Quality of life and swallowing outcomes after early proactive swallowing rehabilitation by either transcutaneous neuromuscular electrical stimulation or exercise-based swallowing training in patients with nasopharyngeal carcinoma after radiotherapy.

Background: Exercise-based swallowing training (EBST) and transcutaneous neuromuscular electrical stimulation (TNMES) are common modalities used to treat late dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC). We aimed to investigate and compare the efficacies of EBST and TNMES as proactive treatments administered early after radiotherapy. Methods: Patients with early post-radiotherapy NPC (n = 120) underwent either TNMES or EBST. Flexible endoscopic evaluation of swallowing (FEES), quality of life (QOL), and swallowing function questionnaires were completed before the intervention as well as immediately, 6, and 12 months after the intervention. Outcome measures included the scores for the swallowing function score (SFS), penetration and aspiration scale (PAS), dynamic imaging grade of swallowing toxicity (DIGEST), functional oral intake scale (FOIS), swallowing performance status scale (SPSS), pharyngeal motor impairment (PMI), pharyngeal function impairment (PFI), and functional assessment after cancer therapy-nasopharyngeal (FACT-NP) questionnaire. Results: Three months after radiotherapy, 31 and 34 patients underwent TNMES and EBST, respectively, and completed swallowing assessments at all four assessment timepoints. All patients showed post-radiotherapy impairments in the SFS, PAS, DIGEST, PMI, and PFI. Compared with the EBST group, the TNMES group showed significant improvements in the PFI and PMI scores, with small-to-medium effect sizes. Additionally, compared with the EBST group, the TNMES group demonstrated a trend toward slightly better improvements in the PAS, DIGEST, FOIS, and SPSS scores immediately and 6 months after the intervention. The SFS scores improved from baseline in both groups; however, the TNMES group showed an earlier improvement. Finally, the TNMES group showed better QOL according to the FACT-NP than the EBST group. Conclusion: Proactive TMNES and EBST are safe and feasible modalities for improving swallowing in patients with NPC when administered early after radiotherapy. Although TNMES showed better results than EBST, these results should be interpreted with caution given the study limitations. Level of evidence: 1B.

Using an academic-community partnership model to deliver evidence-based falls prevention programs in a metropolitan setting: A community case study.

Background: Prevention is an effective approach for mitigating the negative health outcomes associated with falls in older adults. The Administration for Community Living (ACL) has sponsored the implementation of evidence-based falls prevention programs (EBFPPs) across the United States through cooperative agreement grants to decrease the health and economic burden of falls. Marymount University received two of these grants to deliver three EBFPPs into the northern Virginia region. This community case study describes the development of a collaboration between a university and community-based organizations to adopt and implement multiple evidence-based programming in an area where none previously existed. Methods: Through an academic-community partnership, EBFPPs were introduced to and implemented by senior-focused organizations. Target adopters were senior and community centers, multi-purpose senior services organizations, recreational organizations, and residential facilities serving older adults. The three EBFPPs were (1) Stay Active and Independent for Life (SAIL), (2) a Matter of Balance (MOB) and (3) Otago Exercise Program (OEP). Key interdependent project elements included: (1) fostering ongoing community organization collaboration, (2) introducing programs in the community, (3) growing and sustaining delivery sites, (4) preparing trained program leaders, and (5) building community demand for the programs. Results: From August 2016-June 2022, 5,857 older adults participated in one of the three EBFPPs. SAIL classes were offered at 33 sites and MOB workshops at 31 with over 70% of them occurring at community or senior centers. OEP was offered at 4 sites. Factors that influenced the implementation of these programs included having: key advocates at host organizations, programs embedded into site workflows, sufficient capacity and workforce, engaged invested partners, and flexibility in working with a complex set of agencies and systems with different administrative structures. Conclusion: By connecting academic faculty with various community members from multiple sectors, new initiatives can be successfully implemented. Results from this ACL-funded project indicate that using an academic-community partnership model to build relationships and capacity for ongoing delivery of health promotion programming for older adults is feasible and effective in delivering EBFPPs. In addition, academic-community partnerships can develop a strong network of invested partners to foster continued support of fall prevention activities.

Acupuncture for Poststroke Dysphagia: A Pilot, Nonrandomized, Self-Controlled Trial.

