Afectación ocular como primera y única manifestación del síndrome de Bardet-Biedl: presentación de un caso / Ocular impairment as the first and only manifestation of Bardet–Biedl syndrome: A case report

El síndrome de Bardet-Biedl (SBB) es una ciliopatía que se asocia principalmente a distrofia retiniana, disfunción renal, polidactilia posaxial, obesidad, déficit cognitivo e hipogonadismo. Los síntomas vinculados a la distrofia retiniana no suelen aparecer hasta la primera década de vida, por lo que la detección tiende a retrasarse. La afectación ocular puede ser la forma inicial de manifestación de este síndrome, incluso puede ser la única, por lo que se debería tener en cuenta en el diagnóstico diferencial de una ambliopía en un niño que no mejora a pesar del correcto cumplimiento del tratamiento. Se presenta un caso de baja agudeza visual (AV) en una paciente pediátrica como manifestación inicial que lleva al diagnóstico del SBB y que es, además, el único síntoma que exhibe hasta la fecha, a pesar de tratarse de una enfermedad multisistémica.(AU)

Bardet–Biedl syndrome is a ciliopathy mainly associated with retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogonadism. The symptoms associated with retinal dystrophy do not usually appear until the first decade of life, so the diagnosis is usually delayed. Ocular involvement may be the initial form of manifestation of this syndrome, it may even be the only one, so it should be taken into account in the differential diagnosis of amblyopia in a child who does not improve despite correct compliance with treatment. A case of low visual acuity in a pediatric patient is presented as an initial manifestation that leads to the diagnosis of Bardet–Biedl syndrome, and which is also the only symptom that the patient presents to date, despite being a multisystem disease.(AU)

Neuromiotonía ocular: un infrecuente caso tras carcinoma nasofaríngeo tratado con radioterapia local / Ocular neuromyotonia: An unusual case after radiotheraphy for nasopharyngeal carcinoma

La neuromiotonía ocular es una patología poco frecuente caracterizada por episodios recurrentes de diplopía binocular ocasionada por una contracción paroxística mantenida de uno o más músculos extraoculares inervados por un mismo nervio craneal, espontáneamente o inducidos por una versión concreta mantenida en el tiempo, normalmente relacionado con un antecedente de radioterapia local intracraneal. Presentamos el caso de una mujer de 46 años que presenta episodios de diplopía binocular recurrentes, diagnosticada de neuromiotonía ocular del VI nervio craneal izquierdo a los 8 años de padecer un cáncer de cavum tratado mediante radioterapia local y en completa remisión. Aunque es poco frecuente, la radiación a nivel de cavum debe tenerse en cuenta como potencial causa de neuromiotonía ocular, por su proximidad a la base del cráneo y su estrecha relación con el trayecto de los nervios oculomotores, especialmente el VI par craneal, como el caso que se presenta en este artículo.(AU)

Ocular neuromyotonia is an infrequent disorder characterised by recurrent episodes of binocular diplopia caused by paroxysmal contraction of one or several extraocular muscles innervated by the same cranial nerve. It can be triggered spontaneously or caused by prolonged contraction of specific eye muscle(s) and is usually related to a local intracranial radiotherapy antecedent. We report the case of a 46-year-old woman who developed intermittent episodes of binocular diplopia 8 years after radiotherapy for a nasopharyngeal carcinoma. After a complete neuro-ophthalmic assessment we diagnosed the case as an abducens nerve neuromyotonia. Although it is infrequent, radiotherapy to the nasopharynx is a possible cause of ocular neuromyotonia, due to the proximity to the base of the skull and extraocular motor nerve pathways, especially that of the VI cranial nerve, as is the case presented in this article, about a patient whose history is a nasopharyngeal carcinoma treated with local radiotherapy.(AU)

Un caso inusual de oclusión de rama arterial retiniana: posible variante del síndrome de Sneddon / Unusual case of retinal arterial branch occlusion: Possible variant of Sneddon syndrome

