The PRO-ACTIVE trial protocol: a randomized study comparing the effectiveness of PROphylACTic swallow InterVEntion for patients receiving radiotherapy for head and neck cancer.

BACKGROUND: Swallowing therapy is commonly provided as a treatment to lessen the risk or severity of dysphagia secondary to radiotherapy (RT) for head and neck cancer (HNC); however, best practice is not yet established. This trial will compare the effectiveness of prophylactic (high and low intensity) versus reactive interventions for swallowing in patients with HNC undergoing RT. METHODS: This multi-site, international randomized clinical trial (RCT) will include 952 adult patients receiving radiotherapy for HNC and who are at high risk for post-RT dysphagia. Participants will be randomized to receive one of three interventions for swallowing during RT: RE-ACTIVE, started promptly if/when dysphagia is identified; PRO-ACTIVE EAT, low intensity prophylactic intervention started before RT commences; or, PRO-ACTIVE EAT+EXERCISE, high intensity prophylactic intervention also started before RT commences. We hypothesize that the PRO-ACTIVE therapies are more effective than late RE-ACTIVE therapy; and, that the more intensive PRO-ACTIVE (EAT + EXERCISE) is superior to the low intensive PRO-ACTIVE (EAT). The primary endpoint of effectiveness is duration of feeding tube dependency one year post radiation therapy, selected as a pragmatic outcome valued equally by diverse stakeholders (e.g., patients, caregivers and clinicians). Secondary outcomes will include objective measures of swallow physiology and function, pneumonia and weight loss, along with various patient-reported swallowing-related outcomes, such as quality of life, symptom burden, and self-efficacy. DISCUSSION: Dysphagia is a common and potentially life-threatening chronic toxicity of radiotherapy, and a priority issue for HNC survivors. Yet, the optimal timing and intensity of swallowing therapy provided by a speech-language pathologist is not known. With no clearly preferred strategy, current practice is fraught with substantial variation. The pragmatic PRO-ACTIVE trial aims to specifically address the decisional dilemma of when swallowing therapy should begin (i.e., before or after a swallowing problem develops). The critical impact of this dilemma is heightened by the growing number of young HNC patients in healthcare systems that need to allocate resources most effectively. The results of the PRO-ACTIVE trial will address the global uncertainty regarding best practice for dysphagia management in HNC patients receiving radiotherapy. TRIAL REGISTRATION: The protocol is registered with the US Patient Centered Outcomes Research Institute, and the PRO-ACTIVE trial was prospectively registered at ClinicalTrials.gov , under the identifier NCT03455608 ; First posted: Mar 6, 2018; Last verified: Jun 17, 2021. Protocol Version: 1.3 (January 27, 2020).

One Health, One Caribbean, One Love ­ Caribbean Leadership, Regional Cooperation, Local Action

Inter-sectoral collaboration is extremely limited, both at policy and technical levels, across the Caribbean region. However, many of the priority health problems currently facing the region, like climate change, food security, ocean health, and emerging diseases arise from the interactions between people, animals and our shared environment. If these health issues are to be addressed effectively and efficiently, an intersectoral or One Health approach is clearly required. The European Union funded project "One Health, One Caribbean, One Love" set out to promote and entrench a "One Health" approach to priority health issues affecting humans, animals and the environment within the Caribbean region. The project, which spanned from March 2014 and ended in June 2017, successfully built the capacity of the national veterinary, public health and environmental health services, through the development of a cadre of One Health Leaders, the creation of Caribbean regional and national One Health Networks, and the development of a One Health strategic framework. The One Health Leadership Series developed a core group of One Health Leaders from 12 Caribbean countries. The leaders attended a series of 5 themed One Health Leadership workshops, and each country team developed and conducted a One Health project addressing a national priority health issue at the interface between human, animal and environmental health ­ a learning by doing approach. The One Health leadership series has enabled the leaders to more effectively design and manage One Health policies, programs and projects in order to develop more holistic scientific solutions to emerging health problems.

