A Digitally-Controlled Integrated Circuit Solution for Tinnitus Treatment with Charge Balancing.

An integrated circuit specified for tinnitus treatment is described. This chip, realized using a 0.18um BCD high-voltage CMOS process, is capable of generating current stimulus with any wave shape directly into the inner-ear tissue without the need for off-chip control circuitry. Used as part of a multi-chip module that can be implanted into the inner ear, this core chip contains an 8-bit digital-to-analog converter, an amplitude control block, a novel high-voltage drive and charge balance circuit, a high-voltage level shifter, an SRAM, a ROM, and an on-chip central control unit. The chip can achieve ±0.1 mV charge-balance precision.

Rehabilitation Outcomes in Children With Acute Flaccid Myelitis From 2014 to 2019: A Multicenter Retrospective Review.

BACKGROUND: Acute flaccid myelitis (AFM) is a childhood illness characterized by sudden-onset weakness impairing function. The primary goal was to compare the motor recovery patterns of patients with AFM who were discharged home or to inpatient rehabilitation. Secondary analyses focused on recovery of respiratory status, nutritional status, and neurogenic bowel and bladder in both cohorts. METHODS: Eleven tertiary care centers in the United States performed a retrospective chart review of children with AFM between January 1, 2014, and October 1, 2019. Data included demographics, treatments, and outcomes on admission, discharge, and follow-up visits. RESULTS: Medical records of 109 children met inclusion criteria; 67 children required inpatient rehabilitation, whereas 42 children were discharged directly home. The median age was 5 years (range 4 months to 17 years), and the median time observed was 417 days (interquartile range = 645 days). Distal upper extremities recovered better than the proximal upper extremities. At acute presentation, children who needed inpatient rehabilitation had significantly higher rates of respiratory support (P < 0.001), nutritional support (P < 0.001), and neurogenic bowel (P = 0.004) and bladder (P = 0.002). At follow-up, those who attended inpatient rehabilitation continued to have higher rates of respiratory support (28% vs 12%, P = 0.043); however, the nutritional status and bowel/bladder function were no longer statistically different. CONCLUSIONS: All children made improvements in strength. Proximal muscles remained weaker than distal muscles in the upper extremities. Children who qualified for inpatient rehabilitation had ongoing respiratory needs at follow-up; however, recovery of nutritional status and bowel/bladder were similar.

A consensus statement on the use of botulinum toxin in pediatric patients.

Botulinum toxin has been used in medicine for the past 30 years. However, there continues to be controversy about the appropriate uses and dosing, especially in the pediatric population. A panel of nine pediatric physiatrists from different regions and previous training programs in the United States were nominated based on institutional reputation and botulinum toxin (BoNT) experience. Based on a review of the current literature, the goal was to provide the rationale for recommendations on the administration of BoNT in the pediatric population. The goal was not only to review safety, dosing, and injection techniques but also to develop a consensus on the appropriate uses in the pediatric population. In addition to upper and lower limb spasticity, the consensus also provides recommendations for congenital muscular torticollis, cervical dystonia, sialorrhea, and brachial plexus palsies.

Community reintegration needs following paediatric brain injury: perspectives of caregivers and service providers.