OBJECTIVE: To evaluate the effectiveness and safety of acupuncture treatment for dysphagia as a complication of stroke. Methods and Design. This is a multicenter, pragmatic, nonrandomized, self-controlled clinical trial. A total of 39 patients were recruited from several Chinese medicine outpatient clinics and hospital-affiliated speech therapy outpatient clinics in Hong Kong. 26 patients completed all the 24 sessions of acupuncture treatment within two months, and only 12 of them were used as self-control. For the self-control group, the retrospective clinical data was taken from the electronic patient records with patient consent. The descriptive swallowing function data were converted into the quantitative Royal Brisbane Hospital Outcome Measure for Swallowing (RBHOMS) scores by two registered speech therapists through a validation process. And the data were validated by reaching consensus between the two speech therapists. All subjects underwent a baseline assessment before commencement of treatment, and outcome assessments were conducted upon the completion of treatment. The primary outcome measure is the RBHOMS score, which is a swallowing disability rating scale for monitoring difficulties in daily swallowing function. Secondary outcome measures include the Chinese version of the Swallow Quality-of-Life Questionnaire and adverse events. All the primary and secondary outcomes were assessed at baseline as well as at the end of acupuncture treatment (month 2). RESULTS: A total of 39 participants aged 46 to 89 years were enrolled in the study, and the male-to-female ratio was 15 : 11. The mean baseline RBHOMS score of all 39 participants was 5.92 ± 2.23. The mean retrospective RBHOMS score of the 12 subjects who were used as self-control was 5.67 ± 1.72 before enrollment, while the mean RBHOMS score of the 26 participants who completed all the 24 sessions of treatment was 6.92 ± 2.07. There were statistically significant differences between the RBHOMS score at the completion of treatment and baseline (p=0.006), and retrospective data (p=0.042). Moreover, a significant difference was also found in terms of swallow quality-of-life score before and after acupuncture treatment (p < 0.01). CONCLUSIONS: This pilot study provides preliminary evidence for the effectiveness of acupuncture for poststroke dysphagia. The findings from this trial can be used as a foundation for future full-scale randomized controlled clinical trials to assess the efficacy and safety of acupuncture for poststroke dysphagia. Ethics and Dissemination. The ethical approval of the clinical research study was granted by the Research Ethics Committee of both New Territories East and West Cluster of Hong Kong. Written informed consent was obtained from all participants, and the study was undertaken according to the ICH-GCP Guidelines. Trial Registration. This trial is registered with ChiCTR-TRC-12002621 and the registration date is 2012-10-26.

'The public rely on me a lot': Rural pharmacists' perspectives on their roles in oral health care.

OBJECTIVE: To examine rural pharmacists' perspectives on their roles in oral health in rural communities and collaborations with dental practitioners. DESIGN: A qualitative research study using face-to-face, semistructured interviews. Interview data were thematically analysed with the assistance of Nvivo 10. SETTING: Eleven rural communities across rural Tasmania. PARTICIPANTS: Twenty community pharmacists. RESULTS: Five major themes emerged: (i) barriers for patients to access dental services; (ii) oral health presentations to rural pharmacies; (iii) roles of pharmacists in oral health care (subthemes: advice; health promotion; and referrals); (iv) collaborations with dental practitioners; and (v) oral health education and training. CONCLUSION: This study suggests that rural community pharmacists had advisory and referral roles in oral health and acknowledged that they could play a greater role in oral health promotion. It was suggested that oral health could be incorporated into existing pharmacy health promotion and surveillance activities. There was a lack of collaboration between pharmacists and dentists or dental services and limited oral health education and training provided to pharmacists. Stronger collaboration between pharmacists and dental practitioners and better oral health training for pharmacists may enhance their role in promoting oral health within rural communities.

Effects of electrical stimulation on vocal functions in patients with nasopharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: This study aimed to evaluate the effects of neuromuscular electrical stimulation (NMES) on vocal functions in patients with nasopharyngeal carcinoma following radiation therapy. STUDY DESIGN: Prospective, randomized controlled trial. METHODS: One hundred forty newly treated NPC patients were recruited and randomized into NMES or traditional swallowing exercise (TE) group. Participants received intensive NMES or traditional swallowing therapy and were followed up until 12 months postrandomization. Fifty-seven participants completed the treatment and all of the follow-up assessments. The Voice Handicap Index-30 (VHI-30) was used to measure the vocal functions of the participants. RESULTS: The NMES group showed no significant changes to their vocal functions, whereas the TE group showed a short-term deterioration of voice functions at the 6-month follow-up. VHI-30 scores returned to the baseline level for both groups at the 12-month follow-up. CONCLUSIONS: NMES is shown to provide a short-term benefit on vocal functions for NPC patients following radiation therapy. LEVEL OF EVIDENCE: 1b Laryngoscope, 127:1119-1124, 2017.