Identification of genes encoding squalestatin S1 biosynthesis and in vitro production of new squalestatin analogues.

A gene cluster responsible for the biosynthesis of squalestatin S1 (SQS1, 1) was identified by full genome sequencing of two SQS1-producing ascomycetes: Phoma sp. C2932 and unidentified fungus MF5453. A transformation protocol was established and a subsequent knockout of one PKS gene from the cluster led to loss of SQS1 production and enhanced concentration of an SQS1 precursor. An acyltransferase gene from the cluster was expressed in E. coli and the expressed protein MfM4 shown to be responsible for loading acyl groups from CoA onto the squalestatin core as the final step of biosynthesis. MfM4 appears to have a broad substrate selectivity for its acyl CoA substrate, allowing the in vitro synthesis of novel squalestatins.

Temporal and Physiologic Measurements of Deglutition in the Upright and Supine Position with Videofluoroscopy (VFS) in Healthy Subjects.

Cross-sectional imaging has long been employed to examine swallowing in both the sagittal and axial planes. However, data regarding temporal swallow measures in the upright and supine positions are sparse, and none have employed the MBS impairment profile (MBSImP). We report temporal swallow measures, physiologic variables, and swallow safety of upright and supine swallowing in healthy subjects using videofluoroscopy (VFS). Twenty healthy subjects ages 21-40 underwent VFS study upright and supine. Subjects were viewed in the sagittal plane and swallowed 5 mL liquid and pudding barium. Oral transit time, pharyngeal delay time, pharyngeal response time, pharyngeal transit time, and total swallow duration were measured. Penetration/aspiration scores and 14 MBSImP variables were analyzed in both positions. All subjects completed swallows supine, although one aspirated on one liquid bolus. Temporal measures of swallowing were similar for pudding upright and supine. Pharyngeal phase swallow measures were longer for liquids in supine. MBSImP physiologic measures revealed a pharyngeal delay in both positions. Although Pen/Asp range was higher supine, more subjects penetrated upright. Temporal measures were increased for liquids in supine. Although Pen/Asp range was higher in supine, more subjects penetrated upright. These results provide support for cross-sectional supine imaging of swallowing for pudding, but perhaps not thin liquids for dysphagic patients. Slightly thicker liquids might prove reliable in supine without compromising swallow safety. Future research should examine swallow physiology in both positions in dysphagic and older healthy subjects.

Age-Related Changes in Pharyngeal Lumen Size: A Retrospective MRI Analysis.

Age-related loss of muscle bulk and strength (sarcopenia) is often cited as a potential mechanism underlying age-related changes in swallowing. Our goal was to explore this phenomenon in the pharynx, specifically, by measuring pharyngeal wall thickness and pharyngeal lumen area in a sample of young versus older women. MRI scans of the neck were retrospectively reviewed from 60 women equally stratified into three age groups (20s, 60s, 70+). Four de-identified slices were extracted per scan for randomized, blinded analysis: one mid-sagittal and three axial slices were selected at the anterior inferior border of C2 and C3, and at the pit of the vallecula. Pixel-based measures of pharyngeal wall thickness and pharyngeal lumen area were completed using ImageJ and then converted to metric units. Measures of pharyngeal wall thickness and pharyngeal lumen area were compared between age groups with one-way ANOVAs using Sidak adjustments for post-hoc pairwise comparisons. A significant main effect for age was observed across all variables whereby pharyngeal wall thickness decreased and pharyngeal lumen area increased with advancing age. Pairwise comparisons revealed significant differences between 20s versus 70+ for all variables and 20s versus 60s for all variables except those measured at C2. Effect sizes ranged from 0.54 to 1.34. Consistent with existing sacropenia literature, the pharyngeal muscles appear to atrophy with age and consequently, the size of the pharyngeal lumen increases.