PURPOSE: To explore the processes of community reintegration of children and families at least one year following a paediatric brain injury from the perspective of caregivers and outpatient/community service providers. MATERIALS AND METHODS: A qualitative analysis of semi-structured interviews from outpatient or community service providers (N = 14; occupational, physical, and speech and language therapists, neuropsychologists, school counsellors, recreational providers) and caregivers of six children (N = 8) at least one year after their injury. Interviews were transcribed and thematically coded using deductive (employing Bronfenbrenner's ecological systems theory) and inductive approaches. RESULTS: Themes from both providers and caregivers indicated additional supports needed at all levels of Bronfenbrenner's ecological systems theory (i.e., individual, microsystem, mesosystem/exosystem, macrosystem, chronosystem). Participants felt that several characteristics would be needed in an ideal service system following paediatric brain injury including: community solutions ("it takes a village"), long-term approaches to care, and new financial approaches. CONCLUSIONS: The results suggest that children and families have substantial community reintegration needs following paediatric brain injury. Multi-system interventions are needed to support long-term community reintegration, especially those that increase communication and support transitions. There is also a strong need for alternative funding to support these efforts.Implications for RehabilitationFamilies with a child with a moderate to severe brain injury face challenges with community reintegration a year or more after their child's injury.Effort should be put into helping families navigate the complex medical, insurance, and school systems with a navigator service and step-down care to ensure a continuum of care and to support community reintegration.Special support should be provided during transitions, such as transitions from hospital care to outpatient care, and across school transitions.

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.

A 30 $\mu\text{W}$ Remotely Powered Local Temperature Monitoring Implantable System.

An implantable local temperature monitoring system for a laboratory mouse is presented. Magnetic coupling is used to remotely power the passive implant. The temperatures of two local points are monitored by thermistors. A low-power readout circuit is implemented by directly amplifying and resolving the sensor response in the time domain. A free-running oscillator operating at 868 MHz transmits the sensor data to the base station. The average power dissipation of the implant is decreased by time interleaving between the sensor readout and the data communication. The power transfer to the implant is also time interleaved with other operations to avoid interference with data communication. A voltage regulation loop for the implant based on controlling the duration of powering the base station power amplifier is also described. A prototype chip is implemented in 0.18 [Formula: see text] CMOS. The implant requires average RF power of 29.5 [Formula: see text] for operation and is capable of measuring two thermistors with accuracy of ±0.05 °C.

Panobinostat for the management of multiple myeloma.

Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan-deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM.

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

BACKGROUND: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. METHODS: We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 µg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/µl and platelet count >20,000/µl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. RESULTS: Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. CONCLUSIONS: Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.

Evidence that sequence homologous region in LRAT-like proteins possesses anti-proliferative activity and DNA binding properties: translational implications and mechanism of action.

LRAT (lecithin:retinol acyltransferase), an enzyme whose levels are modulated during malignant conversion, has been reported as the founder member of a new LRAT-like family that includes tumor suppressors TIG-3(1-164) and Ha-Rev107(1-162). The mechanisms that link these three proteins to carcinogenesis as well as the significance of a reported shared sequence homologous region remain unclear. This begs the question if the tumor suppressors possess enzyme properties and/or if the LRAT enzyme possesses tumor suppressor properties. We use the reported homologous region as a first approach to address the question from the perspective that all three proteins can possess tumor suppressor properties. We postulated that the homologous sequence harbors an anti-proliferation domain within the full-length proteins and that dodecapeptides of this sequence possess anti-proliferative activity. We report that H-TIG-3(111-123), H-Ha-Rev107-1(111-123) and H-LRAT160-171:C168L exhibited in vitro growth inhibitory activity in a human cutaneous melanoma (HCM) model and affected tumor growth in a nude mouse model. Further, in peptide-sensitive HCM cells, these peptides crossed the plasma membrane and localized to the nucleus, where they could bind and activate promoters of transcription factors involved in G1-->S transition. Moreover, peptide-induced abrogation of cyclin dependent kinase-2 expression was concomitant with sub-cellular re-distribution of cyclins E and A. Indeed, the sequence homologous region within each full-length wild-type protein as well as the growth inhibitory peptides can form alpha helices, a likely configuration for binding to DNA. This is the first report that this sequence homologous region (AA111-123) within these LRAT-like proteins harbors an anti-proliferative domain with DNA binding properties. Sequences from this sequence homologous region can be used as templates for anti-tumor drug design and as probes to investigate disease-related mechanisms and structure-activity relationships of the full-length proteins, TIG-3(1-164), Ha-Rev107(1-162) and LRAT160-171.