Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography–tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T_1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.     

Automated preparation of 2‐[18F]fluoropropionate labeled peptides using a flexible,multi‐stage synthesis platform (iPHASE Flexlab)

Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi‐step procedures, especially for fluorine‐18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2‐[¹⁸F]fluoropropionate labeled RGD‐peptides through use of the iPHASE Flexlab as an effective dual‐stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD‐peptides, [¹⁸F]FP‐GalactoRGD and [¹⁸F]FP‐c(RGDy(SO₃)K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD‐peptides, [¹⁸F]F‐PRGD₂ and [¹⁸F]FP‐E(RGDy(SO₃)K)₂, was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride.     

Ultra‐short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients

We conducted an adaptive design single‐center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra‐short‐term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)‐nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R?). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12‐week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first‐line DAA therapy; and two after retreatment with second‐line DAA). At a median follow‐up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4‐day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%‐20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R ? transplants.     

Biologic Versus Nonbiologic Mesh in Ventral Hernia Repair: A Systematic Review and Meta-analysis

Background

The current standard of treatment for most ventral hernias is a mesh-based repair. Little is known about the safety and efficacy of biologic versus nonbiologic grafts. A meta-analysis was performed to examine two primary outcomes: recurrence and wound complication rates.

Methods

Electronic databases and reference lists of relevant articles were systematically searched for all clinical trials and cohort studies published between January 1990 and January 2012. A total of eight retrospective studies, with 1,229 patients, were included in the final analysis.

Results

Biologic grafts had significantly fewer infectious wound complications (p < 0.00001). However, the recurrence rates of biologic and nonbiologic mesh were not different. In subgroup analysis, there was no difference in recurrence rates and wound complications between human-derived and porcine-derived biologic grafts.

Conclusions

Use of biologic mesh for ventral hernia repair results in less infectious wound complications but similar recurrence rates compared to nonbiologic mesh. This supports the application of biologic mesh for ventral hernia repair in high-risk patients or patients with a previous history of wound infection only when the significant additional cost of these materials can be justified and synthetic mesh is considered inappropriate.     

The clinical spectrum of anxiety in Parkinson's disease

Anxiety is common in Parkinson's disease (PD), and contributes to increased disability and poorer quality of life. In spite of its significant impact, the symptomatology, chronology, and neurobiology of anxiety in PD are all poorly understood, and this hinders accurate diagnosis and development of effective treatment strategies. This review investigates and updates literature related to the clinical spectrum of anxiety in PD. The reported prevalence of anxiety in PD varies considerably, with emerging interest in the frequency of the DSM‐IV residual category of “Anxiety disorder, not otherwise specified” (Anxiety disorder NOS), which is observed in up to 25% of PD patients. By design, there are no standardized diagnostic criteria for Anxiety disorder NOS, because this is the category applied to individuals who do not meet diagnostic criteria for any other current anxiety disorder. Anxiety rating scales incompletely capture anxiety symptoms that relate specifically to PD symptoms and the complications arising from PD therapy. Consequently, these scales have been deemed inappropriate for use in PD, and there remains a need for the development of a new PD‐specific anxiety scale. Research establishing accurate symptom profiles of anxiety in PD is sparse, although characterizing such symptomatology would likely improve clinical diagnosis and facilitate targeted treatment strategies. Research into the neurobiological and psychological underpinnings of anxiety in PD remains inconclusive. Anxiety can precede the onset of PD motor symptoms or can develop after a diagnosis of PD. Further investigations focused on the chronology of anxiety and its relationship to PD diagnosis are required. © 2014 International Parkinson and Movement Disorder Society     

Predicting Psychosocial Outcomes Using a Brief Measure of Quality of Life in a Sample of People with Spinal Cord Injury

Background:

Spinal cord injury (SCI) significantly impacts an individual’s quality of life (QOL). A brief and subjective measure of QOL is necessary to monitor the progress and outcomes of SCI rehabilitation.

Objective:

To determine whether this measure of QOL was associated with clinically important physical and psychosocial outcomes in a sample of people with SCI, to determine how people with SCI scored on this measure of QOL, and to determine whether people with SCI scored differently than nondisabled individuals on the QOL scale.

Methods:

Participants were 134 people with SCI (65% male; 35% female) and 227 nondisabled people (35% male; 65% female). Participants were assessed on a number of psychosocial and physiological variables at a large urban university and rehabilitation center. Variables examined were QOL, life satisfaction, depression, social interaction, pain, fatigue, and level of functioning.

Results:

Participants with SCI reported more low QOL scores and fewer high QOL scores than the nondisabled group. For participants with SCI, QOL was positively related to life satisfaction and social interaction and negatively related to pain, fatigue, and depression.

Conclusions:

Participants with SCI scored lower on the QOL measure than those without a disability, although the difference was not clinically significant. QOL was unrelated to level of functioning; people may still experience a high QOL despite their physical limitations. Depression and social interaction were significantly related to QOL and should be secondary targets for intervention following SCI rehabilitation.Key words: depression, disability, life satisfaction, pain, quality of life, social interaction, spinal cord injuriesQuality of life (QOL) can be defined as the quality of a person’s overall experiences of living. Individuals differ on what values they place on work, leisure activities, relationships with other people, intimacy with a spouse or partner, or participation in sports. Perhaps no other impairment impacts a person’s QOL as much as a spinal cord injury (SCI).¹ After the medical and functional problems are addressed in rehabilitation, individuals begin to think about how they can regain much of their previous lifestyle and QOL. There are substantial barriers in the physical and social environments that stand in the way of higher QOL, including medical issues; difficulties in constructing a suitable home environment; and challenges in keeping the family together, supporting oneself, and dealing with the subtle and not-so-subtle attitudes of others.² These problems and barriers can result in psychological issues, the most common of which is depression.³ It is not surprising that individuals find it difficult to regain a positive level of QOL after SCI.Considering that there are approximately 270,000 people currently living with SCI in the United States, with 12,000 new cases of SCI each year,⁴ the topic of QOL is important to the persons with SCI, their families, and to the clinicians who treat them. However, there is little agreement on the definition of QOL and therefore on its measurement. Most measures of QOL are either too long for clinicians to use in practice or are not measures of QOL itself, but rather are measures of life satisfaction, health status, or well-being. For example, The World Health Organization’s⁵ QOL measure, WHOQOL-BREF, is primarily a life satisfaction measure, and it takes more than 1 hour to administer. Even the SF-36,⁶ which many people inaccurately accept and use as a measure of QOL, is actually a measure of health status, according to the author.Experts in both QOL and SCI, including Dijkers⁷ and Tate,⁸ have argued that there is a need for a subjective measure of QOL that can be used to monitor a person’s progress of rehabilitation and as a measurable outcome of rehabilitation programs. Clinical practice requires brief measures that are reliable and valid and that can be incorporated into progress notes about the patient. This clinically oriented article addresses the issue of whether a brief measure of QOL can stand up to the rigors of scientific standards while still predicting clinically important outcomes of SCI and whether it is suitable for the practitioner as well as for persons with SCI.This article addresses 3 objectives. The first objective was to determine whether this measure of QOL was associated with clinically important physical and psychosocial outcomes in a sample of people with SCI. The second objective was to determine how people with SCI scored on this measure of QOL. The third objective was to determine whether people with SCI scored differently than nondisabled individuals on a subjective, single-item QOL scale.