Uptake and safety of community-based "screen-and-treat" with thermal ablation preventive therapy for cervical cancer prevention in rural Lilongwe, Malawi.

Malawi has the highest invasive cervical cancer (ICC) mortality rate worldwide, and ICC is the leading cause of cancer death among women. In 2004, Malawi adopted visual inspection with acetic acid (VIA) and ablative treatment with cryotherapy. However, screening coverage has remained low (<30%) and few women (<50%) who require ablative treatment receive it. Additional barriers include long distances to health facilities and challenges with maintaining gas supplies. Thermal ablation is a safe and effective alternative to cryotherapy. We assessed the safety and uptake of community-based ICC screening with VIA and same-day treatment using a handheld thermocoagulator (HTU) in rural Malawi. We held educational talks alongside community leaders and conducted VIA screening in nonclinic community settings to nonpregnant women aged 25 to 49 years without history of hysterectomy or genital cancer/precancer. Eligible women received same-day thermal ablation and HIV testing/counseling. We collected cervical biopsies before treatment and followed up women at Weeks 6 and 12, with repeat biopsy at Week 12. Between July and August 2017, 408 (88%) of 463 eligible women underwent VIA. Overall, 7% (n = 30) of women had a positive VIA, of whom 93% (n = 28) underwent same-day thermal ablation. Among the 30 VIA-positive women, 5 had cervical intraepithelial neoplasia (CIN) 1, 4 had CIN 2/3 and 21 had benign histologic findings. Abnormal vaginal discharge (60%) and light vaginal bleeding (52%) were the most reported adverse events. There was high uptake of the community-based ICC screening in the study population and treatment was safe in this setting. Similar strategies that minimize false-positive results are urgently needed in Malawi.

Toward a hybrid exoskeleton for crouch gait in children with cerebral palsy: neuromuscular electrical stimulation for improved knee extension.

BACKGROUND: Neuromuscular Electrical Stimulation (NMES) has been utilized for many years in cerebral palsy (CP) with limited success despite its inherent potential for improving muscle size and/or strength, inhibiting or reducing spasticity, and enhancing motor performance during functional activities such as gait. While surface NMES has been shown to successfully improve foot drop in CP and stroke, correction of more complex gait abnormalities in CP such as flexed knee (crouch) gait remains challenging due to the level of stimulation needed for the quadriceps muscles that must be balanced with patient tolerability and the ability to deliver NMES assistance at precise times within a gait cycle. METHODS: This paper outlines the design and evaluation of a custom, noninvasive NMES system that can trigger and adjust electrical stimulation in real-time. Further, this study demonstrates feasibility of one possible application for this digitally-controlled NMES system as a component of a pediatric robotic exoskeleton to provide on-demand stimulation to leg muscles within specific phases of the gait cycle for those with CP and other neurological disorders who still have lower limb sensation and volitional control. A graphical user interface was developed to digitally set stimulation parameters (amplitude, pulse width, and frequency), timing, and intensity during walking. Benchtop testing characterized system delay and power output. System performance was investigated during a single session that consisted of four overground walking conditions in a 15-year-old male with bilateral spastic CP, GMFCS Level III: (1) his current Ankle-Foot Orthosis (AFO); (2) unassisted Exoskeleton; (3) NMES of the vastus lateralis; and (4) NMES of the vastus lateralis and rectus femoris. We hypothesized in this participant with crouch gait that NMES triggered with low latency to knee extensor muscles during stance would have a modest but positive effect on knee extension during stance. RESULTS: The system delivers four channels of NMES with average delays of 16.5 ± 13.5 ms. Walking results show NMES to the vastus lateralis and rectus femoris during stance immediately improved mean peak knee extension during mid-stance (p = 0.003*) and total knee excursion (p = 0.009*) in the more affected leg. The electrical design, microcontroller software and graphical user interface developed here are included as open source material to facilitate additional research into digitally-controlled surface stimulation ( github.com/NIHFAB/NMES ). CONCLUSIONS: The custom, digitally-controlled NMES system can reliably trigger electrical stimulation with low latency. Precisely timed delivery of electrical stimulation to the quadriceps is a promising treatment for crouch. Our ultimate goal is to synchronize NMES with robotic knee extension assistance to create a hybrid NMES-exoskeleton device for gait rehabilitation in children with flexed knee gait from CP as well as from other pediatric disorders. TRIAL REGISTRATION: clinicaltrials.gov, ID: NCT01961557 . Registered 11 October 2013; Last Updated 27 January 2020.

C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function.

Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs). The two enriched in arginine, poly(GR) and poly(PR), infiltrate liquid-like nucleoli, co-localize with the nucleolar protein nucleophosmin (NPM1), and alter the phase separation behavior of NPM1 in vitro. Here, we show that poly(PR) DPRs bind tightly to a long acidic tract within the intrinsically disordered region of NPM1, altering its phase separation with nucleolar partners to the extreme of forming large, soluble complexes that cause droplet dissolution in vitro. In cells, poly(PR) DPRs disperse NPM1 from nucleoli and entrap rRNA in static condensates in a DPR-length-dependent manner. We propose that R-rich DPR toxicity involves disrupting the role of phase separation by NPM1 in organizing ribosomal proteins and RNAs within the nucleolus.

Clinical breast examination screening by trained laywomen in Malawi integrated with other health services.

BACKGROUND: Breast cancer awareness and early detection are limited in sub-Saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. We aimed to assess feasibility and performance of CBE by laywomen in urban health clinics in Malawi. METHODS: Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. After training, screening was implemented in diverse urban health clinics. Eligible women were ≥30 y, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. In addition, 50 randomly selected women with normal screening CBE underwent breast ultrasound, and 45 different women with normal CBE were randomly assigned to surgeon examination. RESULTS: Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P = 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomized to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval [CI] 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35%-62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended pathologic sampling of a breast lesion, two had cytologic dysplasia and all others benign results. CONCLUSIONS: CBE uptake in Lilongwe clinics was high. CBE by laywomen compared favorably with physician examination and follow-up was good. Our intervention can serve as a model for wider implementation. Performance in rural areas, effects on cancer stage and mortality, and cost effectiveness require evaluation.

Low-cost implementation of a self-paced treadmill by using a commercial depth sensor.

A self-paced treadmill that can simulate overground walking has the potential to improve the effectiveness of treadmill training for gait rehabilitation. We have implemented a self-paced treadmill without the need for expensive equipment such as a motion capture system and an instrumented treadmill. For this, an inexpensive depth sensor, ASUS XtionTM, substitutes for the motion capture system, and a low-cost commercial treadmill is considered as the platform of the self-paced treadmill. The proposed self-paced treadmill is also convenient because the depth sensor does not require markers placed on user's body. Through pilot tests with two healthy subjects, it is quantitatively and qualitatively verified that the proposed self-paced treadmill achieves similar performance as one which utilizes a commercial motion capture system (VICON) as well as an instrumented treadmill.