Solubility Challenges in High Concentration Monoclonal Antibody Formulations: Relationship with Amino Acid Sequence and Intermolecular Interactions.

The purpose of this work was to elucidate the molecular interactions leading to monoclonal antibody self-association and precipitation and utilize biophysical measurements to predict solubility behavior at high protein concentration. Two monoclonal antibodies (mAb-G and mAb-R) binding to overlapping epitopes were investigated. Precipitation of mAb-G solutions was most prominent at high ionic strength conditions and demonstrated strong dependence on ionic strength, as well as slight dependence on solution pH. At similar conditions no precipitation was observed for mAb-R solutions. Intermolecular interactions (interaction parameter, kD) related well with high concentration solubility behavior of both antibodies. Upon increasing buffer ionic strength, interactions of mAb-R tended to weaken, while those of mAb-G became more attractive. To investigate the role of amino acid sequence on precipitation behavior, mutants were designed by substituting the CDR of mAb-R into the mAb-G framework (GM-1) or deleting two hydrophobic residues in the CDR of mAb-G (GM-2). No precipitation was observed at high ionic strength for either mutant. The molecular interactions of mutants were similar in magnitude to those of mAb-R. The results suggest that presence of hydrophobic groups in the CDR of mAb-G may be responsible for compromising its solubility at high ionic strength conditions since deleting these residues mitigated the solubility issue.

Characterization of asparagine 330 deamidation in an Fc-fragment of IgG1 using cation exchange chromatography and peptide mapping.

Deamidation is one of the most common degradation pathways for proteins and frequently occurs at "hot spots" with Asn-Gly, Asn-Ser or Asn-Thr sequences. Occasionally, deamidation may occur at other motifs if the local protein structure can participate or assist in the formation of the succinimide intermediate. Here we report the use of a chymotryptic peptide mapping method to identify and characterize a deamidated form of an IgG1 which was observed as an acidic peak in the cation exchange chromatography (CEX). The antibody was formulated in sodium acetate buffer, pH 5.3 and this deamidated form was observed mainly under thermal stress conditions. It was found that the IgG1 molecule with deamidation in the Fc region at asparagine residue 330 (in a Val-Ser-Asn-Lys motif) is the predominant form in this CEX peak, and was missed by tryptic mapping because the peptides are hydrophilic and elute near the void volume. In addition, a domain-based CEX method using papain digestion was developed to monitor the Asn 330 deamidation. These methods revealed that the Fc deamidation occurs mainly at Asn 330 in the VSNK motif at pH 5.3, whereas at pH 7.5, deamidation occurs predominantly at Asn 389 and Asn 394 in the NGQPENNYK motif.

Asparagine deamidation dependence on buffer type, pH, and temperature.

The deamidation of asparagine into aspartate and isoaspartate moieties is a major pathway for the chemical degradation of monoclonal antibodies (mAbs). It can affect the shelf life of a therapeutic antibody that is not formulated or stored appropriately. A new approach to detect deamidation using ion exchange chromatography was developed that separates papain-digested mAbs into Fc and Fab fragments. From this, deamidation rates of each fragment can be calculated. To generate kinetic parameters useful in setting shelf life, buffers prepared at room temperature and then placed at the appropriate stability temperatures. Solution pH was not adjusted to the same at different temperatures. Deamidation rate at 40°C was faster in acidic buffers than in basic buffers. However, this trend is reversed at 5°C, attributed to the change in hydroxide ion concentration influenced by buffer and temperature. The apparent activation energy was higher for rates generated in an acidic buffer than in a basic buffer. The rate-pH profile for mAb1 can be deconvoluted to Fc and Fab. The Fc deamidation showed a V-shaped profile: deamidation of PENNY peptide is responsible for the rate at high-pH, whereas deamidation of a new site, Asn323, may be responsible for the rate at low-pH. The profile for Fab is a straight line without curvature.

Glycemic outcome not predicted by baseline psychological measures in a diabetes management program.

The Northern Health Diabetes Hospital Admission Risk Program is a chronic disease management program that aims to improve the glycemic management of patients with diabetes. The aim of this project was to determine if there was any relationship between psychological characteristics and glycemic outcome in a diabetes management program. A prospective study of patients attending the diabetes management program investigated validated measures of cognition, stage of change, locus of control, self-efficacy, depression and anxiety, and quality of life. The study investigated 86 type 2 diabetes patients (mean age 59 years, 49% female). Glycemic control (HbA1c) was measured at baseline and after 12 months in the program. Glycemic control was poor on admission to the service with a mean HbA1c of 8.9%. The measures of cognition, self-efficacy, locus of control, mental health, and quality of life were not associated with improvements in HbA1c. Those participants with shorter duration of disease and more contacts with the service were significantly more likely to experience improvements in HbA1c. Psychometric data were not predictive of glycemic outcome. Rather, in this chronic disease management program, glycemia improved more in patients who were seen earlier in their disease course and managed more intensively, regardless of their psychometric status.