El síndrome de Sneddon (SS) se manifiesta por múltiples accidentes cerebrovasculares y livedo reticularis. La vasculopatía livedoide (VL) se caracteriza por una larga historia de ulceración de pies y piernas y una histopatología que indica un proceso trombótico. Se describe una oclusión de rama arterial retiniana en un varón de 52años con VL. No presentó anomalías de laboratorio perceptibles, como anticuerpos antifosfolípidos, ni antecedentes de accidentes cerebrovasculares. La oclusión de arteria retiniana acompañada de VL podría ser una variante del síndrome de Sneddon. Con angiografía por tomografía de coherencia óptica se observó en la mácula en el ojo asintomático una reducción de las capas vasculares, lo que indica cambios microvasculares localizados como marcador evolutivo en la patogénesis del SS.(AU)

Sneddon's syndrome (SS) manifests through multiple strokes and livedo reticularis. Livedoid vasculopathy (LV) is characterized by a long history of foot and leg ulceration and histopathology indicating a thrombotic process. Arterial retinal branch occlusion is described in a 52-year-old male with LV. He did not present noticeable laboratory abnormalities, such as antiphospholipid antibodies, or a history of strokes. Retinal artery occlusion accompanied by LV could be a variant of Sneddon's syndrome. Optical coherence tomography angiography revealed a reduction in the macula's vascular layers in the asymptomatic eye, indicating localized microvascular changes as an evolving marker in the pathogenesis of SS.(AU)

[WHEN MEDICATIONS ARE NOT ENOUGH - NEUROFEEDBACK AS A COMPLEMENTARY TREATMENT FOR POST-TRAUMATIC STRESS DISORDER - A CASE REPORT].

INTRODUCTION: Neurofeedback (NF) therapy is brain training using operant conditioning including real-time displays of brain activity to teach people how to regulate their brain function. We would like to present a treatment for a patient who experienced severe traumatic events on 7/10 including physical injury accompanied by difficulty sleeping for two months, nightmares, intrusive thoughts, difficulties in emotional regulation and difficulty in concentrating. Due to the complexity and difficulties in emotional regulation accompanied by severe sleep disturbances, it was decided to treat with medication in combination with neurofeedback. After several training sessions in addition to pharmaceutical treatment, significant relaxation was observed, there was an improvement in concentration and the patient was able to return to his work and normal social functioning. In addition, intrusive thoughts decreased in intensity and frequency.

Effect of massage on blood pressure in patients with hypertension: A meta-analysis.

BACKGROUND: Hypertension (HTN) is a chronic medical condition that affects 1.13 billion people globally. Successful management of HTN is accomplished through both pharmacological and non-pharmacological interventions. Massage therapy, a widely practiced complementary and alternative medicine therapy that alleviates physical discomfort and promotes overall well-being. The current meta-analysis aims to evaluate the effect of massage on blood pressure in patients with HTN. METHODS: Electronic databases, including PubMed, Prospero, Scopus, ClinicalTrials.gov, Embase, and the Cochrane Library, were searched from their inception up to March 2021. All experimental trials that met the (PICO) criteria were included. The primary outcome of the study was blood pressure. A meta-analysis was conducted using a random-effects model to generate a summary of treatment effects, expressed as the effect size (Standardized Mean Difference - SMD), along with a 95% Confidence Interval (CI). RESULTS: Six studies were included in the review, in which 290 patients participated, 148 were in the experimental group and 142 in the control group. Meta-analysis showed a minimal reduction of systolic blood pressure (SMD: -0.65 mmHg, 95% CI: -4.75, 3.55) and diastolic blood pressure (SMD: -0.68 mmHg, 95% CI: -2.43, 1.06) with considerable heterogeneity (I2> 94%). CONCLUSION: The findings demonstrated that massage therapy resulted in a minimal reduction in blood pressure among patients with hypertension. To suggest massage as an effective intervention to reduce blood pressure further randomized control trials are recommended. Additionally, the literature is limited and still emerging, further large prospective studies with long follow-ups are warranted to verify the findings from this meta-analysis.

Two-stream vision transformer based multi-label recognition for TCM prescriptions construction.

