Belatacept Conversion Protocols and Outcomes in Kidney Transplant Recipients

BackgroundConversion from calcineurin inhibitor (CNI)-based to belatacept-based immunosuppression has become common; however, numerous protocols have emerged in lieu of a standardized protocol. The purpose of this study was to characterize belatacept conversion protocols from multiple centers and observe outcomes.MethodsThis was a retrospective study that included Kaiser Permanente Southern California members. The primary outcome was rejection 6 months after conversion and secondary outcomes included change in serum creatinine and graft loss.ResultsSeventy-eight patients were included. Thirteen distinct protocols were identified from 8 different transplant centers. Protocols varied by initial dose, induction schedule, and CNI taper. The observed rate of rejection was 6%. There was a trend toward an association of rejection with lower tacrolimus exposure at the time of conversion and lower mycophenolic acid dosing postconversion. Graft survival was 88% and patient survival was 94%. There was a significant improvement in creatinine after conversion. Those with early conversions and creatinine >2.0 mg/dL at the time of conversion had the best response.ConclusionsA large variety of belatacept conversion protocols were identified. Protocols were defined by the initial dose, induction regimen, and CNI taper. Rejection rates were low and may be influenced by exposure to maintenance immunosuppression during and after conversion. Most patients showed stabilization and improvement in creatinine postconversion, with the largest effect in those with an early conversion and serum creatinine >2.0 mg/dL.     

Bladder preservation versus radical cystectomy in transitional cell carcinoma and squamous cell carcinoma muscle invasive bladder cancer

Background:Randomizing patients to bladder preservation or radical cystectomy (RC) for the treatment of bladder cancer has not been practical, due to patient and physician preferences. Therefore, continually comparing the 2 treatment modalities is needed, in order to make the proper choice for each patient.Patients and methods:The records of T1–4N0M0 bladder cancer patients, who presented to the South Egypt Cancer Institute between 2007 and 2017 and were treated by either bladder preservation or RC were reviewed.Results:Out of the 166 included patients, 81 (48.8%) patients were treated by bladder preservation and 85 (51.2%) patients had RC. For the patients treated by bladder preservation and the patients treated by RC, the 5-year overall survival (OS) was 56% and 60% (p = 0.67), the 5-year local recurrence-free survival was 69% and 73% (p = 0.69), and the 5-year disease-free survival was 45% and 53% (p = 0.16), respectively. After propensity matching analysis, the mean 5-year OS was 58% for the bladder preservation patients and 61% for the RC patients (p = 0.51). It is notable that among the bladder preservation group, 8 patients (10%) had squamous cell carcinoma (SCC) pathology and refused RC. Their OS was 56% compared to 53% for the SCC patients treated by RC (p = 0.6).Conclusion:Bladder preservation is a safe alternative to cystectomy in transitional cell carcinoma stages T1–4aN0M0, and its use in SCC bladder cancer should be further studied, as it could be feasible to spare them from initial cystectomy.     

The Association Between Neighborhood Social Vulnerability and COVID-19 Testing,Positivity, and Incidence in Alabama and Louisiana

Racial/ethnic and socioeconomic disparities in COVID-19 burden have been widely reported. Using data from the state health departments of Alabama and Louisiana aggregated to residential Census tracts, we assessed the relationship between social vulnerability and COVID-19 testing rates, test positivity, and incidence. Data were cumulative for the period of February 27, 2020 to October 7, 2020. We estimated the association of the 2018 Social Vulnerability Index (SVI) overall score and theme scores with COVID-19 tests, test positivity, and cases using multivariable negative binomial regressions. We adjusted for rurality with 2010 Rural–Urban Commuting Area codes. Regional effects were modeled as fixed effects of counties/parishes and state health department regions. The analytical sample included 1160 Alabama and 1105 Louisiana Census tracts. In both states, overall social vulnerability and vulnerability themes were significantly associated with increased COVID-19 case rates (RR 1.57, 95% CI 1.45–1.70 for Alabama; RR 1.36, 95% CI 1.26–1.46 for Louisiana). There was increased COVID-19 testing with higher overall vulnerability in Louisiana (RR 1.26, 95% CI 1.14–1.38), but not in Alabama (RR 0.95, 95% CI 0.89–1.02). Consequently, test positivity in Alabama was significantly associated with social vulnerability (RR 1.66, 95% CI 1.57–1.75), whereas no such relationship was observed in Louisiana (RR 1.05, 95% CI 0.98–1.12). Social vulnerability is a risk factor for COVID-19 infection, particularly among racial/ethnic minorities and those in disadvantaged housing conditions without transportation. Increased testing targeted to vulnerable communities may contribute to reduction in test positivity and overall COVID-19 disparities.

