Evaluating the Impact of a Youth-Led Sexual Violence Prevention Program: Youth Leadership Retreat Outcomes

Prevention Science - Involving youth in developing and implementing prevention programs to reduce sexual violence (SV) has the potential to improve prevention outcomes. However, there has been...     

A randomized controlled trial evaluating combination detection of HIV in Malawian sexually transmitted infections clinics

IntroductionHIV diagnosis is the necessary first step towards HIV care initiation, yet many persons living with HIV (PLWH) remain undiagnosed. Employing multiple HIV testing strategies in tandem could increase HIV detection and promote linkage to care. We aimed to assess an intervention to improve HIV detection within socio‐sexual networks of PLWH in two sexually transmitted infections (STI) clinics in Lilongwe, Malawi.MethodsWe conducted a randomized controlled trial to evaluate an intervention combining acute HIV infection (AHI) screening, contract partner notification and social contact referral versus the Malawian standard of care: serial rapid serological HIV tests and passive partner referral. Enrolment occurred between 2015 and 2019. HIV‐seropositive persons (two positive rapid tests) were randomized to the trial arms and HIV‐seronegative (one negative rapid test) and ‐serodiscordant (one positive test followed by a negative confirmatory test) persons were screened for AHI with HIV RNA testing. Those found to have AHI were offered enrolment into the intervention arm. Our primary outcome of interest was the number of new HIV diagnoses made per index participant within participants’ sexual and social networks. We also calculated total persons, sexual partners and PLWH (including those previously diagnosed) referred per index participant.ResultsA total of 1230 HIV‐seropositive persons were randomized to the control arm, and 561 to the intervention arm. Another 12,713 HIV‐seronegative or ‐serodiscordant persons underwent AHI screening, resulting in 136 AHI cases, of whom 94 enrolled into the intervention arm. The intervention increased the number of new HIV diagnoses made per index participant versus the control (ratio: 1.9; 95% confidence interval (CI): 1.2 to 3.1). The intervention also increased the numbers of persons (ratio: 2.5; 95% CI: 2.0 to 3.2), sexual partners (ratio: 1.7; 95% CI: 1.4 to 2.0) and PLWH (ratio: 2.3; 95% CI: 1.7 to 3.2) referred per index participant.ConclusionsCombining three distinct HIV testing and referral strategies increased the detection of previously undiagnosed HIV infections within the socio‐sexual networks of PLWH seeking STI care. Combination HIV detection strategies that leverage AHI screening and socio‐sexual contact networks offer a novel and efficacious approach to increasing HIV status awareness.     

The utility of the implementation science framework “Integrated Promoting Action on Research Implementation in Health Services” (i-PARIHS) and the facilitator role for introducing patient-reported outcome measures (PROMs) in a medical oncology outpatient department

Quality of Life Research - We evaluated the utility of the implementation science framework “Integrated Promoting Action on Research Implementation in Health Services” (i-PARIHS) for...     

Pharmacokinetics and Safety of a Selegiline Transdermal System Relative to Single-Dose Oral Administration in the Elderly

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.     

Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway.

PURPOSE: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway EXPERIMENTAL DESIGN: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E. RESULTS: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P < 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P < 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (beta, gamma, and delta) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated alpha isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P < 0.05). CONCLUSIONS: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.     

Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E Succinate and vitamin E analogue, alpha-TEA.

A vitamin E derivative, vitamin E succinate (VES; RRR-alpha-tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (alpha-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with alpha-TEA exhibiting greater proapoptotic effects. Although both VES and alpha-TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only alpha-TEA is an effective inducer of apoptosis. VES or alpha-TEA treatment of cp70 cells with 5, 10, or 20 microg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by alpha-TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of alpha-TEA were demonstrated by high-performance liquid chromatography analyses that showed alpha-TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR-alpha-tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show alpha-TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR-alpha-tocopherol, an ineffective apoptotic-inducing agent.     

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.     

Sexual dysfunction damages: A legal database review

IntroductionProcedural specialties are at higher risk for malpractice claims than non-procedural specialties. Previous studies have examined common damages and malpractice lawsuits resulting from specific procedures. Our goal was to analyze urological interventions that led to sexual dysfunction (SD) claims.MethodsThe Casetext legal research platform was queried using search terms for medical malpractice and common men’s health procedures between 1993 and 2020. In total, 236 cases were found, and 21 cases met the inclusion criteria: malpractice cases against a urologist or urology group, clearly stated legal outcome, and allegation of sexual dysfunction from an intervention that directly caused damages.ResultsA total of 42 damages were cited in 21 lawsuits. The top three damages claimed were erectile dysfunction (ED) (14/42, 33.3%), genital pain syndrome (7/42, 16.7%), and urinary incontinence (5/42, 11.9%). The most commonly cited treatments were urinary catheter placement or removal (3/21, 14.3%), robotic-assisted laparoscopic radical prostatectomy (RALP) (3/21, 14.3%), circumcision (3/21, 14.3%), and penile implant (3/21, 14.3%). In 19 of 21 suits (90.4%), the outcome favored the defendant. Two cases favored the plaintiff: penile implant (failure to prove the patient was permanently, organically impotent prior to the procedure; missed urethral injury at time of surgery, $300 000) and vasectomy (damage to vasculature resulting in loss of testicle, $300 000).ConclusionsMost suspected malpractice cases resulting in SD favored the defendant urologist. Interestingly, urinary catheter placement is as likely to result in litigation as other operative interventions, such as RALP, inflatable penile prosthesis, and circumcision. It is possible that thorough preoperative counselling and increased responsiveness to patients’ postoperative concerns may have avoided litigation in several cases.