Traditional Chinese medicine (TCM) observation diagnosis images (including facial and tongue images) provide essential human body information, holding significant importance in clinical medicine for diagnosis and treatment. TCM prescriptions, known for their simplicity, non-invasiveness, and low side effects, have been widely applied worldwide. Exploring automated herbal prescription construction based on visual diagnosis holds vital value in delving into the correlation between external features and herbal prescriptions and offering medical services in mobile healthcare systems. To effectively integrate multi-perspective visual diagnosis images and automate prescription construction, this study proposes a multi-herb recommendation framework based on Visual Transformer and multi-label classification. The framework comprises three key components: image encoder, label embedding module, and cross-modal fusion classification module. The image encoder employs a dual-stream Visual Transformer to learn dependencies between different regions of input images, capturing both local and global features. The label embedding module utilizes Graph Convolutional Networks to capture associations between diverse herbal labels. Finally, two Multi-Modal Factorized Bilinear modules are introduced as effective components to fuse cross-modal vectors, creating an end-to-end multi-label image-herb recommendation model. Through experimentation with real facial and tongue images and generating prescription data closely resembling real samples. The precision is 50.06 %, the recall rate is 48.33 %, and the F1-score is 49.18 %. This study validates the feasibility of automated herbal prescription construction from the perspective of visual diagnosis. Simultaneously, it provides valuable insights for constructing herbal prescriptions automatically from more physical information.

Effects of soft tissue mobilisation on subacute adherent linear scars: a single-group intervention study.

OBJECTIVE: Scar adherence due to a pathological healing process can cause physical and psychological disturbance. Soft tissue mobilisation (STM) techniques are widely used to treat and prevent scar adherence, but little is known on their effects. We aimed to analyse the effect of STM in patients with subacute post-surgical scar adhesions affecting the extremities. METHOD: A single-group quasi-experimental study was conducted on consecutive patients undergoing post-surgery limb rehabilitation. Patients with a baseline Adhesion Severity (AS) index of <0.5 at the worst scar point, as measured by the Adheremeter, were eligible. All patients who completed a minimum of five manual treatment sessions were included. The primary outcome was the AS index and the secondary outcome was the Italian version of the Patient and Observer Scar Assessment Scales (POSAS-I). RESULTS: A cohort of 19 patients underwent an average of eight STM sessions over a period of one month. The AS index value increased from a median of 0.12 at baseline (interquartile range (IQR): 0.05-0.25) to 0.41 post-treatment (IQR: 0.26-0.63; median change: 0.24; IQR: 0.16-0.40; p<0.001). A large effect size was observed for both AS and Observer Scar Assessment Scale (OSAS-I) (Cohen r=0.6), with a large probability of superiority (PS) (87% and 86%, respectively). A moderate effect was observed for the Patient Scar Assessment Scale (PSAS-I) (Cohen=0.4; PS=71%). Pre-post treatment changes exceeded the minimal detectable changes for the AS and OSAS-I in 68% of subjects, and for PSAS-I in 21% of subjects. CONCLUSION: STM manual techniques may produce a large effect on the mobility of adherent subacute post-surgical scars.

Using slisemap to interpret physical data.

Manifold visualisation techniques are commonly used to visualise high-dimensional datasets in physical sciences. In this paper, we apply a recently introduced manifold visualisation method, slisemap, on datasets from physics and chemistry. slisemap combines manifold visualisation with explainable artificial intelligence. Explainable artificial intelligence investigates the decision processes of black box machine learning models and complex simulators. With slisemap, we find an embedding such that data items with similar local explanations are grouped together. Hence, slisemap gives us an overview of the different behaviours of a black box model, where the patterns in the embedding reflect a target property. In this paper, we show how slisemap can be used and evaluated on physical data and that it is helpful in finding meaningful information on classification and regression models trained on these datasets.

Unusual case of 'scorbutic proptosis'.

Proptosis is a frequent presenting symptom/sign of many paediatric malignancies. Acute-onset proptosis is an ophthalmic emergency that can endanger vision if not treated promptly. Appropriate treatment must be instituted only after investigating for the underlying aetiology. Here, we report a developmentally delayed boy in middle childhood who presented with recent onset bilateral proptosis. Clinical examination followed by radiological evaluation suggested scurvy to be the underlying cause and vitamin C supplementation led to prompt reversal of proptosis. The relevant literature has been reviewed and presented here to apprise the paediatric oncologists about this rare but easily treatable cause of proptosis.

Configuring the Professional Touch in Physical Examinations in Chinese Outpatient Clinical Interaction: Talk, Touch, Professional Vision, and Intersubjectivity.

