Bacteriophage Migration via Nematode Vectors: Host-Parasite-Consumer Interactions in Laboratory Microcosms

Pathogens vectored by nematodes pose serious agricultural, economic, and health threats; however, little is known of the ecological and evolutionary aspects of pathogen transmission by nematodes. Here we describe a novel model system with two trophic levels, bacteriophages and nematodes, each of which competes for bacteria. We demonstrate for the first time that nematodes are capable of transmitting phages between spatially distinct patches of bacteria. This model system has considerable advantages, including the ease of maintenance and manipulation at the laboratory bench, the ability to observe many generations in short periods, and the capacity to freeze evolved strains for later comparison to their ancestors. More generally, experimental studies of complex multispecies interactions, host-pathogen coevolution, disease dynamics, and the evolution of virulence may benefit from this model system because current models (e.g., chickens, mosquitoes, and malaria parasites) are costly to maintain, are difficult to manipulate, and require considerable space. Our initial explorations centered on independently assessing the impacts of nematode, bacterium, and phage population densities on virus migration between host patches. Our results indicated that virus transmission increases with worm density and host bacterial abundance; however, transmission decreases with initial phage abundance, perhaps because viruses eliminate available hosts before migration can occur. We discuss the microbial growth dynamics that underlie these results, suggest mechanistic explanations for nematode transmission of phages, and propose intriguing possibilities for future research

Clinically Significant Gains in Skillful Grasp Coordination by an Individual With Tetraplegia Using an Implanted Brain-Computer Interface With Forearm Transcutaneous Muscle Stimulation

© 2019 American Congress of Rehabilitation Medicine Objective: To demonstrate naturalistic motor control speed, coordinated grasp, and carryover from trained to novel objects by an individual with tetraplegia using a brain-computer interface (BCI)-controlled neuroprosthetic. Design: Phase I trial for an intracortical BCI integrated with forearm functional electrical stimulation (FES). Data reported span postimplant days 137 to 1478. Setting: Tertiary care outpatient rehabilitation center. Participant: A 27-year-old man with C5 class A (on the American Spinal Injury Association Impairment Scale) traumatic spinal cord injury Interventions: After array implantation in his left (dominant) motor cortex, the participant trained with BCI-FES to control dynamic, coordinated forearm, wrist, and hand movements. Main Outcome Measures: Performance on standardized tests of arm motor ability (Graded Redefined Assessment of Strength, Sensibility, and Prehension [GRASSP], Action Research Arm Test [ARAT], Grasp and Release Test [GRT], Box and Block Test), grip myometry, and functional activity measures (Capabilities of Upper Extremity Test [CUE-T], Quadriplegia Index of Function-Short Form [QIF-SF], Spinal Cord Independence Measure–Self-Report [SCIM-SR]) with and without the BCI-FES. Results: With BCI-FES, scores improved from baseline on the following: Grip force (2.9 kg); ARAT cup, cylinders, ball, bar, and blocks; GRT can, fork, peg, weight, and tape; GRASSP strength and prehension (unscrewing lids, pouring from a bottle, transferring pegs); and CUE-T wrist and hand skills. QIF-SF and SCIM-SR eating, grooming, and toileting activities were expected to improve with home use of BCI-FES. Pincer grips and mobility were unaffected. BCI-FES grip skills enabled the participant to play an adapted “Battleship” game and manipulate household objects. Conclusions: Using BCI-FES, the participant performed skillful and coordinated grasps and made clinically significant gains in tests of upper limb function. Practice generalized from training objects to household items and leisure activities. Motor ability improved for palmar, lateral, and tip-to-tip grips. The expects eventual home use to confer greater independence for activities of daily living, consistent with observed neurologic level gains from C5-6 to C7-T1. This marks a critical translational step toward clinical viability for BCI neuroprosthetics

Performance in Physical Education and Health Impairment 30 Years Later—A Community Based Cohort Study

Objective: A main purpose of physical education (PE) in school is to promote future health. However, there is very limited evidence of the effects of PE on the adult health. We hypothesized that a low performance in PE was associated with an increased risk of health impairment by middle age. Methods: We performed a cohort study in a community-based setting in Sweden spanning over three decades. We followed up on 1712 of 2225 students (76.9%) who in 1974–1976 graduated with a grade in PE after 9 years of education (mean subject age 16 years). The grade in PE (compulsory subject) was retrieved from municipal archives. We defined three proxies for health impairment: total number of visits to primary care physicians in 2003–2007, having been hospitalized 2003–2007, and total number of days with sick leave in 2004–2007. Using binomial regression models, we adjusted the risk estimates for level of education and occupation. Subjects with an average grade in PE served as reference category. Results: In both the crude and adjusted model, women with a low grade in PE had more physician visits (adjusted IRR 1.30, 95 % confidence interval 1.06–1.60) and an increased number of days with sick leave (adjusted IRR 1.44, 1.05–1.95). An increased, although not significant, risk was also observed for having received in-patient care (adjusted RR 1.26; 0.88–1.80). No significant results or similar pattern were observed in men. Conclusion: Women with a low grade in PE in adolescence seem to have an increased risk of health impairment by middl

Sonographic assessment of renal length in children: A reappraisal

Ultrasonography (US) has largely replaced the intravenous urogram as the first modality for the evaluation of the kidneys in children suspected of having urinary tract abnormalities. Because many renal disorders are associated with changes in the sizes of the kidneys, normative standards for assessing renal size have been developed. These standards rely upon comparison of the renal lengths or calculated volumes or both, with various assessments of overall body size, including body surface area, weight, height, and chronological age. We discuss some of the limitations of US in assessing renal size in children. Practical recommendations are offered for optimizing the measurement and interpretation of sonographic renal sizes in children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46703/1/247_2005_Article_BF02020164.pd

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.