapidly (bony callus by 14 days) while in animals kept in the cold (8 degrees Celsius) fractures were still at the stage of granulation tissue at this time. Controls were at an intermediate stage. This result might have a clinical application.

Effects of sulphur dioxide and nitrogen dioxide, singly and in mixture, on the macroscopic growth of three birch clones.

An investigation of some aspects of the effects of low concentrations of the gases, sulphur dioxide and nitrogen dioxide, singly and in mixture, was made on the growth of three birch clones, two of Betula pendula Roth. (silver birch) and one of Betula pubescens Ehr. (downy birch). Comparative measurements of the growth form and dry mass increment were made over one year in glasshouses supplied with charcoal-filtered ambient air, and SO(2) and NO(2), singly or in mixture, at mean concentrations of 62 ppb (nl litre (-1)) of one or both gases. The main effects were found in those plants that were fumigated with SO(2) singly, and SO(2) and NO(2) together. Both treatments induced premature leaf loss and reduction in mass, especially of roots, the effects increasing over time. The heights and initial leaf areas were maintained, apparently at the expense of other parameters. NO(2), if present singly, had little or no effect, but it tended to enhance the damaging effect of SO(2) when the two were applied together. The different clones showed different degrees of response to the pollutants, but these differences became less marked during the second season of fumigation. The effects found are discussed in relation to the annual growth of trees, particularly birch.

Fetal salvage with cervical cerclage.

A prospective study to evaluate the fetal salvage rate, cervical morbidity and cesarean section rate in patients with cervical incompetence using a cerclage procedure was conducted at the Jos University Teaching Hospital, Jos, Nigeria. The study group consisted of 71 patients who gave a history suggestive of cervical incompetence, had a dilated cervix at booking and included emergency patients in whom the cervix had dilated because of a febrile illness but had never undergone a cervical cerclage procedure. The fetal salvage rate was 23.7% in pregnancies occurring before and 94.4% after cervical cerclage procedure was performed. There were 57 term pregnancies, 10 pre-term deliveries, and 4 abortions. The study clearly demonstrates the beneficial effects of cervical cerclage operations in patients who have suffered from preventable fetal losses because their incompetent cervix was undiagnosed. Our results were compared with those of other series. The diagnosis of cervical incompetence is discussed with particular emphasis on the use of screening tests in the detection and identification of cervical incompetence.