Touch is a fundamental resource mobilized by clinicians in physical examinations in outpatient clinical consultations. However, few studies have been conducted to explore the sequential organization of touch in the interactional process of physical examinations where clinicians' touch is launched and responded to in Chinese medical settings. Based on a collection of video recordings of naturally occurring clinician-patient interaction in an orthopedic outpatient clinic in China, we observed four types of clinicians' touch in the physical examination framework: the guiding touch, the diagnostic touch, the demonstrative touch, and the therapeutic touch. Together with clinical expertise, the sensorial knowledge obtained through touch enables clinicians to professionally evaluate patients' physical conditions and diagnose their illnesses. We also demonstrated that patients do not merely put themselves into clinicians' hands as clinical objects for inspection and defer to clinicians' medical authority. Instead, they actively and agentively participate in physical examinations to jointly accomplish social actions and activities through the temporal and sequential mobilization of their multimodal resources. This study not only adds to an emerging body of research on touch in medical settings but also sheds some light on the understanding of the clinician-patient interaction in Chinese outpatient clinics.

Failure to Participate in Sports: An Evaluation of Preparticipation Physicals in a Local School District.

PURPOSE: To determine the incidence of the documentation of athlete failure of preparticipation sports physicals. METHODS: This was a retrospective observational study that involved review of preparticipation examination physical form documentation from multiple clinicians for all student athletes who participated in athletics during the 2018 to 2019 academic year at Galveston Independent School District (GISD). We collected the reasons for failure to pass the preparticipation physical examination. RESULTS: Of the approximately 800 student athlete forms reviewed, 183 forms indicated individual athletes failed the visual acuity or cardiovascular portions of the preparticipation physical examination. DISCUSSION: Athlete failures of the preparticipation physical examination may cause delays in sports participation, and time and monetary costs to students and their parents. Inconsistences in guidelines used to clear athletes as well as variation in form completion impacts whether athletes reportedly failed or passed the examination. Mass participation screening becomes a safety net for communities for athletes who may not have primary care providers to encourage follow-up with a regular clinician for previously undiagnosed medical issues and standardizing guideline use and form completion across clinicians who do these exams may improve numbers of athletes who are cleared to play sports. CONCLUSION: Focusing on preventable and addressable preparticipation examination failures may help clinicians who perform these exams, while also establishing a safety net for previously undiagnosed medical conditions. Instituting yearly vision checks, addressing cardiovascular issues, and encouraging yearly follow-up with primary care clinicians can more readily address physical and mental health issues and will provide more comprehensive care to student athletes.

Supine counterstrain technique for rhomboid tender point.

Because poor posture is a common instigating factor in back, shoulder, and neck pain, the rhomboid muscles should be considered in a complete physical evaluation. Previous techniques for treating a rhomboid tender point have addressed only one of the two main actions of the muscle, specifically retraction of the scapula utilizing shoulder abduction. This modified supine counterstrain technique for the rhomboid tender point incorporates both scapular retraction as well as superior, medial rotation of the inferior border of the scapula without abduction, providing a comprehensive treatment to accommodate patients with shoulder movement restrictions. This article discusses indications, contraindications, treatment, and a list of problem-solving strategies for the rhomboid tender point.

Martial Arts: Orthopaedic Injuries and Related Biomechanics.

Martial arts are various systems of combat skills encompassing striking and grappling. Many styles have evolved into modern sports, and some have been included in the Olympics. The physicality of these can predispose practitioners to musculoskeletal injuries, such as anterior cruciate ligament ruptures; patellar, shoulder, or elbow instabilities; extremity fractures; and hand and spine injuries, which have been studied both clinically and biomechanically. The most common injury related to longer time loss from participation is an anterior cruciate ligament rupture. Higher injury incidence is associated with a higher level of experience and competition. Orthopaedic management of martial arts injuries should reflect the specific needs of each martial artist and the biomechanics of motions common to each style. Full-contact practitioners may benefit from broader surgical indications and special attention to the choice and positioning of implants; nonsurgical treatment may be appropriate for certain pediatric or noncontact practitioners. Approximately 60% of martial artists can return to the preinjury level of participation after a major injury. Injury prevention and rehabilitation programs should optimize neuromotor control and core engagement to ensure proper body mechanics. Gradual incorporation of martial arts movement into the postoperative physical therapy curriculum can benefit physical progress and help gain confidence toward full participation.

Effect of a single session of sensorimotor rhythm neurofeedback training on the putting performance of professional golfers.

