Challenges with Forecasting Budget Impact: A Case Study of Six ICER Reports

Background

Payers frequently rely on budget impact model (BIM) results to help determine drug coverage policy and its effect on their bottom line. It is unclear whether BIMs typically overestimate or underestimate real-world budget impact.

Psychometric Properties of a Scale on Judgmental Communication with Peers About Sex Among YMSM and Their Close Friends in Lebanon

AIDS and Behavior - We are not aware of any validated sexual health communication scales for use with young men who have sex with men (YMSM). We used data from an HIV prevention study in Lebanon...     

In vitro stretch injury induces time- and severity-dependent alterations of STEP phosphorylation and proteolysis in neurons

Striatal-enriched tyrosine phosphatase (STEP) has been identified as a component of physiological and pathophysiological signaling pathways mediated by N-methyl-d-aspartate (NMDA) receptor/calcineurin/calpain activation. Activation of these pathways produces a subsequent change in STEP isoform expression or activation via dephosphorylation. In this study, we evaluated changes in STEP phosphorylation and proteolysis in dissociated cortical neurons after sublethal and lethal mechanical injury using an in vitro stretch injury device. Sublethal stretch injury produces minimal changes in STEP phosphorylation at early time points, and increased STEP phosphorylation at 24 h that is blocked by the NMDA-receptor antagonist APV, the calcineurin-inhibitor FK506, and the sodium channel blocker tetrodotoxin. Lethal stretch injury produces rapid STEP dephosphorylation via NR2B-containing NMDA receptors, but not calcineurin, and a subsequent biphasic phosphorylation pattern. STEP(61) expression progressively increases after sublethal stretch with no change in calpain-mediated STEP(33) formation, while lethal stretch injury results in STEP(33) formation via a NR2B-containing NMDA receptor pathway within 1 h of injury. Blocking calpain activation in the initial 30 min after stretch injury increases the ratio of active STEP in cells and blocks STEP(33) formation, suggesting that STEP is an early substrate of calpain after mechanical injury. There is a strong correlation between the amount of STEP(33) formed and the degree of cell death observed after lethal stretch injury. In summary, these data demonstrate that previously characterized pathways of STEP regulation via the NMDA receptor are generally conserved in mechanical injury, and suggest that calpain-mediated cleavage of STEP(33) should be further examined as an early marker of neuronal fate after stretch injury.     

Assessment of Iothalamate Plasma Clearance: Duration of Study Affects Quality of GFR