Osteoradionecrosis of the subaxial cervical spine following treatment for head and neck carcinomas.

OBJECTIVE: To study MRI and positron emission tomography (PET)/CT imaging of osteoradionecrosis (ORN) of the subaxial cervical spine, a serious long-term complication of radiation therapy (RT) for head and neck cancers that can lead to pain, vertebral instability, myelopathy and cord compression. METHODS: This is a single-institution retrospective review of patients diagnosed and treated for ORN of the subaxial cervical spine following surgery and radiation for head and neck cancer. RESULTS: We report PET/CT imaging and MRI for four patients, each with extensive treatment for recurrent head and neck cancer. Osteomyelitis (OM) and discitis are the end-stage manifestations of ORN of the subaxial spine. CONCLUSION: ORN of the subaxial spine has variable imaging appearance and needs to be differentiated from recurrent or metastatic disease. Surgical violation of the posterior pharyngeal wall on top of the compromised vasculature in patients treated heavily with RT may pre-dispose the subaxial cervical vertebrae to ORN, with possible resultant OM and discitis. MRI and PET/CT imaging are complimentary in this setting. PET/CT images may be misinterpreted in view of the history of head and neck cancer. MRI should be utilized for definitive diagnosis of OM and discitis in view of its imaging specificity. ADVANCES IN KNOWLEDGE: We identify the end-stage manifestation of ORN in the sub-axial spine on PET/CT and MRI to facilitate its correct diagnosis.

Reconstructing fungal natural product biosynthetic pathways.

Large scale fungal genome sequencing has revealed a multitude of potential natural product biosynthetic pathways that remain uncharted. Here we describe some of the methods that have been used to explore them via heterologous gene expression. We focus on filamentous fungal hosts and discuss the technological challenges and successes behind the reconstruction of fungal natural product pathways. Optimised, efficient heterologous expression of reconstructed biosynthetic pathways promises progress in the discovery of novel compounds that could be utilised by the pharmaceutical and agrochemical industries.

Development of a new lingual range-of-motion assessment scale: normative data in surgically treated oral cancer patients.

Surgical resection in oral cancer patients can result in altered speech, swallowing, and patient perception of quality of life (QOL). Oral surgery can result in reduced lingual range of motion (ROM). However, few studies have quantified the degree of lingual restriction after surgery. This pilot study describes a new measurement system to define tongue ROM in surgically treated tongue cancer patients. This measurement system was validated by comparing results in these treated surgical patients versus healthy individuals. This scale was further validated by correlating ROM with performance status, oral outcomes, and patient-rated QOL. Thirty-six patients who underwent oral tongue surgery and 31 healthy individuals were included. Tongue ROM was assessed using a novel ROM assessment system. This novel system was examined in these patients versus healthy subjects. This measurement tool was further validated by correlating tongue ROM in treated patients with performance status, oral outcomes, and patient-rated QOL. Tongue ROM was found to be significantly lower in the surgically treated patients than in the healthy individuals (p = 0.0001). Tongue ROM correlated with performance status, oral outcomes, and all QOL measures. This new tongue ROM measurement system defined tongue deficits in surgically treated oral cancer patients. This tool was validated by comparing results to those in healthy individuals, as well as by correlating tongue ROM to performance status, oral outcomes, and QOL. This measurement tool can be used to define baseline and postsurgery tongue ROM in oral cancer patients, as well as track change over time with recovery and therapy. Future studies should examine use of this measurement tool with other populations demonstrating tongue deficits.

Functional outcomes and quality of life after chemoradiotherapy: baseline and 3 and 6 months post-treatment.

