Epidemiological studies considered water use and hygiene practices as central risk factors for diarrhea. Few studies focused on independent association of water quantity with diarrheal diseases. This study aimed to describe the methodological protocol that adapted multidisciplinary and mixed-method research approach to assess how water usage including water quantity influences the attributable risk for diarrhea in a low-income urban community in Bangladesh.'Choleraphone'  was a contemporary approach intended to cut down on resources, reduce research fatigue and provide more accurate data compared to the 'gold standard' (i.e. visiting a household of diarrhea cases within 48 hours) for measuring diarrhea incidence. Development of methods to measure water quantity using qualitative and quantitative approach within a setting where meter water connection is rare was another unique feature of this protocol. This protocol provided guidance and insight on how multiple methods of different disciplines can be combined to enrich understanding of waterborne diseases.The quantitative, anthropological and microbiological approaches were threaded together to provide a greater understanding of the infrastructural, behavioral and microbial interactions to fathom the dimensions of fecal oral transmission pathways within the households. The use of the  Specification Table*Value of the Protocol•Given the current climate change projections, water stress  is expected to increase in Bangladesh , which c•Despite the global concern of waterborne infectious diseases, significant gap remained within the scientific community on epidemiology and transmission dynamics of these diseases. Although people's behaviour in terms of water use and hygiene practices is seen as a central risk factor of waterborne diarrheal disease ,3, littl•Since the water and health outcomes are complex, interactive, nonlinear, and dynamic, and a multiplicity of different transmission pathways are avaiable to most of the waterborne pathogens, a comprehensive multidisciplinary mixed-method research approach is urged to address this major public health problem to provide high quality real time data in a holistic and contextual manner to enhance understanding of disease transmission.•The methodology developed in this protocol will be useful to implement in future studies within different low-income countries to understand the disease dynamics that include complex behavioral, social and environmental exposure pathways of disease transmission.To assess how water usage including availability and quantity for domestic and personal hygiene in different months of the year influence the attributable risk for diarrhea in households in a low-income urban community in Bangladesh.This proposed study was a prospective longitudinal study conducted in the East Arichpur urban area located northwest of Dhaka city in Bangladesh  5]. Mos. Mos5]. paras  within the community, the size of each para, potential informants for group discussion and mapping, probable number of group discussion required in each para and suitable place and time of group discussion and mapping. The team conducted group discussions and mapping to understand the geographical layout of the area and identify clusters of household that share a common yard locally known as 'compound') using different sources of water for domestic use, living and sharing arrangement of water, sanitation and cooking facilities. The team also collected information on regularity of water availability and seasonal availability during this group discussion.The household was the unit of the study. This study used random sampling to recruit study households using the list of households of the community. A team trained in qualitative and quantitative data collection, conducted transect walk, informal group discussions and participatory mapping  to list The participants of the group discussions were the residents who had knowledge about the area to draw the map of their small geographical segment where they lived. The total number of group discussion was decided based on the transect walk. In each group discussion five to ten participants were invited. One researcher facilitated the discussion and mapping exercise, one researcher took notes and another researcher observed and recorded the overall process. The research team and the participants drew the map collectively. Based on the mapping exercise, the team developed a list that included the information on cluster of households within a compound, water source, living and sharing arrangement of water, sanitation and cooking facilities . The houThe team excluded the households that do not share resources  with other households as they did not fall into the low-income urban settings criteria. The team excluded the households if the head of household was unable to provide consent due to illness or disability or any household member refused to participate in the study. The team considered the household as dropped out if: the household migrated to outside of the study area or half of the household members' opt-out of the study or opt-out of diarrhea surveillance procedures. The dropped out household was replaced with another household randomly from the household list of the community.A research team member visited the selected households and asked for consent to participate in this study. Upon consent to participate, the research team set up an appointment to visit the family to complete baseline data collection at a specific time when all household members were expected to be at home . After bIn every six-week interval, one researcher visited the cohort households and collected information on water usage, hygiene, sanitation practices and diarrhea episodes .In each of the visit the researcher conducted spot observation using a structured format and visual documentation to record actual practices hygiene and water use . Any chaThe researcher also recorded the water consumption information by the household members within last 24 h using a 'tally sheet' that included a picture of all the water storage containers of the households . The research team provided a training of the household water collector to record water use in the first six-weekly visit. One day before the six-weekly visits, the researcher provided the 'tally sheet' to the household caretaker  to mark down with tally for each time each of the containers were refilled. The following day, the researcher again visited the household to collect the 'tally sheet'. During this visit, the researcher also conducted probing  following the 'tally sheet' to confirm the recorded water quantity. Any changes in the container or water sources were included in the 'tally sheet' in each visit. The team provided a training of the household water collector to record water use in the first six-weekly visit. The team recorded only frequency of activities that used running tap water. Later water quantity was measured using a proxy for quantity of each activities based on water quantity data that was collected as part of in-depth anthropological exploration in a subset of households .Escherichia coli (E. coli) by membrane filtration of 100 mL water samples according to the method described earlier .Fig.'Choleraphone' consisted of the mobile reporting system as the connection between the call center and the households where the diarrhea cases were identified  published the detail methods of participants selection and the results elsewhere [To improve the mobile phone surveillance system, a team of anthropologists conducted eight FGDs with the household members of selected cohort households to explore perception of diarrhea, barriers and advantages in using the lsewhere . The tea'Choleraphone' surveillance system went through a number of changes. Based on the findings, the word "diarrhea" was replaced with "three or more loose stools in 24 h" as the term 'diarrhea' was described in interchangeable terms with 'cholera' [After the focus group discussions, the cholera' . Based oA team of trained anthropologists collected data using ethnographic approach. The researchers first built good rapport with the community and study households to gain trust. The researchers roamed in the entire community for the first two months and conducted several small groups and individual informal discussions to become acquainted with the community and gain an understanding of the existing water usage and management structure and practices. From the preliminary field exploration, the team identified household with 24 h water availability and households <24 h water availability. Thus, the team categorized households into two groups based on the availability. Within this each group, the team identified 'ease water use' method  and 'difficult water use' method . Thus, the team categorized households in four groups: '24 h available and ease method', '24 h available difficult method', '<24 h water available ease method' and '<24 h water available difficult method' . Based oIn these 24 households, the team conducted day-long observation, semi-structured follow-up interviews and in-depth interviews and to get in-depth insight about the water usages and hygiene practices. The team used audio tape recorder to collect data for all the interviews.To measure the quantity of water usage for each type of domestic and personal purposes and to collect information about changes in practices across and within different seasons, the team conducted bimonthly (once every other month) observations over the course of one year . The 12 To attenuate the observation bias ,23 the tAfter the daylong observation, the team conducted follow-up interviews in the observed households to record the reported water use of two more days within the same week of observation. This follow-up interview was used to cross check the findings of observation and to record changes in frequency, sources and quantity of water for each activity for three days.To obtain an in-depth understanding of the perception and practices on individual and domestic water use, water stress and coping strategies , the teaBesides the in-depth interviews and observation, the team also spent time within the community throughout the data collection period to obtain information of any communal event of activities linked to water usage and infrastructure. As part of this activity the team conducted several FGDs, key information interviews (KII), and informal individual and group discussions with community residents to obtain historical information and changes in water usage practices within the community.During daylong observation, the team also identified potential hotspots within household including kitchen and sanitation facilities. Hotspots are places of possible transmission  where one or more household members can transmit bacteria from one person to the other or “receive” bacteria from the external environment: from food and kitchen implements. The household hotspots are surfaces that are suspected to be contaminated with fecal material  and/or blood or body parts of fish (any type of fish particularly shellfish and sea fish) chicken, and any kind of meat due to frequent touching, infrequent cleaning, and/or poor hygiene. The team identified places that had hand contact with surfaces immediately after coming out of the toilet. The team also observed the food processing and cooking activities to identify possible contaminated kitchen implements. The team also listed the ‘leftover’ food item that was preserved for more than six hours.2 area with