Background and objectives: Measurement of GFR is important for the management of chronic kidney disease (CKD). Although bolus administration of radiocontrast agents is commonly used to measure GFR, the optimal duration of sampling to assess their plasma clearance is unknown. The purpose of this study was to evaluate whether the duration of plasma sampling influences precision and estimation of GFR.Design, setting, participants, & measurements: GFR was measured by sampling plasma 12 times over 5 h in 56 patients with CKD (mean age 64 yr, 98% men, 79% Caucasian, 34% diabetics, estimated GFR 31.8 ± 14.2 ml/min/1.73 m²). In a subset of 12 patients we measured GFR by sampling plasma 17 times over 10 h.Results: Short sampling intervals considerably overestimated GFR measured using total plasma iothalamate clearance, especially in larger patients. In the higher estimated GFR group (>30 ml/min/1.73m²), the 5-h GFR was 17% higher and 2-h GFR 54% higher compared with the 10-h GFR, which averaged 40.3 ml/min/1.73 m². In the lower estimated GFR group (<30 ml/min/1.73m²), the 5-h GFR was 36% higher and 2-h GFR 126% higher compared with the 10-h GFR, which averaged 22.2 ml/min/1.73 m². Short sampling duration also reduced the precision of the estimated GFR from 1.67% for 10-h GFR, to 3.48% for 5-h GFR, and to 7.07% for 2-h GFR.Conclusions: GFR measured over a longer duration with multiple plasma samples spanning the distribution and elimination phases may improve precision and provide a better measure of renal function.The clinical manifestations of chronic kidney disease (CKD) are heterogenous, but it is generally accepted that the staging of CKD rests upon an accurate knowledge of GFR (1). Although urinary clearance of radioactive iothalamate has been used as the reference method to measure GFR (2), many clinical and research laboratories now use plasma clearance of nonradioactive radiocontrast dyes instead (3–7). Plasma clearance of iothalamate can be measured either after continuous infusion of iothalamate to achieve steady state and measuring plasma iothalamate (4,5,7), or after an intravenous bolus (3,6,8). The latter technique involves administering a bolus dose of iothalamate or another radiocontrast dye and sampling blood at timed intervals to study its pharmacokinetics. We and others have reported that plasma iothalamate clearance provides improved precision over urinary clearances (8,9). Because of improved precision, the plasma iothalamate clearance technique appears attractive for longitudinal studies in which sample size can be reduced to detect a given change in GFR (9).The optimal duration of plasma sampling to best ascertain GFR remains undefined—no minimum duration of sampling is recommended. Accordingly, uncertainty exists when planning the optimal duration of GFR studies for the long-term follow-up renal function. Review of published work reveals that the duration of plasma iothalamate clearances measurement has varied anywhere between 2 to 10 h (8,10–12). In a study that measured plasma iothalamate concentration time profile over 10 h (12), plasma clearance was noted to be log-linear in all instances after 120 min, whereas another study reported that a 2-h time frame was perfectly adequate (10). A more recent multicenter study in children in the United States suggested 5 h as an adequate time frame for sampling (6).We sought to evaluate the optimal duration of measurement of plasma iothalamate clearance in a cohort of patients with CKD. We hypothesized that short studies would overestimate GFR and that longer studies would reduce this error. We reasoned that short studies in patients with lower GFR would be associated with greater discrepancy compared with studies with longer sampling duration and tested the hypothesis that shorter duration studies would sacrifice precision compared with longer studies.     

Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians

Objective Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the –420C>G putative gain‐of‐function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans. Design and methods We examined the association of three resistin polymorphisms, –852A>G, –420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C‐reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851). Results Resistin levels were higher, dose‐dependently, with the –420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The –852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor‐receptor 2 (sol‐TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol‐TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores. Conclusions Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.     

Homing defects of B cells in HIV-1 infected children impair vaccination responses

Background

Successful vaccinations rely on antibody responses. Chemokine receptors play an important role in B cell homing to differentiation niches. We assessed CXCR4, CXCR5 and CCR6 expression on B cells during HIV-1 infection and relate it to antibody responses against a HBV vaccine.

Revisit PEG-Induced Precipitation Assay for Protein Solubility Assessment of Monoclonal Antibody Formulations

Pharmaceutical Research - Protein solubility is an important attribute of pharmaceutical monoclonal antibody (MAb) formulations, particularly at high MAb concentrations. PEG-induced protein...     

Detection of Equine Herpesvirus (EHV) ‐1, ‐2, ‐4 and ‐5 in Ethiopian Equids with and without Respiratory Problems and Genetic Characterization of EHV‐2 and EHV‐5 Strains

