Causal pathways of the effects of age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on AIDS development

OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.     

Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions

Background

Guidelines published in major medical journals are very influential in determining clinical practice. It would be essential to evaluate whether conflicts of interests are disclosed in these publications. We evaluated the reporting of conflicts of interest and the factors that may affect such disclosure in a sample of 191 guidelines on therapeutic and/or preventive measures published in 6 major clinical journals (Annals of Internal Medicine, BMJ, JAMA, Lancet, New England Journal of Medicine, Pediatrics) in 1979, 1984, 1989, 1994 and 1999.

Results

Only 7 guidelines (3.7%) mentioned conflicts of interest and all were published in 1999 (17.5% (7/40) of guidelines published in 1999 alone). Reporting of conflicts of interest differed significantly by journal (p=0.026), availability of disclosure policy by the journal (p=0.043), source of funding (p < 0.001) and number of authors (p=0.004). In the entire database of 191 guidelines, a mere 18 authors disclosed a total of 24 potential conflicts of interest and most pertained to minor issues.

Conclusions

Despite some recent improvement, reporting of conflicts of interest in clinical guidelines published in influential journals is largely neglected.

     

CCR2-64I and CXCL12 3'A alleles confer a favorable prognosis to AIDS patients undergoing HAART therapy.

BACKGROUND: The chemokine receptor polymorphisms CCR5Delta32, CXCL12 3'A, CCR2-64I and CCR5-59029 G/A have been demonstrated to affect HIV-1 infection and progression. OBJECTIVE: We studied the impact of the above polymorphisms on the effectiveness of a 30-month treatment with highly active antiretroviral therapy (HAART) in 149 HIV-1 patients. STUDY DESIGN: We stratified the patients according to CD4 CDC criteria and applied Kaplan-Meier analysis using the following end-point criteria: (a) the time from HAART initiation to undetectable viral load (VL) counts (VL<50 copies/ml), (b) the duration of undetectable VL status and (c) the time required for CD4+ T-cell counts to pass over the 500 cells/ml threshold. RESULTS: Our results in the second group (CD4 201-500) revealed that patients with the CCR2-64I allele achieved undetectable VL counts at 3.5+/-0.48 months as compared to 10.26+/-1.42 months in the control group (p=0.018). The VL remained undetectable for 28+/-2 months, in contrast to 20+/-2 months in the control group (p=0.048). Patients carrying CXCL12 3'A restored the CD4 population faster than the control group (9+/-2 and 14+/-2 months, respectively, p=0.023). The CCR5Delta32 and CCR5-59029 G/A alleles did not appear to affect the parameters studied. CONCLUSIONS: Our results suggest that patients carrying either CCR2-64I or CXCL12 3'A have a more favorable prognosis during HAART treatment.     

Fast Eating Is Associated with Increased BMI among High-School Students

Fast self-reported eating rate (SRER) has been associated with increased adiposity in children and adults. No studies have been conducted among high-school students, and SRER has not been validated vs. objective eating rate (OBER) in such populations. The objectives were to investigate (among high-school student populations) the association between OBER and BMI z-scores (BMIz), the validity of SRER vs. OBER, and potential differences in BMIz between SRER categories. Three studies were conducted. Study 1 included 116 Swedish students (mean ± SD age: 16.5 ± 0.8, 59% females) who were eating school lunch. Food intake and meal duration were objectively recorded, and OBER was calculated. Additionally, students provided SRER. Study 2 included students (n = 50, mean ± SD age: 16.7 ± 0.6, 58% females) from Study 1 who ate another objectively recorded school lunch. Study 3 included 1832 high-school students (mean ± SD age: 15.8 ± 0.9, 51% females) from Sweden (n = 748) and Greece (n = 1084) who provided SRER. In Study 1, students with BMIz ≥ 0 had faster OBER vs. students with BMIz < 0 (mean difference: +7.7 g/min or +27%, p = 0.012), while students with fast SRER had higher OBER vs. students with slow SRER (mean difference: +13.7 g/min or +56%, p = 0.001). However, there was “minimal” agreement between SRER and OBER categories (κ = 0.31, p < 0.001). In Study 2, OBER during lunch 1 had a “large” correlation with OBER during lunch 2 (r = 0.75, p < 0.001). In Study 3, fast SRER students had higher BMIz vs. slow SRER students (mean difference: 0.37, p < 0.001). Similar observations were found among both Swedish and Greek students. For the first time in high-school students, we confirm the association between fast eating and increased adiposity. Our validation analysis suggests that SRER could be used as a proxy for OBER in studies with large sample sizes on a group level. With smaller samples, OBER should be used instead. To assess eating rate on an individual level, OBER can be used while SRER should be avoided.     