Concomitant chemoradiotherapy provides organ preservation for those patients with head and neck cancer. We report the results of a prospective study that examined functional outcomes and quality of life (QOL) after chemoradiotherapy over the first 6 months post-treatment (tx). Twenty-nine patients with head and neck cancer were treated with chemoradiotherapy. All were seen baseline and 3 and 6 months post-tx. Assessments included the performance status scale (PSS), Karnofsky performance status scale, tongue strength, jaw opening, and saliva weight. QOL was patient-rated using the eating assessment tool (EAT-10), MD Anderson dysphagia inventory, speech handicap index (SHI), and the EORTC H&N35 scale. Repeated-measures ANOVAs were used, with significance at p < 0.05. PSS scores were significantly different across time points. Tongue strength, jaw range of motion (ROM), and saliva weight were significantly lower at 3 and 6 months than at baseline. QOL was significantly worse after tx, although it improved by 6 months as rated with the EAT-10 and the SHI scores were significantly worse at 3 and 6 months. EORTC domains of swallowing, senses, speech, dry mouth, and sticky saliva were significantly worse at 3 and 6 months. Concomitant chemoradiotherapy for treatment of head and neck tumors can result in impaired performance outcomes and QOL over the first 6 months post-tx. However, performance status, tongue strength, jaw ROM, and eating QOL were only mildly impaired by 6 months post-tx. Saliva production and speech QOL remained significantly impaired at 6 months post-treatment. Current studies are examining outcomes at 12 and 24 months post-treatment to better predict outcomes over time in this population.

Effects of exercise on swallowing and tongue strength in patients with oral and oropharyngeal cancer treated with primary radiotherapy with or without chemotherapy.

Tongue strength is reduced in patients treated with chemoradiotherapy for oral/oropharyngeal cancer. Tongue strengthening protocols have resulted in improved lingual strength and swallowing in healthy individuals, as well as in patients following a neurological event. However, no studies have examined the efficacy of tongue strengthening exercises on tongue strength, swallowing, and quality of life (QOL; Head and Neck Cancer Inventory) in patients treated with chemoradiotherapy. A randomized clinical trial examined the effects of a tongue strengthening programme paired with traditional exercises vs. traditional exercises alone. Dependent variables included tongue strength, swallowing, and QOL in a group of patients with oral and oropharyngeal cancer treated with primary radiotherapy with or without chemotherapy. Differences with regard to tongue strength and oropharyngeal swallow efficiency (OPSE) were not observed within or between groups. QOL in the eating and speech domains improved following treatment in both groups. However, the experimental group demonstrated greater impairment in QOL in the social disruption domain following treatment, whereas the control group demonstrated a slight improvement in functioning. Tongue strengthening did not yield a statistically significant improvement in either tongue strength or swallowing measures in this patient cohort. Patient compliance and treatment timing may be factors underlying these outcomes.

Behavioral and neurochemical effects of dietary methyl donor deficiency combined with unpredictable chronic mild stress in rats.

Methyl donor deficiencies and chronic stress cause depression independently, but their interaction has never been thoroughly evaluated. In our study, methyl donor deficient diet and chronic stress condition consisted respectively of a B2, B9, B12, and choline-free diet and a chronic mild stress procedure. Rats were randomly assigned to six groups with three "diet" conditions (free-feeding, pair-fed and methyl donor deficient diet) and two "stress" conditions (no-stress and stress) and were evaluated in the open-field, the elevated plus-maze and the forced swimming test. After the behavioral evaluation, corticosterone and homocysteine plasma levels were measured and dopamine, DOPAC, serotonin, 5HIAA concentrations were evaluated in several brain areas. Rats given a methyl donor deficient diet for 11 weeks causing elevated plasma homocysteine levels were compared to pair-fed and free-feeding rats with or without unpredictable chronic mild stress. Regardless of stress environmental conditions, the methyl donor deficient diet decreased plasma corticosterone levels and caused disinhibition in the elevated plus-maze condition relative to both control groups. However, stress potentiated the effects of the deficient regimen on rearing in the open-field and climbing in the forced swim test. The dietary changes involved in behavior and plasma corticosterone could be caused by homocysteine-induced decreases in dopamine and 5-hydroxytryptamine metabolites in selective brain regions and it can be noted that regardless of stress-conditions, methyl donor deficient diet decreases DOPAC/dopamine and 5HIAA/serotonin ratios in striatum and hypothalamus and selectively 5HIAA/serotonin ratio in the sensorimotor cortex. Our experimental data is particularly relevant in the context of neuropsychiatric disorders frequently associated with folate deficiency and hyperhomocysteinemia.

