Foundations in physiology: an introductory course using the core concepts.

As one element of an extensive revision to program curriculum, the Integrative Physiology and Health Science Department at a small, private, liberal arts institution developed a novel introductory course for the major, focusing specifically on the "core concepts" of physiology. Intended to provide the initial step in explicit scaffolding for student success and, ultimately, transfer of knowledge across the curriculum, development and assessment of the first offering of the course were completed. In the fall of 2021, IPH 131: Foundations in Physiology was launched. The specific core concepts covered were as follows: causality, scientific reasoning, physics/chemistry, structure-function, homeostasis, flow-down gradients, cell membrane, energy, cell-cell communication, and interdependence/integration. To assess student learning, the Phys-MAPS (Measuring Achievement and Progress in Science for Physiology) assessment tool was administered to students during the first week of class and again in the final week of the semester. Average scores revealed significant learning gains by the end of the semester (0.497 ± 0.058 vs. 0.538 ± 0.108 correct as a proportion of the total number of questions, P = 0.0096). While a modest gain in learning outcomes, these data provide early evidence that a course specifically addressing the core concepts of physiology can be an appropriate introduction to the physiology curriculum.NEW & NOTEWORTHY This article will detail the development and implementation of an introductory course using the "core concepts." Specifics of course design, assessment, and challenges encountered will be presented for those interested in this approach.

Consensus Statement for the Management and Treatment of Sturge-Weber Syndrome: Neurology, Neuroimaging, and Ophthalmology Recommendations.

BACKGROUND: Sturge-Weber syndrome (SWS) is a sporadic, neurocutaneous syndrome involving the skin, brain, and eyes. Because of the variability of the clinical manifestations and the lack of prospective studies, consensus recommendations for management and treatment of SWS have not been published. OBJECTIVE: This article consolidates the current literature with expert opinion to make recommendations to guide the neuroimaging evaluation and the management of the neurological and ophthalmologic features of SWS. METHODS: Thirteen national peer-recognized experts in neurology, radiology, and ophthalmology with experience treating patients with SWS were assembled. Key topics and questions were formulated for each group and included (1) risk stratification, (2) indications for referral, and (3) optimum treatment strategies. An extensive PubMed search was performed of English language articles published in 2008 to 2018, as well as recent studies identified by the expert panel. The panel made clinical practice recommendations. CONCLUSIONS: Children with a high-risk facial port-wine birthmark (PWB) should be referred to a pediatric neurologist and a pediatric ophthalmologist for baseline evaluation and periodic follow-up. In newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms, routine screening for brain involvement is not recommended, but brain imaging can be performed in select cases. Routine follow-up neuroimaging is not recommended in children with SWS and stable neurocognitive symptoms. The treatment of ophthalmologic complications, such as glaucoma, differs based on the age and clinical presentation of the patient. These recommendations will help facilitate coordinated care for patients with SWS and may improve patient outcomes.

Mitochondrial DNA abnormalities provide mechanistic insight and predict reactive oxygen species-stimulating drug efficacy.

BACKGROUND: Associations between mitochondrial genetic abnormalities (variations and copy number, i.e. mtDNAcn, change) and elevated ROS have been reported in cancer compared to normal cells. Since excessive levels of ROS can trigger apoptosis, treating cancer cells with ROS-stimulating agents may enhance their death. This study aimed to investigate the link between baseline ROS levels and mitochondrial genetic abnormalities, and how mtDNA abnormalities might be used to predict cancer cells' response to ROS-stimulating therapy. METHODS: Intracellular and mitochondrial specific-ROS levels were measured using the DCFDA and MitoSOX probes, respectively, in four cancer and one non-cancerous cell lines. Cells were treated with ROS-stimulating agents (cisplatin and dequalinium) and the IC50s were determined using the MTS assay. Sanger sequencing and qPCR were conducted to screen the complete mitochondrial genome for variations and to relatively quantify mtDNAcn, respectively. Non-synonymous variations were subjected to 3-dimensional (3D) protein structural mapping and analysis. RESULTS: Our data revealed novel significant associations between the total number of variations in the mitochondrial respiratory chain (MRC) complex I and III genes, mtDNAcn, ROS levels, and ROS-associated drug response. Furthermore, functional variations in complexes I/III correlated significantly and positively with mtDNAcn, ROS levels and drug resistance, indicating they might mechanistically influence these parameters in cancer cells. CONCLUSIONS: Our findings suggest that mtDNAcn and complexes I/III functional variations have the potential to be efficient biomarkers to predict ROS-stimulating therapy efficacy in the future.