Heterotopic Ossification Negatively Influences Range of Motion After Revision Total Knee Arthroplasty

BackgroundThe incidence of heterotopic ossification (HO) after total knee arthroplasty (TKA) varies and is of unclear clinical significance. This study aimed to identify the incidence of HO in patients undergoing revision TKA for either stiffness or aseptic loosening/instability and determine if the presence of HO is associated with inferior absolute range of motion (ROM) and ROM gains.MethodsEighty-seven patients were prospectively enrolled and separated into 2 cohorts to evaluate ROM after revision TKA (2017-2019). Group 1 (N = 40) patients were revised for stiffness, while group 2 (N = 47) patients were revised for either aseptic loosening or instability. Goniometer-measured ROM values were obtained preoperatively and at 6 weeks, 6 months, and 1 year postoperatively. Statistical analysis included a Fisher’s exact test to assess for an association between preoperative HO and final ROM at 1 year after revision TKA.ResultsHO was identified on preoperative radiographs in 17 patients (20%). There was a significantly higher rate of preoperative HO in patients revised for stiffness compared to patients revised for instability or loosening (30% vs 11%; P = .03). Five cases of HO qualitatively identified as most clinically severe were associated with lower ROM at each time point compared to the remainder of HO cases in this study cohort (P < .02).ConclusionThe presence of HO is greater in patients undergoing revision TKA for stiffness. Additionally, HO severity appears to have a major effect on preoperative and postoperative ROM trajectory. This information should help guide patient expectations and highlight the need for a comprehensive, standardized classification system for HO.     

An Overview of Telehealth in Total Joint Arthroplasty

With the increase in technological advances over the years, telehealth services in orthopedic surgery have gained in popularity, yet adoption among surgeons has been slow. With the onset of the COVID-19 pandemic, however, orthopedic surgery practices nationwide have accelerated adaptation to telemedicine. Telehealth can be effectively applied to total joint arthroplasty, with the ability to perform preoperative consultations, postoperative follow-up, and telerehabilitation in a virtual, remote manner with similar outcomes to in-person visits. New technologies that have emerged, such as virtual goniometers, wearable sensors, and app-based patient questionnaires, have improved clinicians’ ability to conduct telehealth visits. Benefits of using telehealth include high patient satisfaction, cost-savings, increased access to care, and more efficiency. Notably, some challenges still exist, including widespread accessibility and adaptation of new technologies, inability to conduct an in-person orthopedic physical examination, and regulatory barriers, such as insurance reimbursement, increased medicolegal risk, and privacy and confidentiality concerns. Despite these hurdles, telehealth is here to stay and can be successfully incorporated in any total joint arthroplasty practice with the appropriate adjustments.     

Association of sleep duration and quality with immunological response after vaccination against severe acute respiratory syndrome coronavirus-2 infection

Growing evidence suggests that sleep could affect the immunological response after vaccination. The aim of this prospective study was to investigate possible associations between regular sleep disruption and immunity response after vaccination against coronavirus disease 2019 (COVID-19). In total, 592 healthcare workers, with no previous history of COVID-19, from eight major Greek hospitals were enrolled in this study. All subjects underwent two Pfizer–BioNTech messenger ribonucleic acid (mRNA) COVID-19 vaccine BNT162b2 inoculations with an interval of 21 days between the doses. Furthermore, a questionnaire was completed 2 days after each vaccination and clinical characteristics, demographics, sleep duration, and habits were recorded. Blood samples were collected and anti-spike immunoglobulin G antibodies were measured at 20 ± 1 days after the first dose and 21 ± 2 days after the second dose. A total of 544 subjects (30% males), with median (interquartile range [IQR]) age of 46 (38–54) years and body mass index of 24·84 (22.6–28.51) kg/m² were eligible for the study. The median (IQR) habitual duration of sleep was 6 (6–7) h/night. In all, 283 participants (52%) had a short daytime nap. In 214 (39.3%) participants the Pittsburgh Sleep Quality Index score was >5, with a higher percentage in women (74·3%, p < 0.05). Antibody levels were associated with age (r = −0.178, p < 0.001), poor sleep quality (r = −0.094, p < 0.05), insomnia (r = −0.098, p < 0.05), and nap frequency per week (r = −0.098, p < 0.05), but after adjusting for confounders, only insomnia, gender, and age were independent determinants of antibody levels. It is important to emphasise that insomnia is associated with lower antibody levels against COVID-19 after vaccination.     