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.

Viral loads and duration of viral shedding in adult patients hospitalized with influenza.

BACKGROUND: The goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza. METHODS: This was a 1-year prospective, observational study involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real-time reverse-transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models. RESULTS: One hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age+/-standard deviation, 72+/-16 years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting>2 days after symptom onset (mean+/-standard deviation, 5.06+/-1.85 vs 3.62+/-2.13 log10 copies/mL; P=.005; beta, +0.86 [95% confidence interval, +0.03 to +1.68]). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir-treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean beta [standard error], -1.19 [0.43] and -0.68 [0.33] log10 copies/mL for patients treated on day 1 and days 2-3, respectively; P<.05) and viral RNA clearance at 1 week (odds ratio, 0.10 [95% confidence interval, 0.03-0.35] and 0.30 [0.10-0.90] for patients treated on day 1-2 and day 3-4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; P=.001). CONCLUSION: Patients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance.

Altered trunk position sense and its relation to balance functions in people post-stroke.

OBJECTIVE: To determine whether trunk position sense is impaired in people with poststroke hemiparesis. BACKGROUND: Good trunk stability is essential for balance and extremity use during daily functional activities and higher level tasks. Dynamic stability of the trunk requires adequate flexibility, muscle strength, neural control, and proprioception. While deficits of trunk muscle strength have been identified in people post-stroke, it is not clear whether they have adequate postural control and proprioception to ensure a stable foundation of balance to enable skilled extremity use. Trunk position sense is an essential element of trunk postural control. Even a small impairment in trunk position sense may contribute to trunk instability. However, a specific impairment of trunk position sense has not been reported in people post-stroke. SUBJECTS: Twenty subjects with chronic stroke and 21 nonneurologically impaired subjects participated in the study. MAIN OUTCOME MEASURES: Trunk repositioning error during sitting forward flexion movements was assessed using an electromagnetic movement analysis system, Flock of Birds. Subjects post-stroke were also evaluated with clinical measures of balance (Berg Balance Scale), postural control (Postural Assessment Scale for Stroke), and extremity motor impairment severity (Fugl-Meyer Assessment-Motor Score). RESULTS: There were significant differences in absolute trunk repositioning error between stroke and control groups in both the sagittal (P = 0.0001) and transverse (P = 0.0012) planes. Mean sagittal plane error: post-stroke: 6.9 +/- 3.1 degrees, control: 3.2 +/- 1.8 degrees; mean transverse plane error: post-stroke 2.1 +/- 1.3 degrees, control: 1.0 +/- 0.6 degrees. There was a significant negative correlation between sagittal plane absolute repositioning error and the Berg Balance Scale score (r = -0.49, P = 0.03), transverse plane absolute repositioning error and Berg Balance Scale score (r = -0.48, P = 0.03), and transverse plane repositioning error and the Postural Assessment Scale for Stroke score (r = -0.52, P = 0.02) CONCLUSIONS: Subjects with poststroke hemiparesis exhibit greater trunk repositioning error than age-matched controls. Trunk position sense retraining, emphasizing sagittal and transverse movements, should be further investigated as a potential poststroke intervention strategy to improve trunk balance and control.

A survey of therapeutic ultrasound use by physical therapists who are orthopaedic certified specialists.

BACKGROUND AND PURPOSE: For many years, ultrasound (US) has been a widely used and well-accepted physical therapy modality for the management of musculoskeletal conditions. However, there is a lack of scientific evidence on its effectiveness. This study examined the opinions of physical therapists with advanced competency in orthopedics about the use and perceived clinical importance of US in managing commonly encountered orthopedic impairments. SUBJECTS: Four hundred fifty-seven physical therapists who were orthopaedic certified specialists from the Northeast/Mid-Atlantic regions of the United States were invited to participate. METHODS: A 77-item survey instrument was developed. After face and content validity were established, the survey instrument was mailed to all subjects. Two hundred seven usable survey questionnaires were returned (response rate=45.3%). RESULTS: According to the surveys, the respondents indicated that they were likely to use US to decrease soft tissue inflammation (eg, tendinitis, bursitis) (83.6% of the respondents), increase tissue extensibility (70.9%), enhance scar tissue remodeling (68.8%), increase soft tissue healing (52.5%), decrease pain (49.3%), and decrease soft tissue swelling (eg, edema, joint effusion) (35.1%). The respondents used US to deliver medication (phonophoresis) for soft tissue inflammation (54.1%), pain management (22.2%), and soft tissue swelling (19.8%). The study provides summary data of the most frequently chosen machine parameters for duty cycle, intensity, and frequency. DISCUSSION AND CONCLUSION: Ultrasound continues to be a popular adjunctive modality in orthopedic physical therapy. These findings may help researchers prioritize needs for future research on the clinical effectiveness of US.