sterile cotton swab stick soaked with Phosphate Buffer Saline (PBS) and the swab sticks were returned to the tube containing 3 ml of PBS. All samples of leftover/pre-cooked rice, eggs, lentils, meats, fish and shellfish that had been resting at room temperature or warmer for more than 6 h were taken as because the conditions were found conducive for reaching infective levels (more than 106 cells) of V. cholerae [E. coli contamination by quantifying CFU in chromogenic selective media (mTEC) for thermotolerant E. coli. Detection of V. cholerae prevalence was conducted by targeting the species-specific gene ompW in PCR.During six-weekly visit, environmental swab samples or “hotspot” samples among 32 households (average 16 households each month) were collected from 4 hotspots of direct exposure within household domain: cutting knife, food plate, latrine doorknob, drinking water vessel surface. Hotspot surface samples were obtained by swabbing approximately 10 cmcholerae .To colleWe used descriptive statistics mean, range, standard deviation to measure the water quantity liter per capita per day (LCPD) for each household. To categorize the households with different water usage group, the four categories of water usage group was considered which was defined as part of in-depth anthropological exploration . The annThe interviewers transcribed the audio-recorded data. The team expanded the observation field notes and typed in ‘Microsoft word’ for soft copy. After note expansion and transcription, each researcher prepared a code list separately considering the objectives and emerging theme of the study. The team members sat together with their code lists and prepared a final code list. All data were coded manually using the code list. Coded data was summarized according to the study objectives and relevant themes. The team thoroughly reviewed all summarized data to understand the relationships between different themes and subthemes. Later on comparison and triangulation were made among the different tools and findings. Triangulation is important for the rigor of qualitative research . This anE. coli and V. cholerae contamination in drinking water, leftover food and hotspot surfaces. The proportions of water samples positive for E. coli and V. cholerae in point-of-drinking and communal source water were calculated. Logistic regression test was employed to examine the association of E. coli and V. cholerae between point-of-drinking and sources, treated and non-treated drinking water, drinking vessel type. A subset of hotspot samples was further analyzed by PCR to detect the virulence factors of five different diarrheagenic pathotypes of E. coli. From PCR positive samples, V. cholerae strains were isolated for further genotypic and phenotypic characterization. For both E. coli and V. cholerae, seasonal prevalence of contamination was estimated in hotspot and food samples.A descriptive analysis was performed for households where we portrayed the percentage of households that had Informed written consent was obtained from all the study households. The data collection team obtained written informed consent from all the participants or their guardians (for children) included in this study. The protocol has been internationally peer reviewed before the submission to the Research Review Committee (RRC) of icddr,b. The Ethical Review Committee (ERC) of icddr,b, Bangladesh reviewed and approved the study protocol.•In the initial design, participatory mapping was planned to be implemented. During the data collection period the team identified that using this method for entire mapping was not possible due to limited time and availability of the community residents. In an urban setting, individuals are less available compared to a rural setting. Thus the team employed both participatory mapping and mapping by the research team members by visiting door-to-door to complete the household listing.•V. cholerae through rectal swab sample out of 281 reported diarrhea cases. We found some reasons for low incidence which are as follows: a) our qualitative exploration identified that community people have common practices of taking medication  without consulting with a formal health practitioner when they realize that they having loose stools. b) Despite of thorough mock training on rectal swab sample collection, the team made incorrect use of 70 % ethanol  for moistening the rectal swabs, and set the wrong temperature for the incubation for first few samples and we excluded these samples from our analysis. Later on, we provided hands-on training to the team for rectal swab sample collection.Identifying incidence of cholera was one of the specific objectives of this study but we found only eight cases of •For anthropological exploration, in-depth interview was planned to be the first method of exploration. However, in first few days of rapport building, the team identified that the study households were biased by the exposure of quantitative baseline data collection and tended to inform the researcher that 'they did not have any diarrhea', 'they washed their hands always' and 'keep themselves clean always'. Thus, the team decided to conduct the observation as a first method so that they could build a good relationship with the study households and then conducted the in-depth interview as the second method.There were some changes made during field work due to field situation and field experience as outlined below. This information would be useful for future replication of the protocol.The detail baseline questionnaire (STable 2), six-weekly visit questionnaire (STable 3), diarrhea reporting questionnaire (STable 4) and in-depth interview guideline (STable 5) were included as supplementary documents.Rebeca Sultana: Conceptualization, Methodology, Investigation, Writing - original draft, Data curation, Visualization, Project administration, Funding acquisition. Charlotte Crim Tamason: Conceptualization, Methodology, Data curation, Formal analysis, Writing - review & editing, Project administration, Funding acquisition. Leela Sengupta Carstensen: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing - review & editing, Visualization, Project administration. Jannatul Ferdous: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing - review & editing, Visualization, Project administration. Zenat Zebin Hossain: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Writing - review & editing, Visualization, Project administration. Anowara Begum: Resources, Writing - review & editing, Supervision. Peter Kjær Mackie Jensen: Conceptualization, Methodology, Resources, Writing - review & editing, Supervision, Funding acquisition.Authors have no conflict of interest


Median nerve entrapment after supracondylar humeral fracture in children is rare. We report a case of Gartland type III supracondylar humeral fracture complicated by an entrapment of the median nerve following closed reduction and percutaneous pinning in a 5-year-old child. The diagnosis of entrapment was made 14 months post injury following progressive motor and sensory palsy. Resection and end-to-end suture were performed, leading to complete sensory and motor recovery eight months later. This nerve complication is often unnoticed and should be suspected systematically before and after reduction of all displaced supracondylar humeral fracture in children. The indication of resection-suture or nerve graft depends on the entrapment and the delay of the palsy. Gartland type III supracondylar humeral fractures (SCHF) in children are known for their severe neurovascular complications. Extension-type fractures with posterolateral displacement are the most frequent and responsible for nerve or neurovascular injuries with a frequency of 9% to 17% . The injThe patient is a 5-year-old right-handed child, admitted to the pediatric emergency room for trauma of the left elbow after falling from a 1.5 meter height. Initial clinical examination found a deformity of the elbow with swelling, ecchymosis in the anterolateral side, and absence of the radial pulse but with a well perfused hand. Neurological examination was very difficult because of the child's young age and the painful trauma. Radiographic examination of the elbow revealed a Gartland type III SCHF with posterolateral displacement . Closed One year and two months later, the parents noted that their child had a functional discomfort when using the left hand and an amyotrophy of the thenar eminence and the forearm. Clinical examination found sensory-motor deficit in the median nerve with hypoesthesia and palsy of both the thumb opposition and AIN. Electroneuromyography confirmed severe truncal injury of the median nerve with an advanced denervation pattern of the abductor pollicis brevis muscle; the topography was in favor of a lesion nerve at the healed fracture site. Ultrasonography of the elbow revealed an entrapment of the nerve within the fracture callus. The median nerve was thickened (0.56 cm of diameter) entering the bone callus; invisible downstream along a 1.5 cm, it reappeared at the level of the elbow joint space with a normal diameter (0.18 cm). MRI confirmed the entrapment of the median nerve within the callus Figures  and 5 wiSurgical exploration and dissection under a microscope following an anterior Henry approach revealed the presence of substantial fibrosis in the anteromedial side of the elbow facing the fracture callus. After careful dissecting and excision of the fibrosis, the proximal end of the median nerve was greatly thickened and entrapped within the bone callus. Its atrophic distal end was sheathed within a fibrosis facing the callus along a 1.5 cm section . The resFollow-up at four months postoperatively showed normal mobility of the elbow and a travelling Tinel sign 3.5 cm below the elbow, demonstrating nerve regeneration. Partial motor recovery of the AIN was observed through the return of the distal interphalangeal joint flexion and the improvement of the thumb-index pinch. Eight months postoperatively, motor and sensory recovery was complete and amyotrophy of the thenar eminence and the forearm had disappeared. At the latest follow-up of twelve months, total return function was observed and the child could use normally again his left hand without discomfort or dysesthesia.Neurological complications in extension-type III SCHF in children represent 15% of cases , most ofThe early diagnosis of the median nerve entrapment would reduce morbidity in such cases. The challenge of performing an urgent thorough examination of the neurological status, particularly in young children with type III SCHF, is responsible for the most part of diagnosis delay. Posterolateral displacement, vascular injury, imperfect reduction, and postreduction interfragment gap must encourage the search for median nerve entrapment , 2. RepeMedian nerve entrapment after displaced SCHF in children remains rare but must not be underestimated, particularly in young children. Advances in noninvasive imagery, ultrasonography, and particularly MRI allow for an early and even preoperative diagnosis of entrapment within the fracture site and for rapid intervention by simple surgical exploration and neurolysis. At a later stage, resection-end-to-end suture of the nerve, when possible, may allow for complete recovery in a young child. Other surgical procedures reserved for old entrapment with extended nerve injuries such as nerve resection-graft do not always allow for a complete recovery, requiring further palliative surgery by tendinous transfer.