Probable nosocomial transmission of listeriosis in neonates.

Listeria monocytogenes was isolated in two neonates born consecutively in the same hospital in France. The isolates had indistinguishable pulsed-field electrophoresis profiles. Retrospective epidemiological investigations found no evidence of a food-borne or environmental source. Infection control protocols and decontamination processes were in accordance with standard recommendations. The timing of onset of these infections within the same maternity unit, and the similarity of pulsed-field gel electrophoresis profiles suggests cross-infection of L. monocytogenes between the two neonates.

Quality of life after management of advanced osteoradionecrosis of the mandible.

Osteoradionecrosis (ORN) of the mandible is a severe complication of radiation therapy for head and neck cancer. In this case series, the authors analyzed their treatment and quality of life outcomes over the past 6 years. A retrospective chart review of 42 patients treated surgically for advanced ORN was conducted. A telephone survey was conducted and quality of life (QOL) questionnaires were completed in a subset of patients. 30 patients responded to the telephone survey assessing QOL for speech, swallowing and overall functioning correlated with oral nutrition and performance status. Surgery for ORN can result in an improved QOL. Functional outcomes of oral intake, speech intelligibility, and eating in public correlated with patient rated QOL measures. A lack of improvement in QOL, despite the restoration of an intact mandible, relates to the persistent effects of chemoradiotherapy.

Toward a better understanding of brain lesions during metachromatic leukodystrophy evolution.

BACKGROUND AND PURPOSE: The prospect of new therapies in MLD stresses the need to refine the indications for treatment. The aim of this study was, therefore, to perform a detailed analysis of MRI brain lesions at diagnosis and follow-up, to better understand the natural history of MLD. MATERIAL AND METHODS: This retrospective case-control study (2005-2010) looked at 13 patients with MLD (2-5 years of age) with 28 MRIs (mean follow-up, 2 years), compared with 39 age- and sex-matched controls. All MRIs were evaluated qualitatively and semiquantitatively. The Student t test, Wilcoxon signed rank test, and Pearson correlation were used for statistical analysis (P < .05). RESULTS: In addition to diffuse symmetric supratentorial WM T2 hyperintensities with a tigroid pattern (70%) and T2 hyperintensities in the CC (100%) and internal capsules (46%), we found significant GM abnormalities such as thalamic T2 hypointensity (92%), thalamic (23%, P < .05, EJ) and caudate nuclei (23%, P < .05, EJ) atrophy, and cerebellar atrophy without WM involvement (15%). The pattern of splenium involvement progression was misleading, with initially diffuse high signal intensity, which later became curvilinear before finally progressing to atrophy (23%, P < .05; EJ). This should not be mistaken for a disease regression. Spectroscopy confirmed a decrease in the NAA/Cr ratio, an increase in the Cho/Cr ratio and in myo-inositol, and a lactate resonance. CONCLUSIONS: Thalamic changes may be a common finding in MLD, raising the prospect of primary GM lesions. This may prove important when evaluating the efficacy of new treatments.

Laparoscopically inserted button colostomy as a venting stoma and access port for the administration of antegrade enemas in African degenerative leiomyopathy.

African degenerative leiomyopathy (ADL) is a rare incurable disorder seen in African children, predominantly in southern and south-eastern Africa. ADL presents as chronic intestinal pseudo-obstruction. Management is traditionally conservative, with surgery restricted to the management of complications. We have placed Malone antegrade continence enema (MACE) stomas in the grossly dilated colon to vent accumulated gas and administer antegrade bowel enemas. This is done mainly for relief of gaseous distension and constipation in an attempt to provide symptomatic relief and improve quality of life. In this article, we present our preliminary results of laparoscopically assisted technique to insert a Mic-Key gastrostomy device as a 'button colostomy' in 8 patients over the past 6½ years.