Sensorimotor rhythm (SMR) activity has been associated with automaticity and flow in motor execution. Studies have revealed that neurofeedback training (NFT) of the SMR can improve sports performance; however, few studies have adequately explored the effects of a single session of such NFT or examined the possible mechanisms underlying these effects on sports performance. This study recruited 44 professional golfers to address these gaps in the literature. A crossover design was employed to determine the order of the participation in the NFT and no-training control conditions. The participants were asked to perform 60 10-foot putts while electroencephalograms (EEGs) were recorded before and after the tasks. In pre-and post-tests, visual analog scales were used to assess the psychological states associated with SMR activities including the levels of attention engagement, conscious motor control, and physical relaxation. The results revealed that a single NFT session effectively increased SMR power and improved putting performance compared with the control condition. The subjective assessments also revealed that the participants reported lower attention engagement, less conscious control of the motor details and were more relaxed in the putting task, suggesting that SMR NFT promoted effortless and quiescent mental states during motor preparation for a putting task. This study aligns with theoretical hypotheses and extends current knowledge by revealing that a single session of SMR NFT can effectively enhance SMR power and improve putting performance in professional golfers. It also provides preliminary evidence of the possible underlying mechanisms that drive the effect of SMR NFT on putting performances.

Spinal manipulation and electrical dry needling as an adjunct to conventional physical therapy in patients with lumbar spinal stenosis: a multi-center randomized clinical trial.

BACKGROUND CONTEXT: Nonoperative management of lumbar spinal stenosis (LSS) includes activity modification, medication, injections, and physical therapy. Conventional physical therapy includes a multimodal approach of exercise, manual therapy, and electro-thermal modalities. There is a paucity of evidence supporting the use of spinal manipulation and dry needling as an adjunct to conventional physical therapy in patients with LSS. PURPOSE: This study aimed to determine the effects of adding thrust spinal manipulation and electrical dry needling to conventional physical therapy in patients with LSS. STUDY DESIGN/SETTING: Randomized, single-blinded, multi-center, parallel-group clinical trial. PATIENT SAMPLE: One hundred twenty-eight (n=128) patients with LSS from 12 outpatient clinics in 8 states were recruited over a 34-month period. OUTCOME MEASURES: The primary outcomes included the Numeric Pain Rating Scale (NPRS) and the Oswestry Disability Index (ODI). Secondary outcomes included the Roland Morris Disability Index (RMDI), Global Rating of Change (GROC), and medication intake. Follow-up assessments were taken at 2 weeks, 6 weeks, and 3 months. METHODS: Patients were randomized to receive either spinal manipulation, electrical dry needling, and conventional physical therapy (MEDNCPT group, n=65) or conventional physical therapy alone (CPT group, n=63). RESULTS: At 3 months, the MEDNCPT group experienced greater reductions in overall low back, buttock, and leg pain (NPRS: F=5.658; p=.002) and related-disability (ODI: F=9.921; p<.001; RMDI: F=7.263; p<.001) compared to the CPT group. Effect sizes were small at 2 and 6 weeks, and medium at 3 months for the NPRS, ODI, and RMDI. At 3 months, significantly (p=.003) more patients in the MEDNCPT group reported a successful outcome (GROC≥+5) than the CPT group. CONCLUSION: Patients with LSS who received electrical dry needling and spinal manipulation in addition to impairment-based exercise, manual therapy and electro-thermal modalities experienced greater improvements in low back, buttock and leg pain and related-disability than those receiving exercise, manual therapy, and electro-thermal modalities alone at 3 months, but not at the 2 or 6 week follow-up.

Effect of electroacupuncture on brachial plexus post-traumatic neuralgia: A case report.

Background: Brachial plexus injury is a serious peripheral nerve injury that severely disables upper limbs and affects patients' daily life and work Acupuncture and Electroacupuncture have traditionally been used to treat neuropathic pain. However, there is still lacking evidence as regard to their effects on pain following traumatic nerve and plexus lesions. Neurotmesis after brachial plexus injury also causes movement disorders of the denervated muscles and loss of sensory function in the skin. Case report: We report a case of a brachial plexus injury due to humeral fracture, predominantly involving the lower trunk and the medial cord, treated with electroacupuncture. Results. We documented a positive significant response, based on clinical examination, pain scores and neurophysiologic findings. Conclusions: Repeated Electroacupuncture can relieve neuropathic pain due to brachial plexus injury. However, additional studies are needed to verify the efficacy and effectiveness of this approach.