Lymphoma originating from the middle ear is rare. The diagnosis of lymphoma as with other cancers of the temporal bone is often made late, and this has a negative implication on the treatment and prognosis of the condition. The delay of diagnosis is mainly due to the similar presentation shared with other benign conditions of the middle ear. We present a case of a 62-year-old man who was treated as a case of chronic otitis media for a period of time before presenting with advanced symptoms; a final diagnosis of lymphoma of the middle ear was given. Other similar cases in the literature are discussed and reviewed. Severe and persistent symptoms of the middle ear should raise red flags and warrant detailed investigations. Lymphoma is a cancer of the reticuloendothelial system; it has two subtypes, Hodgkin's lymphoma and non-Hodgkin's lymphoma. Furthermore, lymphomas constitute 10% of all head and neck tumors; 60% of these are non-Hodgkin's lymphoma and the other 40% are Hodgkin's lymphoma.Diffuse large cell B lymphoma is the largest subunit of non-Hodgkin's lymphoma, and it is characterized by extranodal involvement. The most common sites of extranodal involvement are the stomach and the gastrointestinal tract; however, lymphoma can present in any type of tissues. The bony involvement comprises 1-2% of malignant lymphomas and 3–5% of extranodal lymphomas; involvement of temporal bone is extremely rare with only few reported cases in the literature [A 62-year-old man presented to the otolaryngology clinic with a House-Brackmann grade 4 left lower motor facial nerve palsy with a 10-day history of left postauricular pain. This was preceded by 6 months of intermittent purulent discharge from the left ear for which he received multiple antibiotic courses. On examination, the patient was vitally stable; however, he was febrile. The left postauricular area was mildly tender on palpation and the overlying skin was normal. Otoscopic examination of the left ear was only significant for an erythematous and retracted tympanic membrane. The rest of the examination of the right ear along with a full head and neck exam was unremarkable. White blood count was elevated with 13900 .The patient was admitted to the hospital and had an initial diagnosis of mastoiditis with facial nerve paralysis. He was started on intravenous antibiotics. High-resolution computed tomography (HRCT) and magnetic resonance imaging were performed Figures –4.Due to the severe complication of the facial nerve palsy a decision was made for surgical intervention; cortical mastoidectomy with facial nerve decompression and left middle ear exploration was performed. Granulation tissue in the mastoid air cells and the middle ear were encountered and removed. Biopsies were also taken and sent for histopathology.The histopathological assessment of the tissue revealed diffuse proliferation of large monomorphic atypical lymphoid cells admixed with few medium-sized cells (centroblastic and prominent immunoblastic lymphoid cells) .The cells showed scant to moderate amphophilic cytoplasm, vesicular nuclei, or focal irregular chromatin clumping with prominent 1-2 nucleoli.Frequent mitoses and few tumor giant cells were regarded along with subendothelial infiltrate and occasional pseudorosette Figures  and 7.The proliferative fraction as detected by Ki67 immunostaining is very high (80–90% positivity) .The patient was then transferred to the oncology unit for staging and further management. There was no distant spread and the patient was treated with courses of chemotherapy. At the most recent follow-up his ear symptoms of otalgia and persistent discharge have resolved; however, he still showed a House-Brackmann grade 3 left lower motor neuron facial palsy.Carcinoma of the temporal bone is rare, and most of the pathological diagnosis in such cases turns out to be squamous cell carcinoma. In addition, adenoid cystic carcinoma, adenocarcinoma, and basal cell carcinomas along with metastasis are also reported. Other malignant tumors that can occur in the temporal bone are melanoma, rhabdomyosarcoma, chondrosarcoma, and lymphoma .Lymphoma of the middle ear can arise from the mucosa of the mastoid antrum, tympanum, or the tympanic orifice of the eustachian tube. In addition to that it can arise primarily from the temporal bone, as in our case, which is in the mastoid part of the temporal bone.Diagnosis of cancer in the middle ear and the mastoid process is seldom made early; this can contribute to the unique anatomy of middle ear and the fact that many benign pathologies such as otitis media and its complications share similar clinical presentations; most commonly reported symptoms include otorrhea, otalgia, aural fullness, tinnitus, and hearing loss .Severe hearing loss, facial nerve weakness, and vestibular dysfunction are advanced sequel of middle ear pathology that should raise red flags for a more sinister cause. In addition to malignancy, autoimmune conditions such as granulomatosis with polyangiitis and sarcoidosis and immunodeficiency conditions should also be considered in the differential diagnosis of cases of refractory chronic otitis media with facial nerve palsy. Delay in management of such cases usually occurs due to a low index of suspicion of the treating physician.Saito et al. presented a similar case in a 58-year-old woman who presented with headache and auditory disturbances in addition to otitis media; further investigations revealed that the patient has transverse sinus thrombosis. Surgery was performed 6 years after initial presentation, when only the diagnosis of lymphoma was made. The patient then recovered fully after a course of chemotherapy. They have also reviewed the literature and found 10 cases of lymphoma arising around the middle ear; the most common presentations were facial nerve palsy and otorrhea which is consistent with the presentation of our case [Roberts et al. have presented a case of a 78-year-old woman with large B-cell lymphoma of the middle ear presenting as chronic otomastoiditis. However, in their case there was no involvement of any of the cranial nerves, and emphasis was made on the early detection of temporal bone malignancy through neurotological examination and imaging as early diagnosis and aggressive chemotherapeutic treatment for primary lymphoma of the middle ear lymphoma are crucial for a good outcome [Our case presented similarly to other cases in the literature; however, earlier detection within the period where he had persistent symptoms refractory to medical treatment may have prevented the advanced complication of facial nerve palsy and increased his chances of cure.Lymphoma in the temporal bone is very rare; it may manifest with symptoms that are similar to other common benign middle ear pathologies. In severe and persistent symptoms a malignant cause should be put into consideration; this ensures early detection and thus management of the condition.