Multicenter Research Data of Epilepsy Management in Patients With Sturge-Weber Syndrome.

BACKGROUND: Epilepsy in typical Sturge-Weber syndrome (SWS) is common, and many questions remain regarding the treatment outcomes. We analyzed a large multicenter database with focus on neurological drug treatment in different demographic and SWS characteristic groups. METHODS: A total of 268 patients with brain involvement and a history of seizures were selected from a research data registry generated from a multicenter cross-sectional questionnaire. We examined associations between medication use and binary variables such as sex, ethnicity, and brain, skin, and eye involvement laterality. We analyzed group differences in mean number of antiseizure medications and age at diagnosis, enrollment, and seizure onset and examined differences in median SWS neurological scores in groups of interest. RESULTS: The most frequently used medications were levetiracetam (48.1%), low-dose aspirin (44.8%), oxcarbazepine (39.9%), and phenobarbital (14.9%). Lamotrigine was more frequently used in adults than in children (P = 0.001). History of neurosurgery was associated with no current antiseizure medication use (P = 0.001), whereas bilateral brain involvement and family history of seizures were associated with using a higher number of antiseizure medications (P = 0.002, P = 0.027, respectively). Subjects with bilateral brain involvement and early seizure onset were associated with using a higher number of antiseizure medications (P = 0.002) and phenobarbital use (0.003). CONCLUSIONS: Levetiracetam, low-dose aspirin, and oxcarbazepine were the most frequently used medications. More severely affected patients were frequently on a greater number of antiseizure medications. Surgery for epilepsy was associated with the ability to discontinue antiseizure medication. Longitudinal studies are needed to further investigate medication use in patients with SWS.

Supporting people who have eating and drinking difficulties.

Eating and drinking are essential for maintenance of nutrition and hydration, but are also important for pleasure and social interactions. The ability to eat and drink hinges on a complex and coordinated system, resulting in significant potential for things to go wrong.The Royal College of Physicians (RCP) has published updated guidance on how to support people who have eating and drinking difficulties, particularly towards the end of life.Decisions about nutrition and hydration and when to start, continue or stop treatment are some of the most challenging to make in medical practice. The newly updated guidance aims to support healthcare professionals to work together with patients, their families and carers to make decisions around nutrition and hydration that are in the best interests of the patient. It covers the factors affecting our ability to eat and drink, strategies to support oral nutrition and hydration, techniques of clinically-assisted nutrition and hydration, and the legal and ethical framework to guide decisions about giving and withholding treatment, emphasising the two key concepts of capacity and best interests.This article aims to provide an executive summary of the guidance.

A Springboard for physicians returning to practice.

BACKGROUND: Many physicians take time out of training and have decreased confidence and poor performance ratings on their return. Courses employing multiple educational methods have been shown to be effective in easing learners into new clinical roles during transition periods but, to date, there is limited evidence for courses to support trainees returning to practice (RTP). METHODS: A 2-day course, named Springboard, was developed, specifically to address the needs of trainee physicians RTP. It employed a blended, multi-modal approach to learning, including lectures, workshops, case-based sessions, interactive panel discussions, small group teaching, peer-led practical advice sessions and simulation training. Springboard was delivered eight times between 2014 and 2019 with a total of 540 doctors attending. We analysed participant pre-and post-course questionnaire feedback. RESULTS: Reasons for doctors taking time out of training included parental leave, research, fellowships in education and leadership, health-related absence and career breaks. Time out of training ranged between 3 months and 6 years. A significant pre/post-course increase in candidates' self-reported leadership skills and confidence in being prepared to return to practice was demonstrated alongside an appreciation of a multi-modal, 'boot camp' course delivered by expert faculty and a networking experience. DISCUSSION: Dedicated training courses tailored to the needs of physicians RTP provide an opportunity for improving confidence relating to many areas of clinical and non-clinical practice as well as providing an environment for networking and sharing experiences. Further work would be valuable to establish the potential of providing this on a larger scale.