Infections with equine herpesviruses (EHVs) are widespread in equine populations worldwide. Whereas both EHV‐1 and EHV‐4 produce well‐documented respiratory syndromes in equids, the contribution of EHV‐2 and EHV‐5 to disease of the respiratory tract is still enigmatic. This study describes the detection and genetic characterization of EHVs from equids with and without clinical respiratory disease. Virus‐specific PCRs were used to detect EHV‐1, ‐2, ‐4 and ‐5. From the total of 160 equids with respiratory disease, EHV‐5 was detected at the highest prevalence (23.1%), followed by EHV‐2 (20.0%), EHV‐4 (8.1%) and EHV‐1 (7.5%). Concurrent infections with EHV‐2 and EHV‐5 were recorded from nine (5.2%) diseased horses. Of the total of 111 clinically healthy equids, EHV‐1 and EHV‐4 were never detected whereas EHV‐2 and EHV‐5 were found in 8 (7.2%) and 18 (16.2%) horses, respectively. A significantly higher proportion of EHV‐2‐infected equids was observed in the respiratory disease group (32/160, 20.0%; P = 0.005) compared to those without disease (8/111; 7.2%). EHV‐2‐positive equids were three times more likely to display clinical signs of respiratory disease than EHV‐2‐negative equids (OR 3.22, 95% CI: 1.42–7.28). For EHV‐5, the observed difference was not statistically significant (P = 0.166). The phylogenetic analysis of the gB gene revealed that the Ethiopian EHV‐2 and EHV‐5 strains had a remarkable genetic diversity, with a nucleotide sequence identity among each other that ranged from 94.0 to 99.4% and 95.1 to 100%, respectively. Moreover, the nucleotide sequence identity of EHV‐2 and EHV‐5 with isolates from other countries acquired from GenBank ranged from 92.9 to 99.1% and 95.1 to 99.5%, respectively. Our results suggest that besides EHV‐1 and EHV‐4, EHV‐2 is likely to be an important contributor either to induce or predispose equids to respiratory disease. However, more work is needed to better understand the contribution of EHV‐2 in the establishment of respiratory disease.     

Prevalence and associated factors of depression among patients with HIV/AIDS in Hawassa,Ethiopia, cross-sectional study

Background

Globally, 350 million people are affected by depression and 800,000 people die due to suicide every year due to depression. People living with HIV/AIDS face different challenges, including HIV-related perceived stigma, lack of social support and also depression. This study aimed to assess prevalence and factors associated with depressive symptom among people living with HIV/AIDS attending Hawassa University Comprehensive Specialized Hospital, Hawassa, Ethiopia.

Methods

Hospital-based cross-sectional study was implemented in 2016. A total of 401 HIV-positive patients who had regular visit at Hawassa University Comprehensive Specialized Hospital, Hawassa, Ethiopia were included in the study. Systematic random sampling technique was used to recruit study participants. Patient Health Questionnaire item nine (PHQ-9) was used to assess depressive symptoms. In addition to this, Oslo social support scale and HIV perceived stigma scale were used to assess social support and HIV-related perceived stigma, respectively.

Results

A total of 401 study participants were included in the study, giving a response rate of 96.2%. The mean age of the respondents was 38 years (SD?±?10.23). This study revealed that 48.6% of HIV-positive patients had depression. Patients who had poor social support [AOR?=?2.53, (95% CI 1.70, 9.13)], HIV-related perceived stigma [AOR?=?2.83, (95% CI 1.78, 4.48)] and CD4 cell count?<?200 [AOR?=?3.89, (95% CI 1.02, 14.83)] were more likely to have depression as compared to individuals who had good social support, no perceived HIV stigma and CD4 cell count?>?200, respectively.

Conclusion

Having poor social support, HIV-related perceived stigma and low CD4 cell count (<?200) had statistically significant association with depressive symptom. Training of health workers in ART clinics and availing manuals on assessing mental health issues is useful to screen and treat depression among HIV patients.

     

Identification of a New Genotype of African Swine Fever Virus in Domestic Pigs from Ethiopia

African swine fever (ASF) is an important emerging transboundary animal disease (TAD), which currently has an impact on many countries in Africa, Eastern Europe, the Caucasus and the Russian Federation. The current situation in Europe shows the ability of the virus to rapidly spread, which stands to threaten the global swine industry. At present, there is no viable vaccine to minimize spread of the disease and stamping out is the main source of control. In February 2011, Ethiopia had reported its first suspected outbreaks of ASF. Genomic analyses of the collected ASF virus (ASFV) strains were undertaken using 23 tissue samples collected from domestic swine in Ethiopia from 2011 to 2014. The analysis of Ethiopian ASFVs partial p72 gene sequence showed the identification of a new genotype, genotype XXIII, that shares a common ancestor with genotypes IX and X, which comprise isolates circulating in Eastern African countries and the Republic of Congo. Analysis of the p54 gene also followed the p72 pattern and the deduced amino acid sequence of the central variable region (CVR) of the B602L gene showed novel tetramer repeats not previously characterized.