As acute stroke treatments advance, more people survive the initial stroke event and live with long-term neurological impairments that impact functional outcomes and quality of life. In accordance with International Classification of Functioning (ICF), living with long-term neurological impairments can limit survivors' activity performance and restrict participation in valued life roles and routines. Research focused on longitudinal analysis of functional measures and outcomes after stroke are critical for determining early indicators of long-term participation and quality of life and guiding rehabilitation resource allocation. As core members of the interdisciplinary stroke recovery treatment team throughout the post-acute care continuum, occupational therapists (OTs) directly address stroke survivors' ability to participate in meaningful daily activities to promote function and quality of life. Just as in clinical care in which multidisciplinary, team-based perspectives are vital, OTs provide invaluable perspectives for stroke recovery research. Here we describe OTs' role in a collaborative, interdisciplinary research study aimed at comprehensively understanding upper extremity motor recovery after stroke and its impact on individuals across the post-acute care continuum. This article discusses the importance of the OTs' perspectives in conducting interdisciplinary, longitudinal stroke recovery research. The challenges, strategies and recommendations for future directions of advancing the role of OTs in multidisciplinary stroke recovery research are highlighted. We use this perspective as a call to action to the stroke recovery field to incorporate OTs as members of the research team and for OTs to provide their perspectives on ongoing stroke recovery research. Despite continuous advances in acute interventions, stroke remains the leading cause of disability worldwide . Given tThe clinical care of patients with stroke employs an interdisciplinary approach. This approach should also be emphasized in stroke research, starting in the acute care setting and across the post-acute care continuum. Occupational therapists (OTs) are essential members of the interdisciplinary team who address all domains of the ICF after stroke across the continuum of care. The overarching goal of occupational therapy is to improve a stroke survivor's ability to engage in meaningful activities, promoting function and quality of life . Here weThis perspective discusses the feasibility of conducting stroke recovery research through the lens of an inpatient occupational therapy department. We highlight the example of clinical OTs (full-time clinicians) in a busy academic, acute care, clinical department participating in stroke-recovery research and becoming integral members of a clinical-research study team. The context of this research, challenges, strategies, and recommendations for future directions are highlighted.The Stroke Motor Rehabilitation and Recovery Study (SMaHRT) is a neurology, physician-scientist led longitudinal, single site study aimed at understanding the natural history of upper extremity motor recovery after ischemic stroke. Participants are enrolled during their acute stroke hospitalization at Massachusetts General Hospital (MGH) in Boston, MA with the aim of rigorously examining the behavioral, neuroanatomic, and neurophysiologic underpinnings of recovery. The ultimate goal is to develop personalized strategies and neuro-technologies to facilitate neurorehabilitation and enable better recovery for our patients. Launched in June 2017, OTs on the inpatient service at MGH participated in study design and became an integral part of this interdisciplinary research team. The team of OTs perform standardized clinical assessments in the acute care setting as baseline measures. These assessments were paired with longitudinal follow-up in a neurologist-led integrated clinical research outpatient clinic at 6 weeks, 3 months, 6 months and 1-year post stroke. All participants in the study provided written informed consent. The Institutional Review Board at Partners Healthcare approved the study.MGH is recognized as a Comprehensive Stroke Center by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) for its specialized ability to treat the most complex stroke patients. The MGH Inpatient Occupational Therapy Department leadership team includes a clinical director and four clinical specialists with advanced knowledge and experience in specialized areas of clinical care. The clinical specialists oversee clinical practice, support professional development amongst staff and perform quality process improvement initiatives. There are 28 licensed OTs with 6 assigned to the neurology units . OTs rotate through neurology units every 12–15 months and work closely with the occupational therapy clinical specialist in neurology to develop expertise related to this population. In addition to the licensed clinicians, the department also includes one rehabilitation aide who assists with hands-on support and environmental set up for occupational therapy interventions.The physician-scientist investigators included occupational and physical therapy leadership in the design phase of this study to select appropriate assessments. The study was initially focused on arm motor impairment but, with perspectives of the occupational therapy team, the aims were refocused to understand how arm impairment influences activity and participation restrictions. Qualifications for OTs to act as study staff included completion of a rotation on the neurology service, commitment to a 2-year time period of data collection, maintenance of typical clinical caseload and productivity expectations, and participation in study trainings. Six OTs were selected to perform inpatient testing. OTs who administered assessments to study participants were sometimes involved in the clinical care of the study participants but did not bill for the study visit since it was not considered standard clinical care.A series of meetings were held between physicians and occupational and physical therapists to decide on the best research tests to capture not only arm impairment but also activity limitations and participation restrictions. Decisions regarding test selection were based on goals of the study, commonly accepted research measures, clinical relevance, psychometric properties, practicality, and time to complete. Each assessment needed to be administered in an efficient timeframe on an inpatient acute hospital unit with minimal equipment. The interdisciplinary research group selected the final battery of assessments . The OTsOne hundred patients with stroke consented and enrolled in SMaHRT between June 2017 and April 2019 and continue to be followed as outpatients for integrated clinical research visits. Of the 100 participants, 55 were assessed by OTs. The first 30 participants were enrolled and tested prior to the OTs receiving formal training on the battery of assessments. Due to time constraints of the inpatient occupational therapy group, another 15 participants' assessments were completed by non-OT members of the research team. The reasons for this included therapist availability for participants enrolled on the weekend or after work hours and time sensitivity related to impending discharge.Ongoing discussions with leaders of the SMaHRT research team have highlighted the critical role of OTs in this ongoing stroke recovery research study. First, with regard to study design, stroke recovery research studies do not often account for how stroke affects the individual comprehensively. In this study, given the involvement of OTs in even the beginning stages of study design, all aspects of the ICF were included in study outcome measures. The study continues to benefit from never losing the perspective of the comprehensive ICF framework. Second, with regard to study implementation, OTs are familiar with standardized upper extremity motor assessments, as well as cognitive assessments from their clinical work. Having these perspectives are invaluable to inform the feasibility of research outcomes. The OTs specifically contributed to identifying a combination of outcome measures for UE motor function that are both meaningful and practical. This practical application of clinical practice and knowledge added to the efficiency of research testing which is critical for feasibility in the acute care setting. Third, performing clinical research on patients during the acute phase of stroke recovery poses challenges to a patient's limited physical, emotional, and mental endurance for tolerating activity. To this end, OTs' expertise at providing clinical care to patients with impaired arousal and attention allowed for discussion amongst research staff on how to best optimize participation in outcome assessments. Recommendations for environmental set-up and strategies to facilitate arousal and attention were also important contributions to efficiently and safely enable patient testing in the dynamic acute hospital setting.There are many factors that contributed to the ongoing success of inpatient OTs participating in clinical research and data collection during acute hospitalization for stroke. These include the infrastructure of the inpatient occupational therapy department and hospital culture regarding OT's contribution to the multidisciplinary team, the value placed on research, interdisciplinary approach to stroke care and a strong relationship with academic rehabilitation science researchers. These factors are discussed below.The size and structure of the MGH Inpatient Occupational Therapy Department contributes to the ability to have 1-year rotations on specific service areas, such as neurology, where OTs have exposure to sub-groups of patient populations over time. This model allowed for clinicians involved in the study to use their advanced clinical skills and knowledge to assist in developing guidelines for the research assessment battery. The advanced knowledge of stroke recovery and stroke unit systems allowed clinicians to problem solve research participation and coordination of care issues. There was a large enough pool of clinicians both interested in contributing to research and qualified to serve as study staff who joined the study to prevent burnout among study staff. The OT Clinical Specialist in neurology at MGH has a unique role which includes overseeing clinical practice, supporting professional development of staff and leading quality process improvement initiatives on the neurology service. The OT Clinical Specialist's