[Application of Light Therapy in Dementia Care].

Patients with dementia often display related sleep disturbance, depression, and behavioral and psychological symptoms, which are traditionally managed through the use of antipsychotic medications or physical restraint. However, these management interventions can have negative effects on the physical and psychological health of patients. The results of several meta-analyses suggest non-pharmacological interventions, including light therapy, should be used for the first-line management of these dementia symptoms. Light therapy uses artificial light to compensate for insufficient light exposure during the daytime and to help patients with dementia properly regulate their circadian rhythms. Sleep disturbance and depression in those with dementia may be effectively relieved through the application of light therapy. Nurses should assess the needs and symptoms of patients with dementia and consider applying light therapy as a complementary care intervention to improve quality of care.

Slower respiration rate is associated with higher self-reported well-being after wellness training.

Mind-body interventions such as mindfulness-based stress reduction (MBSR) may improve well-being by increasing awareness and regulation of physiological and cognitive states. However, it is unclear how practice may alter long-term, baseline physiological processes, and whether these changes reflect improved well-being. Using respiration rate (RR), which can be sensitive to effects of meditation, and 3 aspects of self-reported well-being (psychological well-being [PWB], distress, and medical symptoms), we tested pre-registered hypotheses that: (1) Lower baseline RR (in a resting, non-meditative state) would be a physiological marker associated with well-being, (2) MBSR would decrease RR, and (3) Training-related decreases in RR would be associated with improved well-being. We recruited 245 adults (age range = 18-65, M = 42.4): experienced meditators (n = 42), and meditation-naïve participants randomized to MBSR (n = 72), active control (n = 41), or waitlist control (n = 66). Data were collected at pre-randomization, post-intervention (or waiting), and long-term follow-up. Lower baseline RR was associated with lower psychological distress among long-term meditators (p* = 0.03, b = 0.02, 95% CI [0.01, 0.03]), though not in non-meditators prior to training. MBSR decreased RR compared to waitlist (p = 0.02, Cohen's d = - 0.41, 95% CI [- 0.78, - 0.06]), but not the active control. Decreased RR related to decreased medical symptoms, across all participants (p* = 0.02, b = 0.57, 95% CI [0.15, 0.98]). Post-training, lower RR was associated with higher PWB across training groups compared to waitlist (p* = 0.01, b = 0.06, 95% CI [0.02, 0.10]), though there were no significant differences in change in PWB between groups. This physiological marker may indicate higher physical and/or psychological well-being in those who engage in wellness practices.

[Analysis on status quo of outcomes and measurement instruments of randomized controlled trials of acupuncture for post-stroke dysphagia].

OBJECTIVE: To analyze the report status of outcomes and measurement instruments of randomized controlled trials (RCTs) of acupuncture for post-stroke dysphagia, so as to provide a basis for designing clinical trials and developing the core outcome set in acupuncture for post-stroke dysphagia. METHODS: RCTs of acupuncture for post-stroke dysphagia were searched in databases i.e. CNKI, SinoMed, Wanfang, PubMed, EMbase, Web of Science and clinical trial registries i.e. ClinicalTrials.gov and Chinese Clinical Trial Registry (ChiCTR), from January 1st, 2012 to October 30th, 2021. By literature screening and data extraction, outcomes and measurement instruments were summarized and analyzed. RESULTS: A total of 172 trials (including 165 RCTs and 7 ongoing trials registrations) were included, involving 91 outcomes. The outcomes could be classified into 7 domains according to functional attributes, namely clinical manifestation, physical and chemical examination, quality of life, TCM symptoms/syndromes, long-term prognosis, safety assessment and economic evaluation. It was found that there were various measurements instruments with large differences, inconsistent measurement time point and without discriminatively reporting primary or secondary outcomes. CONCLUSION: The status quo of outcomes and measurement instruments of RCTs of acupuncture for post-stroke dysphagia is not conducive to the summary and comparison of each trial's results. Thus, it is suggested to develop a core outcome set for acupuncture for post-stroke dysphagia to improve the normative and research quality of their clinical trial design.