Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology

Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na⁺ and K⁺ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology.     

Suicide vs medical assistance in dying (MAiD): A secondary qualitative analysis

Abstract

This is a secondary analysis of three qualitative studies about MAiD in which researchers asked about the differences between suicide and MAiD. In all, researchers interviewed 52 Canadians; 7 were people who had requested MAiD and had been found ineligible, 6 were MAiD providers and 39 were socially and economically marginalized. The overwhelming response was that MAiD is better than suicide in the context of suffering at the end of life. Whereas these people perceived suicide as uncertain, difficult, and something that was usually done alone and without support, they thought MAiD was certain, painless, and more socially acceptable.     

Effect of reverse manual wheelchair propulsion on shoulder kinematics,kinetics and muscular activity in persons with paraplegia

Objective: Shoulder pain after spinal cord injury (SCI) is attributed to increased mobility demands on the arms and negatively impacts independence and quality of life. Repetitive superior and posterior shoulder joint forces produced during traditional wheelchair (WC) locomotion can result in subacromial impingement if unopposed, as with muscular fatigue or weakness. ROWHEELS^® (RW), geared rear wheels that produce forward WC movement with backward rim pulling, could alter these forces.

Design: Cross sectional.

Setting: Research laboratory at a rehabilitation hospital.

Participants: Ten manual WC users with paraplegia.

Outcome measures: Propulsion characteristics and right upper extremity/trunk kinematics and shoulder muscle activity were collected during ergometer propulsion: (1) self-selected free speed reverse propulsion with RW, (2) matched-speed reverse (rSW), and (3) forward propulsion (fSW) with instrumented Smartwheels (SW). Inverse dynamics using right-side SW rim kinetics and kinematics compared shoulder kinetics during rSW and fSW.

Results: Free propulsion velocity, cycle distance and cadence were similar during RW, rSW and fSW. Overall shoulder motion was similar except that peak shoulder extension was significantly reduced in both RW and rSW versus fSW. Anteriorly and inferiorly directed SW rim forces were decreased during rSW versus fSW propulsion, but posteriorly and superiorly directed rim forces were significantly greater. Superior and posterior shoulder joint forces and flexor, adductor, and external rotation moments were significantly less during rSW, without a significant difference in net shoulder forces and moments. Traditional propulsive-phase muscle activity was significantly reduced and recovery-phase muscle activity was increased during reverse propulsion.

Conclusion: These results suggest that reverse propulsion may redirect shoulder demands and prevent subacromial impingement, thereby preventing injury and preserving independent mobility for individuals with paraplegia.     

Binge drinking concurrent with anal intercourse and condom use among men who have sex with men

Men who have sex with men (MSM) are the demographic group most severely affected by HIV in the USA. Global association studies have shown that MSM who binge drink are more likely to engage in risky sexual behaviors and day- and event-level analyses have linked binge drinking to sexual risk behavior on specific days and during specific sexual encounters. Despite this strong foundation of research, no studies have examined the association between the frequency of situational binge drinking (i.e., binge drinking concurrent with sexual activity) and aggregated sexual risk over periods of longer duration. We used multivariable logistic regression to assess the relationship between situational binge drinking (i.e., binge drinking concurrent with anal intercourse) and condomless anal intercourse (CAI) and among a cross-sectional sample of 124 MSM in San Francisco, CA. There was a positive relationship between frequency of situational binge drinking and CAI (1–5 times vs. never: adjusted odds ratio?=?2.78, 95% CI?=?1.01–7.63; 6–10 times vs. never: 6.19, 1.27–30.22; more than 10 times vs. never: 11.88, 1.31–107.60). By filling a methodological gap and complementing existing global and event-level analyses, this positive situational relationship strengthens the evidence linking binge drinking and sexual risk, enhances the comparability of the existing literature, and further suggests that the integration of dual strategies that aim to prevent HIV and reduce binge drinking may be warranted.     

HPTN 068: A Randomized Control Trial of a Conditional Cash Transfer to Reduce HIV Infection in Young Women in South Africa—Study Design and Baseline Results

Young women in South Africa are at high risk for HIV infection. Cash transfers offer promise to reduce HIV risk. We present the design and baseline results from HPTN 068, a phase III, individually randomized trial to assess the effect of a conditional cash transfer on HIV acquisition among South African young women. A total of 2533 young women were randomized to receive a monthly cash transfer conditional on school attendance or to a control group. A number of individual-, partner-, household- and school-level factors were associated with HIV and HSV-2 infection. After adjusting for age, all levels were associated with an increased odds of HIV infection with partner-level factors conveying the strongest association (aOR 3.05 95 % CI 1.84–5.06). Interventions like cash transfers that address structural factors such as schooling and poverty have the potential to reduce HIV risk in young women in South Africa.