clinical care expectations is only 70%, allowing for the flexibility in the remaining 30% time to participate in weekly research meetings and to develop roles and responsibilities for other OTs within the study. This role was imperative to maintaining successful operations both within the interdisciplinary research team as well as the research OT group.There is a strong value placed on research at MGH as an institution as well as within the occupational therapy department. Research OTs volunteered their time to complete the assessments, often needing to extend their work day to meet their clinical productivity expectations. Although this highlights one of the significant challenges, it also demonstrates the powerful commitment of these OTs to research and the motivation to contribute to the evidence that promotes stroke recovery for patients. The MGH Inpatient Occupational Therapy Department has a strong relationship with the OT faculty at the MGH Institute of Health Professions. This academic-practice partnership blends clinical and research expertise to maximize OT involvement and contribution to this study. The research expert for stroke UE motor recovery on the occupational therapy faculty at the MGH Institute of Health Professions was critical to the development of training protocols. These training protocols ensured occupational therapy research staff demonstrated continued proficiency in standard administration of tests. The physician-scientists who had the vision to create the interdisciplinary research team are to be commended for their commitment to an approach that recognizes and values the contribution of each discipline in caring for patients with stroke. This emphasis on interdisciplinary research is critical for moving the rehabilitation field forward to optimize outcomes for individuals who experience stroke.F = 49.5, p < 0.001], confirming prior reports of the high inter-rater reliability of the Fugl-Meyer  during their time on the study, which brought up challenges for coordinating care as they were often treating patients on services located in different buildings throughout the hospital. Study staff found that with increased experience performing the assessment battery, their proficiency in administering the assessments improved which had a direct and positive impact on efficiency. Another challenge to efficiency is the preparation prior to and just after test administration, which includes gathering/putting away testing materials, scoring and inputting results, environmental set-up and positioning needed to maximize participation. To combat this challenge, we utilized exercise physiology students and our occupational therapy aide to assist with care coordination, environmental set-up/clean up, gathering/putting away testing materials and electronic entry of test scores.Given the often fluctuating medical status of acute stroke patients and variability of post-stroke deficits, OTs with previous experience working with this complicated and heterogeneous population of patients were critical to successful data collection. In the early stages of recovery, a participant's cognitive status can often fluctuate and may interfere with their ability to effectively engage in assessments. At times, some participants' deficits in arousal, attention, and short-term memory required graded cueing or arousal stimulation. In addition, visual attention and processing, spatial awareness, praxis, postural control, and motor deficits might require adaptations to the environment and/or positioning of the patient. Participant fatigue, especially after stroke, is also an important factor influencing research testing. Having worked specifically with the stroke population for at least a 1-year rotation prior to joining the study, our research OTs could efficiently and effectively provide these adaptations as well as verbal and visual cues to maximize the patient's ability to perform the desired movement patterns for research testing. It is important to understand stroke impairments' effects on test performance and scoring criteria to maintain fidelity to testing instructions, maintain inter-rater reliability and document any interventions that may have affected these. OT study staff also utilized their advanced understanding and knowledge to assess patient's appropriateness for engaging in the assessment battery and recognizing when timing may improve test performance. If participants reported fatigue, study staff would terminate research testing and return later to complete assessments. Flexibility here was again key. Appreciating and understanding the acuity and fragility of this population in the acute hospital setting impacts the many factors that make research in this setting feasible.To advance stroke rehabilitation research and approaches to improve recovery after stroke, it is clear that an interdisciplinary approach that addresses all domains of the ICF and spans the post-acute care continuum must be used. Stroke recovery research, starting in the acute phase after stroke, is challenging due to the need for coordination between research staff with clinical teams as well as the complexity and medical needs of acute stroke patients. OTs have distinct expertise in ICF domains as well as in stroke client factors and can be invaluable assets to the research team. Due to the heterogeneity of stroke, large sample sizes are needed to address important research questions; therefore, challenges identified must be addressed in order to support ongoing, multi-site data collection. This perspective is a call to action to the field for stroke recovery researchers to integrate clinical OT perspectives into ongoing research and for OTs to participate and lend their perspectives to ongoing studies. A summary of the perspectives of MGH acute care OTs on stroke recovery research is outlined in Box 1Stroke recovery research too often occurs in silos, focused on one domain of the ICF and one professional perspective.To advance stroke recovery research, all aspects of the ICF should be accounted for in research studies. Clinical occupational therapists, core members of the interdisciplinary stroke recovery team, have unique perspectives on stroke survivors' ability to engage in meaningful activities to promote functioning and quality of life.Occupational therapists with full-time clinical commitments participated in a physician-scientist led stroke recovery research study at Massachusetts General Hospital, becoming integral members of the multidisciplinary study team and shaping all aspects of the study from study design to data collection and analysis.Unique contributions of OTs to the stroke recovery research study include addition of outcome measures measuring different domains of the ICF beyond body-structure/function, valuable perspectives on the feasibility of outcome measures, and unique qualifications for day-day research data collection in a busy inpatient stroke unit.Factors contributing to the success of OTs becoming integral members of the stroke recovery research team include (1) the infrastructure of the OT department, (2) the value placed on research in both the department and the institution, (3) the interdisciplinary approach to clinical stroke care translated into research, and (4) a strong relationship with academic rehabilitation science researchers.Potential barriers to clinical OTs participating in research are (1) time required for research assessment training and maintaining proficiency in tests (inter-rater reliability) (2) coordinating time for research testing for patients in the context of a busy acute stroke hospitalization (3) study staff balancing time for research with a busy clinical schedule and  complex Strategies for success to overcome these barriers include (1) designing flexibility into the research schedule (2) ensuring regular communication between research and clinical staff (3) utilizing students and aides to maximize research testing efficiency and (4) applying clinical knowledge of patient factors to maximize research assessments.JR, JA, AC, KC, HT, NF, CS, DL, and AR contributed to initial concept and perspectives. JR, JA, KC, HT, NF, CS, and AR developed the initial version of the manuscript. KE, CS, JR, and DL critically revised the manuscript. AC and DL provided objective data. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Targeted sequencing using capture probes has become increasingly popular in clinicalapplications due to its scalability and cost-effectiveness. The approach also allows forhigher sequencing coverage of the targeted regions resulting in better analysisstatistical power. However, because of the dynamics of the hybridization process, it isdifficult to evaluate the efficiency of the probe design prior to the experiments whichare time consuming and costly.We developed CapSim, a software package for simulation of targeted sequencing. Given agenome sequence and a set of probes, CapSim simulates the fragmentation, the dynamics ofprobe hybridization and the sequencing of the captured fragments on Illumina and PacBiosequencing platforms. The simulated data can be used for evaluating the performance ofthe analysis pipeline, as well as the efficiency of the probe design. Parameters of thevarious stages in the sequencing process can also be evaluated in order to optimize theexperiments.https://github.com/Devika1/capsim.CapSim is publicly available under BSD license at Bioinformatics online. High-throughput sequencing (HTS) has tremendously revolutionized genomic studies for theability for cost- and time-effective characterization of the complete genetic information ofa sample. In many clinical applications, only a panel of actionable regions are the subjectfor investigation . Once sequencing reads are simulated using CapSim, users can align the reads to thereference genome and assess the performance of the capture design. A customized script toidentify probes leading to off-target capture is also provided with CapSim (details inGitHub). This will allow users to identify probes which needs to be removed from the designto reduce the off-target capture to improve their design. We believe CapSim is applicablefor all hybridization based capture methods, however the data presented in here wassimulated with Agilent XT and more assessment needs to be performed to determine if thesimulation data could be comparable for other capture methods.The research is supported by funding from the National Health and Medical Research Council(APP1052303).Conflict of Interest: none declared.Supplementary DataClick here for additional data file.