Developing a disease prevention strategy in the Caribbean: the importance of assessing animal health-related risks at regional level.

In 2009 CaribVET conducted a survey among Caribbean national Veterinary Services to assess perceptions of risk assessment and to identify the principal exotic diseases of concern in the region and their means of introduction. The results showed that the introduction of live animals was considered the most likely route of introduction of exotic animal pathogens, followed by the uncontrolled introduction of animal products by boat passengers. The results were used to define a regional strategy for assessing animal health risks that highlights the importance of within-region exchanges.

Effects of ethanol and ecstasy on conditioned place preference in the rat.

The club drug ecstasy (3,4-methylenedioxymethylamphetamine or MDMA) is often taken recreationally with ethanol (EtOH). We have shown previously that EtOH potentiates the psychomotor effects of MDMA in rats. More recently, we demonstrated in striatal slices that MDMA produced preferential release of serotonin, but when combined with EtOH, the preferential release shifted to dopamine, raising the possibility that administration of EtOH may increase the reward effect of MDMA. To address this possibility, adult male Long-Evans rats were tested for conditioned place preference following treatment with saline, EtOH (0.75 g/kg), MDMA (6.6 mg/kg) or the combination. The only condition that produced a preference for the compartment associated with the drug was that of the drug combination. The current data are in line with anecdotal reports and one study in humans, indicating that EtOH alters the pharmacological effects of MDMA including self reports of enhanced or prolonged euphoria. Thus, administration of EtOH might increase the risk for compulsive use of MDMA, an issue that warrants further study.

Neonatal hyperbilirubinemia management: a model for change.

Currently, active public health surveillance of hyperbilirubinemia and kernicterus is lacking. Recently, the Hospital Corporation of America (HCA), a private health care system with an estimated quarter of a million births annually, instituted recommendations to provide universal hyperbilirubinemia screening before discharge for all infants born within their system. Over 98% of the infants born at HCA hospitals were screened within the first year of the recommendations. From May to December 2004, 13 infants were identified with total serum bilirubin (TSB) >/=30 mg per 100 ml, but that number was reduced in 2006, with only seven infants born in HCA hospitals developing a TSB of >/=30 mg per 100 ml. This program provides a model for actively monitoring the occurrence of hyperbilirubinemia and for tracking its occurrence, thus improving health care quality for patients while collecting important public health information.

Electrolytic lesions of the ventral subiculum weakly alter spatial memory but potentiate amphetamine-induced locomotion.

Adult Long-Evans male rats were subjected to electrolytic lesions of the ventral subiculum, and tested for locomotor activity in the home cage, reference and working memory in the water maze, working memory in the radial maze, and D-amphetamine-induced locomotion (1mg/kg, i.p.). When compared to their sham-operated counterparts, lesioned rats showed nocturnal hyperactivity, no reference memory deficit, but working memory was impaired in the water maze and during the initial stage of radial-maze testing. Their locomotor responsiveness to D-amphetamine was exaggerated. Histological verifications confirmed lesions in the ventral subiculum. Material stained for acetylcholinesterase activity indicated septohippocampal and commissural/associational sprouting, accounting for partial damage to the perforant paths. These results showed that ventral subiculum lesions (i) do not alter the capability of rats to learn repeatedly presented spatial information, and (ii) impair, but do not prevent, spatial working memory, suggesting that the ventral subiculum is preferentially involved in short-term memory for spatial locations. Given the electrolytic nature of the lesion, the lesion-induced potentiation of the locomotor response to amphetamine is probably easier explained by partial disruption of the perforant paths than by damage to neurons of the ventral subiculum.