     

A qualitative exploration of barriers to HIV prevention,treatment and support: Perspectives of transgender women and service providers

Transgender (trans) women experience barriers to access to HIV care, which result in their lower engagement in HIV prevention, treatment and support relative to cisgender people living with HIV. Studies of trans women's barriers to HIV care have predominantly focused on perspectives of trans women, while barriers are most often described at provider, organisation and/or systems levels. Comparing perspectives of trans women and service providers may promote a shared vision for achieving health equity. Thus, this qualitative study utilised focus groups and semi-structured interviews conducted 2018–2019 to understand barriers and facilitators to HIV care from the perspectives of trans women (n = 26) and service providers (n = 10). Barriers endorsed by both groups included: (a) anticipated and enacted stigma and discrimination in the provision of direct care, (b) lack of provider knowledge of HIV care needs for trans women, (c) absence of trans-specific services/organisations and (d) cisnormativity in sexual healthcare. Facilitators included: (a) provision of trans-positive trauma-informed care, (b) autonomy and choice for trans women in selecting sexual health services and (c) models for trans-affirming systems change. Each theme had significant overlap, yet nuanced perspective, between trans women and service providers. Specific recommendations to improve HIV care access for trans women are discussed. These recommendations can be used by administrators and service providers alike to work collaboratively with trans women to reduce barriers and facilitators to HIV care and ultimately to achieve health equity for trans women.     

A Systematic Overview of Radiation Therapy Effects in Cervical Cancer (Cervix Uteri)

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn.There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer.There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer.The NCI has recently published an announcement stating that cisplantin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages (>IIB).There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea.There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer.There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Functional and anatomical evaluation of the effect of nepafenac in prevention of macular edema after phacoemulsification in diabetic patients

AIM: To evaluate the effect of prophylactic administration of nepafenac in prevention of macular edema occurring in diabetic patients after phacoemulsification and to investigate the correlation between optical coherence tomography (OCT) foveal thickness and multifocal electroretinogram (MF-ERG) parameters. METHODS: The study included two groups. Group 1 included 50 diabetic patients with senile cataract (50 eyes, 30 females, 20 males, aged 55±7y) received nepafenac 0.1% eye drop. Group 2 included another 50 diabetic patients with senile cataract (50 eyes, 22 female, 28 males, aged 53.8±8y) did not receive nepafenac. All patients were followed up for 3mo postoperatively. OCT and MF-ERG were done preoperative and at 1wk, 1, 2 and 3mo. RESULTS: The mean foveal thickness was statistically significantly lower in Group 1. Five eyes in Group 2 developed clinical cystoid macular oedema (CMO) (10%), and no patients in Group 1 developed central macular thickening more than 50 μm. There were insignificant differences in MF-ERG amplitudes and latencies between the two groups except in the five eyes that developed CMO, there statistically significant reduction of MF-ERG amplitude with increase in foveal thickness. CONCLUSION: Perioperative nepafenac reduces the incidence of CMO following uncomplicated phacoemulsification significantly. Nepafenac has no side effects.     

Cytotoxic effects of extracts obtained from plants of the Oleaceae family: bio-guided isolation and molecular docking of new secoiridoids from Jasminum humile

ContextTraditionally, Oleaceae plants are used to treat many diseases, such as rheumatism, hypercholesterolaemia, or ulcers.ObjectivesTo investigate the cytotoxic potential of Jasminum humile L., Jasminum grandiflorum L., and Olea europaea L. (Oleaceae) extracts against selected human cancer cells lines, followed by a phytochemical investigation of the most potent one.Materials and methodsThe 95% ethanol extracts of aerial parts of three oleaceous plants were examined for their cytotoxicity against HepG-2, MCF-7, and THP-1 cell lines using MTT assay and doxorubicin (positive control). J. humile was bio-selected and submitted to bio-guided fractionation. Chromatographic workup of ethyl acetate and n-butanol fractions afforded two new compounds; 1-methoxyjasmigenin (1) and 1-methyl-9-aldojasmigenin (2), along with five known ones (3–7). Structures were unambiguously elucidated using 1D/2D NMR and ESI-HRMS. Isolated compounds were assessed for their anti-proliferative potential, and both selectivity index and statistical significance were determined. Molecular docking was conducted against the Mcl-1 receptor using (AZD5991) as a standard.ResultsJasmoside (5) was the most potent anticancer compound showing IC₅₀ values of 66.47, 41.32, and 27.59 µg/mL against HepG-2, MCF-7, and THP-1 cell lines, respectively. Moreover, isojasminin (4) exhibited IC₅₀ values of 33.49, 43.12, and 51.07 µg/mL against the same cell lines, respectively. Interestingly, 5 exhibited the highest selectivity index towards MCF-7 and THP-1, even greater than doxorubicin. Molecular docking results were in full agreement with the MTT assay and the proposed SAR.ConclusionIn this study, two new compounds were purified. The biological activity highlighted jasmoside (5) as a lead anticancer drug for further future investigation.