Haemangioma is the most common benign tumour of the liver. However, an exophytic hepatic haemangioma, especially the pedunculated form, is very rare. Giant pedunculated haemangiomas are prone to complications because of the narrow size of the pedicle. A large number of lesions can potentially present as exophytic liver masses, and accurate diagnosis can sometimes be challenging. We report a case of an incidentally discovered asymptomatic giant pedunculated liver haemangioma in the region of the lesser sac in a prospective renal donor, which was initially suspected to be a gastrointestinal stromal tumour of the stomach wall. Multiphasic computed tomography and confirmatory magnetic resonance imaging scans ultimately revealed the true nature of the lesion, which turned out to be an exophytic pedunculated hepatic haemangioma from the left lobe of the liver. The lesion was then surgically resected and histopathologically confirmed to be a haemangioma. The patient subsequently underwent successful renal donation as planned. Being a benign lesion with characteristic imaging features, accurate radiological diagnosis is absolutely essential for the appropriate management of such atypical haemangiomas. The prevalence is about 0.4% – 20% in necropsies. Haemangiomas are usually solitary, occur more commonly in women and are usually found in the posterior segments of the right lobe of the liver. In most cases, they are small and asymptomatic and found incidentally on imaging studies.3 In almost half of the reported cases, pedunculated haemangiomas were found to be symptomatic at diagnosis.1 Giant pedunculated haemangiomas are even more likely to be symptomatic and are usually diagnosed because of complications secondary to the size of the lesion and its narrow pedicle. Asymptomatic cases frequently put forth a challenge in the radiological diagnosis because of difficulty in defining the origin of the mass, as the thin pedicle may sometimes be radiologically undetectable.1Exophytic hepatic haemangiomas, especially the pedunculated forms, are very rare; only a few cases of these have been reported in literature.Here we present a case of a middle-aged female patient who was being evaluated with multidetector computed tomography (MDCT) renal angiography as a prospective renal donor. A giant pedunculated haemangioma from the left liver lobe was incidentally discovered and thought to be a gastrointestinal stromal tumour (GIST) from the gastric wall. This lesion presented a diagnostic dilemma.A 51-year-old healthy asymptomatic female underwent MDCT renal angiography as a prospective renal donor. A large, well-defined, heterogeneously hypoattenuating mass lesion, 11.20 cm in the largest dimension, was incidentally discovered in the region of the lesser sac on the non-contrast computed tomography scan (NCCT). The origin of the lesion could not be delineated on a non-contrast scan, as it did not show a definite claw sign with any of the intra-abdominal organs. It was seen to abut and scallop the left lobe of the liver medially and abut the lesser curvature of the stomach posterolaterally; however, there was no obvious infiltration of the lesion into any of the adjacent organs. No significant regional lymphadenopathy or ascites could be identified. With an initial suspicion of a GIST arising from the stomach wall, MDCT renal angiography was performed in the arterial, portovenous and delayed (5 min) phases, with inclusion of the entire lesion in the scan plane.The lesion in question showed patchy peripheral post-contrast enhancement in the arterial phase matching the aortic attenuation, predominantly in the superomedial juxtahepatic region of the mass. Progressive filling in of the mass with contrast was noted in the venous and delayed phases with a few non-enhancing areas within it . On multOn account of the importance of an accurate diagnosis in this patient in view of clearance for a renal transplant, magnetic resonance imaging (MRI) was performed in order to confirm the diagnosis. The mass appeared hypointense on T1 with a cleft-like area of lower signal intensity within and diffusely hyperintense on T2/T2 SPAIR  (light bulb sign) with a cleft-like area of markedly higher signal intensity within. Further, dynamic contrast-enhanced MRI was performed which showed a similar pattern of enhancement in the arterial, portovenous and delayed phases as seen on MDCT angiography . The cenUltrasound Doppler scan was performed in order to further correlate the findings and confirm the flow pattern within the vessels. The bridging vessels between the liver and the mass were identified, with detectable arterial flow within them . A finalThe patient proceeded to surgery for removal of the haemangioma prior to renal donation, and histopathological examination of the mass confirmed the diagnosis of cavernous haemangioma . The pat4 It is usually solitary and located in a subcapsular location and is more common in the right lobe of the liver, the most frequent location being the posterior segment of the right lobe. Hepatic haemangiomas are usually <3 cm in diameter.5 Brancatelli et al. have reported that 12% of haemangiomas demonstrate exophytic growth.6 However, pedunculated cases are very rare.3Hepatic haemangioma has a female predominance and may occur at any age, but more frequently occurs in the 30–50 years age group, with the mean age being 44 years.7The first case of a giant pedunculated haemangioma was reported by Ellis et al. in 1985. In their case, the haemangioma had presented with renal insufficiency and had been found to displace the retroperitoneal fat anteriorly simulating a retroperitoneal mass and was initially diagnosed as an adrenal mass. At surgery, the pathological examination of the mass provided the diagnosis of a giant pedunculated haemangioma.Subsequently, occasional case reports of giant pedunculated haemangiomas presenting with various symptoms or complications have been published in literature. However, these are few and far between on account of the rarity of the condition. Reports have become more commonplace in recent years, probably because of an increase in detection rates because of increasing numbers of patients undergoing MDCT scans for various indications and the development of state-of-the-art MDCT scanners.1 Giant haemangiomas may result in symptoms because of mass effect secondary to their size and may present with abdominal mass, vague abdominal pain, nausea or vomiting.8 Much rarer complications include congestive heart failure secondary to arteriovenous shunting in the haemangioma and thrombocytopenia with consumptive coagulopathy because of the lesion (Kasabach Meritt syndrome).9 Other rare complications include haemorrhage and rupture of the haemangioma.1Most hepatic haemangiomas, being small and intrahepatic, are usually asymptomatic and discovered incidentally.10 mimicking a number of other conditions. There have been reports of torsion of a giant pedunculated haemangioma masquerading as acute appendicitis.11 Diagnosis in such cases is also challenging as the typical enhancement pattern of haemangioma may not be present because of vascular compromise.A complication specific to pedunculated haemangioma is torsion around its pedicle, subsequent to which the haemangioma undergoes vascular compromise (because of twisting of vessels in the pedicle) followed by infarction, thereby becoming symptomatic. Pain is the most frequent symptom in such cases, and it can then present as acute abdomen,12 Further, they may have atypical imaging appearances. Correct diagnosis of the various conditions is vital, as the management principles are drastically different for the various lesions.Even otherwise, pedunculated haemangiomas of the liver are sometimes difficult to diagnose. Several conditions can present as exophytic liver masses which can provide a diagnostic challenge. Hepatic cysts, haemangiomas, focal nodular hyperplasia, hepatocellular adenomas, hepatocellular carcinoma and metastases can all present as exophytic liver masses to mention a few.13Moon et al. reported a case of pedunculated hepatic haemangioma mimicking a submucosal tumour of the stomach; the lesion was symptomatic, producing epigastric discomfort with dyspepsia, and was initially suspected to be a submucosal tumour of the gastric wall on the basis of an upper gastrointestinal barium study. Computed tomography (CT) subsequently revealed a giant pedunculated haemangioma arising from the left lobe of the liver and compressing the fundus of the stomach.1 A notable exception is the case report published by El Hajjam et al. where a giant pedunculated hepatic haemangioma was incidentally discovered in an asymptomatic patient being worked up for an anal cancer; the mass was initially suspected to be an infrahepatic peritoneal metastasis, but detailed CT and MRI examinations had revealed the characteristic enhancement pattern of a haemangioma and a thin pedicle originating from the segment IV-B of the liver. Pathological examination confirmed the diagnosis of a pedunculated hepatic haemangioma.14Giant pedunculated haemangiomas are, unlike in our case, usually symptomatic.15 However, pedunculated haemangiomas, particularly larger ones, are usually surgically resected even if asymptomatic because of the high risk of torsion and spontaneous rupture.8The majority of haemangiomas are asymptomatic and do not require treatment in the absence of any definite risk factors for complications. In symptomatic cases, the treatment options include surgery, either laparoscopy or open surgery, or interventional radiology in the form of angioembolisation. The indications for surgical intervention in any haemangioma include a palpable mass, rapid growth, thrombocytopenia, symptomatic patient with abdominal discomfort or pain or complications such as rupture with intraperitoneal bleeding.Pedunculated giant haemangioma of the liver is very rare but should always be considered as a possibility in case of an upper abdominal solid lesion in relation to the liver. It is usually symptomatic and presents with complications but may be completely asymptomatic and an incidental finding. It can be confused with a variety of other upper abdominal masses including gastric GIST as in our case. Pedunculated giant haemangiomas usually require surgical resection even if asymptomatic in view of the high risk for the development of complications. Accurate diagnosis can be difficult on the basis of imaging features but is vital in order to avoid unnecessary invasive diagnostic procedures and anxiety for the patient. The importance of the condition lies in the consequences of a misdiagnosis in terms of patient management. The onus of an accurate diagnosis lies on the radiologist.