Herbicide reduction through the use of weedmat undervine treatment and the lack of impact on the aromatic profile and volatile composition of Malbec wines.

Viticultural practices to control the undervine environment have relied on chemical herbicides. Herbicides usage has resulted in resistance by weeds, alterations in soil environments, as well as not meeting the needs of the organic market. Consequently, black and white weedmat was utilized to manage the undervine area over multiple vintages and its influence on the resultant wines examined. Apart from a difference in juice soluble solids, there was no impact on grape yield. In the 2017 vintage, black weedmat wines had the largest variation in aromatic profile when compared to control; additionally white weedmat was more closely related to the control. These differences had disappeared in the 2018 vintage with all wines having similar aromatic profile concentrations. Trained sensory panel could not discriminate treatment effects on wine flavor and aroma for either vintage. Ultimately, these findings support the use of weedmats in the viticulture setting to eliminate herbicide usage.

Consensus Statement for the Management and Treatment of Port-Wine Birthmarks in Sturge-Weber Syndrome.

Importance: Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome involving the skin, brain, and eyes. Consensus recommendations for management are lacking. Objective: To consolidate the current literature with expert opinion to make recommendations that will guide treatment and referral for patients with port-wine birthmarks (PWBs). Evidence Review: In this consensus statement, 12 nationally peer-recognized experts in dermatology with experience treating patients with SWS were assembled. Key topics and questions were formulated for each group and included risk stratification, optimum treatment strategies, and recommendations regarding light-based therapies. A systematic PubMed search was performed of English-language articles published between December 1, 2008, and December 1, 2018, as well as other pertinent studies identified by the expert panel. Clinical practice guidelines were recommended. Findings: Treatment of PWBs is indicated to minimize the psychosocial impact and diminish nodularity and potentially tissue hypertrophy. Better outcomes may be attained if treatments are started at an earlier age. In the US, pulsed dye laser is the standard for all PWBs regardless of the lesion size, location, or color. When performed by experienced physicians, laser treatment can be safe for patients of all ages. The choice of using general anesthesia in young patients is a complex decision that must be considered on a case-by-case basis. Conclusions and Relevance: These recommendations are intended to help guide clinical practice and decision-making for patients with SWS and those with isolated PWBs and may improve patient outcomes.

Lasers, Birthmarks, and Sturge-Weber Syndrome: A Pilot Survey.

BACKGROUND AND OBJECTIVES: There is limited or no data on the experience of patients with Sturge-Weber Syndrome (SWS) and/or their parents who seek out laser treatments for their port-wine birthmark (PWB). Our study aimed to develop a survey to understand patient perspectives on laser therapy and subsequent behaviors while focusing on three elements of the health belief model: perceived susceptibility, perceived benefits, and perceived barriers. STUDY DESIGN/MATERIALS AND METHODS: A 31 item survey was developed and sent to 650 members of the Sturge-Weber Foundation. The survey included questions regarding four domains: demographics, disease severity, laser experience, and perceptions and behaviors. Logistic regression models and bivariate analyses were conducted to analyze the results. RESULTS: Among the 123 respondents, earlier initiation of laser treatments was associated with greater birthmark satisfaction. Overall satisfaction increased up to 20 treatments and then leveled off. Color satisfaction increased up to 100 laser treatments; however, the flatness of the PWB was not associated with the number of laser treatments. The perceived benefits of lasers were not associated with the number of lifetime treatments or with spending. However, the perceived susceptibility was associated with greater spending on travel and medical expenses. CONCLUSION: The results of our survey provide insight into SWS patient experiences, beliefs, and behaviors regarding laser therapy. Further exploration of these variables may allow for the improvement of the care experience. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

How COVID-19 Patients Were Moved to Speak: A Rehabilitation Interdisciplinary Case Series.