Cerebrovascular effects of nitric oxide manipulation in spontaneously hypertensive rats

1. Evidence that nitric oxide (NO) bioactivity is altered in chronic hypertension is conflicting, possibly as a result of heterogeneity in both the nature of the dysfunction and in the disease process itself. The brain is particularly vulnerable to the vascular complications of chronic hypertension, and the aim of this study was to assess whether differences in the cerebrovascular responsiveness to the NO synthase (NOS) inhibitors, N^G-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), and to the NO donor 3-morpholinosydnonimine (SIN-1) might indicate one possible source of these complications.
2. Conscious spontaneously hypertensive (SHR) and WKY rats, were treated with L-NAME (30 mg kg⁻¹, i.v.), 7-NI (25 mg kg⁻¹, i.p.), SIN-1 (0.54 or 1.8 mg kg⁻¹ h⁻¹, continuous i.v. infusion) or saline (i.v.), 20 min before the measurement of local cerebral blood flow (LCBF) by the fully quantitative [¹⁴C]-iodoantipyrine autoradiographic technique.
3. With the exception of mean arterial blood pressure (MABP), there were no significant differences in physiological parameters between SHR and WKY rats within any of the treatment groups, or between treatment groups. L-NAME treatment increased MABP by 27% in WKY and 18% in SHR groups, whilst 7-NI had no significant effect in either group. Following the lower dose of SIN-1 infusion, MABP was decreased to a similar extent in both groups (around −20%). There was no significant difference in MABP between groups following the higher dose of SIN-1, but this represented a decrease of −41% in SHR and −21% in WKY rats.
4. With the exception of one brain region (nucleus accumbens), there were no significant differences in basal LCBF between WKY and SHR. L-NAME produced similar decreases in LCBF in both groups, ranging between −10 and −40%. The effect of 7-NI upon LCBF was more pronounced in the SHR (ranging from −34 to −57%) compared with the WKY (ranging from −14 to −43%), and in seven out of the thirteen brain areas examined there were significant differences in LCBF.
5. Following the lower dose of SIN-1, in the WKY 8 out of the 13 brain areas examined showed significant increases in blood flow compared to the saline treated animals. In contrast, only 2 brain areas showed significant increases in flow in the SHR. In the rest of the brain areas examined the effects of SIN-1 upon LCBF were less marked than in the WKY.
6. Infusion of the higher dose of SIN-1 resulted in further significant increases in LCBF in the WKY group (ranging between +30% and +74% compared to saline-treated animals), but no significant effects upon LCBF were found in the SHR. As a result, there were significant differences in LCBF between SIN-1-treated WKY and SHR in six brain areas. In most brain areas examined, cerebral blood flow in SHR following the higher dose of SIN-1 was less than that measured with the lower dose of SIN-1.
7. Despite comparable reductions in MABP (∼20%) in both groups, calculated cerebrovascular resistance (CVR) confirmed that the vasodilator effects of the lower dose of SIN-1 were significantly more pronounced throughout the brain in the WKY (ranging between −3% and −50%; median=−38%) when compared to the SHR (ranging between −10% and −36%; median=−26%). In the animals treated with the higher dose of SIN-1, CVR changes were broadly similar in both groups (median=−45% in WKY and −42% in SHR), but with the reduction in MABP in SHR being twice that found in WKY, this is in keeping with an attenuated blood flow response to SIN-1 in the SHR.
8. The results of this study indicate that NO-dependent vasodilator capacity is reduced in the cerebrovasculature of SHR. In addition, the equal responsiveness to a non-specific NOS inhibitor but an enhanced effectiveness of a specific neuronal NO inhibitor upon LCBF in the SHR could be consistent with an upregulation of the neuronal NO system.