R334Q). This variant is the most common mutation responsible for early onset sarcoidosis (EOS)/Blau syndrome, an autoinflammatory disease characterized by granulomatous inflammation of joints, skin and eyes. The early onset of symptoms and presence of multinucleated giant cells and granuloma in this case are in keeping with a diagnosis of EOS/Blau syndrome. The patient responded well to treatment with methotrexate and etanercept. This case extends the clinical spectrum of EOS/Blau syndrome, which should be considered for GCTTS and other unusual presentations of tendon inflammation in children, even in the absence of the characteristic triad of arthritis, dermatitis and uveitis.Giant cell tumor of tendon sheath (GCTTS) is characterized by diffuse proliferation of synovial-like cells and multinucleated giant cells along tendon sheaths. This benign tumor typically presents in the third to fourth decade of life and is exceeding rare in children. Here we describe a case of a 10-years-old girl with a history of soft tissue swelling involving the third digit of left hand, bilateral wrists and ankles. Pathology of the finger mass revealed abundant multinucleated giant cells consistent with GCTTS. Resection of the tendinous masses from the ankles also showed multinucleated giant cells along with chronic bursitis. She began to show features of polyarticular arthritis by age 7. Due to progression of arthritis, whole exome sequencing was performed and found a  Giant cell tumor of tendon sheath (GCTTS) is the second most common tumor of the hand, typically presenting in the third to fourth decade of life . Also knNOD2 responsible for early onset sarcoidosis , an autoinflammatory syndrome characterized by granulomatous arthritis, uveitis and dermatitis.GCTTS is rare in children with only one large case series of 29 patients describing this entity in the pediatric population . Most ofWe present a 10-years-old girl with a history of tissue swelling involving the third digit of left hand, bilateral wrists and ankles. At 2 years of age, she first developed soft tissue masses above both wrists and ankles without pain, warmth or redness. She did not receive any treatment and the soft tissue masses enlarged slowly. Two years later, she underwent surgery to remove the ankle masses and pathology was reported to be consistent with chronic bursitis. However, swelling gradually recurred near the surgical sites within 1 year.At 6 years of age, a new mass appeared on the palmar aspect of the left hand at the base of the third digit . The masWith progression of symptoms, the patient was referred to our Rheumatology Clinic for evaluation. Physical examination was notable for symmetric soft tissue masses along the anterior tibialis tendon of ankles and extensor tendons of the wrists . She hadMRI of wrists showed synovial thickening with abnormal signals around the tendon sheath, with evidence of wrist bone erosions . Ophthalde novo heterozygous mutation in NOD2  that was not found in either parent , a growth factor for monocytes/macrophages  is among the most common mutations found in EOS/Blau syndrome. More than 15 mutations in NOD2 are closely associated with the disease  or interleukin-1 , 18. EffIn summary, we present a young child with EOS that developed GCTTS and tendon inflammation early in the disease course in the absence of dermatitis or uveitis. This case suggests an intriguing link between GCTTS and EOS/Blau syndrome, two conditions that share the hallmark of multinucleated giant cells and tendon inflammation. EOS/Blau syndrome should be considered in children with GCTTS and unusual presentations of tendon inflammation even in the absence of the characteristic triad of arthritis, rash and uveitis.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Ethics committee of Guangdong Second Provincial General Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SZ supervised the data collection and drafted the manuscript. PL designed the study and revised the manuscript. YH analyzed the data and drafted part of the manuscript. AW carried out the pathological analyses. TL designed the study, assigned the treatment protocol, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Adverse Drug Reactions (ADRs) are a major clinical and public health problem world-wide. The prompt reporting of suspected ADRs to regulatory authorities to activate drug safety surveillance and regulation appears to be the most pragmatic measure for addressing the problem. This paper evaluated a pharmacovigilance (PV) training model that was designed to improve the reporting of ADRs in public health programs treating the Human Immunodeficiency Virus (HIV), Tuberculosis (TB) and Malaria.A Structured Pharmacovigilance and Training Initiative (SPHAR-TI) model based on the World Health Organization accredited Structured Operational Research and Training Initiative (SOR-IT) model was designed and implemented over a period of 12 months. A prospective cohort design was deployed to evaluate the outcomes of the model. The primary outcomes were knowledge gained and Individual Case Safety Reports (ICSR) (completed adverse drug reactions monitoring forms) submitted, while the secondary outcomes were facility based Pharmacovigilance Committees activated and health facility healthcare workers trained by the participants.Fifty-five (98%) participants were trained and followed up for 12 months. More than three quarter of the participants have never received training on pharmacovigilance prior to the course. Yet, a significant gain in knowledge was observed after the participants completed a comprehensive training for six days. In only seven months, 3000 ICSRs (with 100% completeness) were submitted, 2,937 facility based healthcare workers trained and 46 Pharmacovigilance Committees activated by the participants. Overall, a 273% increase in ICSRs submission to the National Agency for Food and Drug Administration and Control (NAFDAC) was observed.Participants gained knowledge, which tended to increase the reporting of ADRs. The SPHAR-TI model could be an option for strengthening the continuous reporting of ADRs in public health programs in resource limited settings. Adverse Drug Reactions (ADRs) have emerged as a major clinical and public health problem responsible for approximately 5 to 35% of hospital admissions in both developed and developing countries –7. In thPrompt reporting of ADRs to drug regulatory bodies is an important drug safety measure but under-reporting is a major challenge even in developed countries with adequate human and material resources to tackle the problem  and 10. Prompt reporting is pragmatic and arguably, the best method for drug safety surveillance . The delPublic health programs, especially the HIV/AIDS, Tuberculosis and Malaria have the greatest risk of ADRs because millions of people are treated with a wide range of drugs, some of which have serious/life threatening adverse reactions –38. In tPharmacovigilance systems (PVS) refer to schemes that are established to facilitate the reporting of suspected ADRs to national or international bodies responsible for the monitoring of drug safety and regulations. Countries participating in the international drug monitoring scheme are required by regulation to collect and submit their reports to the International Drug Monitoring Center in Geneva.th member country. The National Agency for Food and Drug Administration and Control (NAFDAC)–the body responsible for drug safety and regulation in Nigeria, thereafter, developed a National Pharmacovigilance Policy and instituted an administrative structure, consisting of the National Pharmacovigilance Center (NPC) in Abuja and Zonal Pharmacovigilance Centers (ZPC) in each of the six geopolitical regions of the country.Nigeria joined the International Drug Monitoring Scheme in 2004 and became the 74NAFDAC also instituted the National Pharmacovigilance System which involves signal detection, collection, collation and analysis of ADRs . Organizhttps://www.nafdac.gov.ng. This form is similar to the United Kingdom’s Yellow Card and has five major sections, which must all be accurately completed. A fully completed ADR form is known as the “Individual Case Safety Report” (ICSR).The primary tool for reporting ADRs in Nigeria is a structured in-take form known as the “Adverse Drug Reactions Form” (ADR Form) Adverse drug reaction Suspected drug Concomitant medicines Source of reportThe reporting of ADRs to NAFDAC follows two major steps:Accurate completion of the ADR forms when a suspected ADR is observed by healthcare providers or reported by a patient during routine treatment of health conditions. Marketing Authorization Holders (MAH) are also expected to complete the ADR forms when suspected ADR are reported to them by patients, health institutions or the healthcare workers within and outside the country.Dispatch the ICSRs to the NPC in Abuja.https://www.who-umc.org/vigibase/vigibase/) hosted at the WHO collaborating center for international drug monitoring in Uppsala, Sweden.The ICSRs are dispatched to the NPC in Abuja through different means; the frequently used method is surface mail posting of the ICSRs to the NPC by the health facilities or visiting the health facilities by the NAFDAC designated staff to pick up the ICSRs. ICSRs could also be scanned and sent as “attachment” through emails communication. The NPC validate and analyze the submitted ICSRs and extract the relevant information into VigiBase–a proprietary web database  of the healthcare workers that participated in the course have never received training in pharmacovigilance but were nonetheless working in public health institutions or hospitals directly treating HIV/AIDS, Tuberculosis and Malaria through the respective public health disease control programs. Some studies have reported high prevalence of ADRs emanating from the HIV/AIDS, TB and Malaria public health programs , 39, 40,The SPHAR-TI model refer