Background: Up to 36% of patients admitted to the ICU for COVID-19 require tracheostomy. While the literature recommends the use of multidisciplinary teams in the management of patients with tracheostomy for other diseases, little is known on the collaborative administration of physical therapy and speech language pathology services in the COVID-19 population. Purpose: We sought to determine the outcomes of a collaboration between physical therapy (PT) and speech language pathology (SLP) in the treatment of patients who underwent tracheostomy placement as part of their treatment for COVID-19 at our facility. Methods: We conducted a retrospective case series on patients with COVID-19 who had a tracheostomy. We included patients who had undergone mechanical ventilation for 14 days or longer, had a surgical tracheostomy, been discharged from intensive care to a medical unit, and received PT and SLP referrals. We compiled retrospective data from electronic medical records, analyzing days from tracheostomy to achievement of PT and SLP functional milestones, including mobility, communication, and swallowing. Of six critically ill patients with COVID-19 who had tracheostomy placement at our facility, three met inclusion criteria: patient 1, a 33-year-old woman; patient 2, an 84-year-old man; and patient 3, an 81-year-old man. For all patients, PT interventions focused on breathing mechanics, secretion clearance, posture, sitting balance, and upper and lower extremity strengthening. SLP interventions focused on cognitive reorganization, verbal and nonverbal communication, secretion management, and swallowing function. Intensity and duration of the sessions were adapted according to patient response and level of fatigue. Results: We found that time to tracheostomy from intubation for the three patients was 23 days, 20 days, and 24 days, respectively. Time from tracheostomy insertion to weaning from ventilator was 9 days for patient 1, and 5 days for patient 2 and patient 3. Regarding time to achieve functional PT and SLP milestones, all patients achieved upright sitting with PT prior to achieving initial SLP milestone of voicing with finger occlusion. Variations in progression to swallowing trials were patient specific and due to respiratory instability, cognitive deficits, and limitations in production of an effortful swallow. Patient participation in therapy sessions improved following establishment of oral verbal communication. Conclusion: Interdisciplinary cooperation and synchronized implementation of PT and SLP interventions in three COVID-19 patients following prolonged intubation facilitated participation in treatment and achievement of functional milestones. Further study is warranted.

Arranging good clinical practices training and trial monitoring for a vaccine efficacy study during a public health emergency of international concern.

The 2014-2015 outbreak of Ebola Virus Disease (EVD) in West Africa was unprecedented in size and scope. The World Health Organization, government of Guinea and other partners undertook a field trial of efficacy of an Ebola vaccine in Guinea, with a parallel immunogenicity study in front-line workers. However, several obstacles had to be overcome. One was the need to teach Good Clinical Practices to a large group of field workers who had never participated in vaccine clinical trial research. Because the trial design was complex, performing this efficacy trial during an Ebola outbreak would have been challenging even for experienced investigators. For field workers who had never previously participated in a clinical trial, this constituted a daunting challenge. Another challenge was to provide independent monitoring to document the quality and validity of the field trial data to support future regulatory agency licensure. Here we discuss how these challenges were overcome, and what lessons can be drawn for the future. Intensive GCP was expeditiously arranged for 251 clinical study staff on-site in Guinea. The trials were initiated within days after completion of training. Monitoring (100% of participants in the efficacy trial and 50% in the immunogenicity trial) began at the onset of the trials. Early monitoring detected many minor errors but prompt feedback and guidance from the monitors, who explained the mistakes and proposed corrective actions, diminished error frequency as the trials progressed. Monitoring later in the trials showed what one would expect in a study conducted by experienced investigators. Should a vaccine field trial have to be hastily arranged during a future emerging disease outbreak in a developing country setting, our methods of training and monitoring could provide a model.

ROS as a novel indicator to predict anticancer drug efficacy.

BACKGROUND: Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells' response to ROS-stimulating therapy. METHODS: Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. RESULTS: Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. CONCLUSIONS: Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

Sturge-Weber Syndrome Patient Registry: Delayed Diagnosis and Poor Seizure Control.