Analysis of RNA recovery and gene expression in the epidermis using non-invasive tape stripping.

BACKGROUND: The recovery of RNA from the upper epidermis by tape stripping yields variable RNA mass but has not been evaluated for its dependence on anatomical location. Gene expression at different body locations and the origin of RNA recovered by tape stripping have not been investigated. OBJECTIVES: To characterize the recovery of RNA from different anatomical locations by tape stripping; to correlate the recovery of RNA and removal of barrier by tape stripping, as assayed by transepidermal water loss; and to investigate gene expression in the upper epidermis at different body locations. METHODS: Twelve subjects were tape stripped at 15 body locations. RNA mass was evaluated and gene expression assayed. Subjects were tape stripped 4, 8 and 12 times on the upper back and transepidermal water loss and RNA recovery assayed. RESULTS: Ranked by median RNA recovery, the following order was observed: mastoid>forehead>chest>upper back>mid back>cheek>lower back>deltoid>forearm>abdomen>ventral thigh>inner arm>shin>dorsal thigh>lower leg. Expression of the housekeeping gene mRNAs is found to be uniform and reproducible while IL-8 and TNFalpha mRNAs are expressed in different quantities both at different body sites within an individual and between individuals at a specific anatomical site. Data show a significant and high correlation between the number of tapes used to strip a site and transepidermal water loss but no strong correlation between transepidermal water loss and RNA recovery or number of tapes used to strip a site and RNA recovery. CONCLUSIONS: Subjects and anatomical location are shown to be significantly different for the ability to recover RNA by tape stripping. We hypothesize that RNA recovered by tape strip is not derived from corneocytes but from cells associated with the stratum corneum.

An analysis of select pathogenic messages in lesional and non-lesional psoriatic skin using non-invasive tape harvesting.

We report the use of non-invasive tape stripping to sample psoriatic lesional and non-lesional skin in 96 patients. The procedure was well tolerated with any discomfort described as mild; we did not observe any cases of Koebner phenomena at any non-lesional tape-stripped sites. Tape-harvested epidermis was extracted for RNA, which was profiled by semiquantitative reverse transcriptase-PCR. This analysis revealed that mRNAs for tumor necrosis factor alpha, IFNgamma, Krt-16, CD2, IL-23A, IL-12B, and vascular endothelial growth factor are overexpressed in the "average" psoriatic lesion in a majority of patients. In addition, 10 of these patients were biopsied at lesional and non-lesional sites and the expression data compared to tape-stripping data. This comparison shows that five of seven mRNA are more highly expressed in cells captured by tape stripping than biopsy, suggesting that the upper aspect of a lesion contains cells very active in the disease. The tape-harvesting data reveal that approximately 46% of lesions have at least one pathogenic mRNA within non-lesional skin limits. Data demonstrate that tape stripping reveals mRNA markers not detected in biopsy samples and thus the method may be a useful supplement to biopsy.

Use of RT-PCR and DNA microarrays to characterize RNA recovered by non-invasive tape harvesting of normal and inflamed skin.

We describe a non-invasive approach for recovering RNA from the surface of skin via a simple tape stripping procedure that permits a direct quantitative and qualitative assessment of pathologic and physiologic biomarkers. Using semi-quantitative RT-PCR we show that tape-harvested RNA is comparable in quality and utility to RNA recovered by biopsy. It is likely that tape-harvested RNA is derived from epidermal cells residing close to the surface and includes adnexal structures and present data showing that tape and biopsy likely recover different cell populations. We report the successful amplification of tape-harvested RNA for hybridization to DNA microarrays. These experiments showed no significant gene expression level differences between replicate sites on a subject and minimal differences between a male and female subject. We also compared the array generated RNA profiles between normal and 24 h 1% SLS-occluded skin and observed that SLS treatment resulted in statistically significant changes in the expression levels of more than 1,700 genes. These data establish the utility of tape harvesting as a non-invasive method for capturing RNA from human skin and support the hypothesis that tape harvesting is an efficient method for sampling the epidermis and identifying select differentially regulated epidermal biomarkers.