OBJECTIVE: To examine the symptomatology and treatment of Sturge-Weber syndrome (SWS) from a large patient registry to identify common symptoms, clinical outcomes, and areas of unmet clinical need. STUDY DESIGN: An online patient questionnaire was completed by 628 patients with clinically diagnosed SWS and/or a port-wine birthmark over a 19-year period. Statistical analysis focused on seizures as a primary outcome measure, as well as associated neurologic, ophthalmologic, and dermatologic attributes to understand some of the natural history of the disorder. RESULTS: The majority (92%) of patients had a port-wine birthmark, and 60% of the patients had neurologic symptoms, including seizures and stroke-like episodes. Glaucoma was present in 48% of the patients. Other common symptoms included behavioral (46%) and hearing (or vestibular) disorders (24%). Delayed diagnosis of SWS beyond 1 year after presentation of initial symptoms occurred in 16% of the patients, with 68% having clear preexisting comorbidities, especially headaches. Birthmarks on the forehead and scalp were associated with seizures (P < .001), whereas bilaterality of birthmarks was not. Only 49% of patients being treated for epilepsy were free of seizures. CONCLUSIONS: Seizures and glaucoma were the primary drivers for a diagnosis of SWS in patients with delayed diagnosis, and hearing (or vestibular) and behavioral problems were also prevalent. The diagnosis of SWS was delayed when the predominant symptom was headache. Seizure control was quite poor in many patients with SWS. Our findings highlight an important need for detailed, longitudinal data to improve our understanding of SWS and develop better treatment strategies for patients with this disorder.

Neurological Complications of Sturge-Weber Syndrome: Current Status and Unmet Needs.

OBJECTIVE: We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome. METHODS: An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed. RESULTS: Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials. CONCLUSION: We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy.

Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome (SWS) is caused by a somatic mutation in GNAQ leading to capillary venous malformations in the brain presenting with various neurological, ophthalmic, and cognitive symptoms of variable severity. This clinical variability makes accurate prognosis difficult. We hypothesized that the greater extent of physical factors (extent of skin, eye, and brain involvement), presence of possible genetic factors (gender and family history), and age of seizure onset may be associated with greater symptom severity and need for surgery in patients with SWS. METHODS: The questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. RESULTS: Bilateral brain involvement was associated with both learning disorder and intellectual disability, whereas port-wine birthmark extent was associated with epilepsy and an increased likelihood of glaucoma surgery. Subjects with family history of vascular birthmarks were also more likely to report symptomatic strokes, and family history of seizures was associated with earlier seizure onset. Learning disorder, intellectual disability, strokelike episodes, symptomatic stroke, hemiparesis, visual field deficit, and brain surgery were all significantly associated with earlier onset of seizures. CONCLUSION: The extent of brain and skin involvement in SWS, as well as the age of seizure onset, affect prognosis. Other genetic factors, particularly variants involved in vascular development and epilepsy, may also contribute to neurological prognosis, and further study is needed.

A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome is a neurocutaneous disorder associated with port-wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Because of its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving ahead will be to turn knowledge gaps and unmet needs into new research directions. METHODS: On October 1-3, 2017, the Sturge-Weber Foundation assembled clinicians from the Clinical Care Network with patients from the Patient Engagement Network of the Sturge-Weber Foundation to identify our current state of knowledge, knowledge gaps, and unmet needs. RESULTS: One clear unmet need is a need for consensus guidelines on care and surveillance. It was strongly recommended that patients be followed by multidisciplinary clinical teams with life-long follow-up for children and adults to monitor disease progression in the skin, eye, and brain. Standardized neuroimaging modalities at specified time points are needed together with a stronger clinicopathologic understanding. Uniform tissue banking and clinical data acquisition strategies are needed with cross-center, longitudinal studies that will set the stage for new clinical trials. A better understanding of the pathogenic roles of cerebral calcifications and stroke-like symptoms is a clear unmet need with potentially devastating consequences. CONCLUSIONS: Biomarkers capable of predicting disease progression will be needed to advance new therapeutic strategies. Importantly, how to deal with the emotional and psychological effects of Sturge-Weber syndrome and its impact on quality of life is a clear unmet need.