to  was a 12This manuscript complies with the STROBE reporting standard for observational studies.Ethics approval for the evaluation was given to the Institute of Human Virology Nigeria by the National Health Research Ethics Committee of Nigeria under the title: “Engaging indigenous organization to sustain and enhance clinical services for the prevention, care and treatment of HIV/AIDS in the Federal Republic of Nigeria under the President’s Emergency Plan for AIDS Relief (PEPFAR)”; Number: NHREC/01/01/2007; dated August 12, 2016.The workshop was conducted in the Federal Capital Territory, Abuja but the participants were selected from health facilities and institutions in the six geopolitical regions of Nigeria. Nigeria has six geopolitical regions with a population of 170 million inhabitants. These regions include the North-east, North-west, North-central, South-west, South-east and South-south.The study population consisted of health care workers  who were selected for the SPHAR-TI course based on rigorous selection criteria . Data on the number of healthcare workers trained by the participants and the Pharmacovigilance Committees activated were submitted online not later than 10th December 2016.A prospective cohort design was deployed for the evaluation of the SPHAR-TI model. Participants that attended the SPHAR-TI’s workshop described in The aim of the model was to improve the reporting of ADRs from both hospitals based and more importantly, community based public health programs controlling the AIDS epidemic, Tuberculosis and Malaria. The primary outcomes were knowledge gained and the number of ICSRs submitted to NAFDAC. We expected to see a significant gain in knowledge and a remarkable increase in the reporting of ADRs if the model was effective. The secondary outcomes were the health facility staff trained by the participants through the step-down training and the Pharmacovigilance Committees activated.The secondary outcomes were evaluated because NAFDAC encourages the setting up of Pharmacovigilance Committees in health facilities as a pragmatic strategy for promoting the reporting of ADRs. During the workshop, participants were taught and encouraged to step-down the workshop and activate the committees. We expected the participants to be able to train others and set up new Pharmacovigilance Committees if the model was effective.The overall outcome of the model was assessed by comparing the number of ICSRs submitted by the national health workforce in seven months with the number submitted by the participants in seven months. The primary and secondary outcomes were evaluated as described below:Gain in knowledge was assessed using a structured questionnaire, consisting of 24 questions developed by expert physicians and pharmacists in the three diseases . The questions covered the clinical management of HIV/AIDS, Tuberculosis and Malaria and the ADRs associated with the use of antiretroviral, anti-tuberculosis and anti-malaria drugs. The questionnaire also assessed the knowledge of Nigeria’s ADR reporting and pharmacovigilance system.Prior to the commencement of the workshop, the questionnaire was administered for an hour (pre-test). At the end of the workshop, which was five days after the pre-test, the same questionnaire was re-administered (post-test). To minimize measurement biases, the questionnaire was withdrawn immediately after the pre-test and participants were not warned the questionnaire would be re-administered after the workshop. Participants did not also know the result of the pre-test until after the post-test. The pass mark for the pre and post-tests was 45%.The correctness and completeness of the ICSR and the quantities submitted online were assessed. All submitted ICSRs were manually checked for correctness and completeness and the total number of correctly completed forms were counted and recorded in each cycle. The number of ICSRs submitted within seven months were summed up and compared with the amount that would have been submitted by the national health workforce in seven months in 2015.To assess the two variables, participants were given a spreadsheet for recording their step-down activities after the workshop. The spreadsheet included the following variables:Status of the health facilityDate of trainingDescription of trainingObjectives of the trainingMode of delivery of training contentNumber of doctors, nurses and pharmacists in attendanceNumber of Pharmacovigilance Committees activatedInvolvement of hospital managementCollaboration with a pharmaceutical company in the trainingCollaboration with NAFDAC.th December, 2016. We extracted the number of health facility staff trained and the number of Pharmacovigilance Committees’ activated into a template for analysis.The completed spreadsheets were submitted to NAFDAC online at different times but not later than 10We applied descriptive statistics  in the analysis of the bio-demographic data and primary and secondary outcomes. The overall outcome of the model was analyzed by calculating the percentage increase in ADR submission using the arithmetic formula: T-M/M*100 . According to NAFDAC, in 2015, the over 323,941 national health workforce submitted 1,385 ICSRs  participating rate. Participants’ characteristics are presented in The outcomes of the model are presented in the The major finding of this evaluation is the significant gain in knowledge observed among the participants generally. NAFDAC’s concordance on the effectiveness of the model to significantly improve the reporting of ADRs in Nigeria  and Bilateral Gynaecomastia (BG). Secondly, the rate of ADR reporting increased by 273%, when compared with the average reporting rate in the general population over the past 12 years. This finding is consistent with the findings from previous studies that examined the impact of training at improving the reporting of ADRs , 59. ThiWe also observed two unintended outcomes of the application of the SPHAR-TI’s model. The first is the detection and reporting of SJS and BG by some participants. SJS is a fatal ADR associated with the use of Nevirapine, a popular antiretroviral drug that constitutes the backbone of first line antiretroviral regimen. This finding confirms that Nigerians are also susceptible to the SJS of Nevirapine as reported in other climes. Further analysis of the submitted ICSRs might reveal other life threatening ADRs in the Nigerian population, which the National Agency for the Control of AIDS (NACA) need to pay close attention to. The second outcome is the interplay of several factors resulting to the increase in the reporting of ADRs. The model combined at least six factors: training, mobilization of participants with resources , which has the largest public health programs treating millions of people with HIV, Tuberculosis and Malaria. Currently, over 20 million people must be placed on antiretroviral drugs according to the new WHO treatment guidelines for HIV . The risAnother factor that favors the training of healthcare providers for ADR reporting, which justifies the use of the SPHAR-TI model, is the acute shortage of healthcare workers in Africa. The “Brain Drain” report by Rebecca Coombes showed that the number of healthcare workers in many African countries is shrinking . Ghana wAn important piece of information the SPHAR-TI model has demonstrated is that short training alone is not sufficient to stem the tide of under-reporting of ADRs. In fact, most developing countries, including Nigeria, provide trainings to healthcare workers to boost the reporting of ADRs but the crisis of under-reporting is not going away. What may be lacking are some of the factors the SPHAR-TI model seems to illustrate, which include: poor mobilization of healthcare providers, a weak monitoring and evaluation with complete absence of feedback mechanisms when ICSRs are submitted to central regulatory authorities, lack of a clear and practical means of submitting ICSRs, lack of private-public collaboration, weak leadership and low motivation of the workforce. If all these factors are combined appropriately, the reporting of ADRs could significantly increase.The model has some limitations that need to be considered alongside the positive outcomes. The participants were practicing doctors, nurses and pharmacists with some experience in the pharmacotherapy of AIDS, tuberculosis and malaria. This knowledge may have contributed to the knowledge gained through the SPHAR-TI training. This argument may however not hold true because the medical doctors expected to have the highest level of knowledge and should have demonstrated higher scores in the post-test compared to the pharmacists and nurses actually scored less. The age of the participants is another factor; majority of the participants were mid-career professionals occupying lower positions of responsibilities and were likely to be less busy and quick learners. Elderly people with many social and professional responsibilities and perhaps with a “slow to learn” disposition would probably have performed poorly. But again, the results in We are recommending the use of the SPHAR-TI’s model to minimize the worrisome under-reporting of ADRs in the developing world. As stated earlier, under-reporting of ADRs prevents drug safety monitoring and regulation, which adds to the disease burden and mortality. Nigeria and other developing countries may not be able to absorb additional health challenges caused by ADRs as these countries are already overstretched by communicable and non-communicable diseases. The SPHAR-TI model may be an effective approach that would complement existing models of ADRs reporting in Africa and elsewhere.The systematic and output driven training and follow-up of healthcare providers had a positive impact on the reporting of ADRs. The SPHAR-TI principles effectively contributed to the success of the model and are recommended to institutions or organizations providing pharmacovigilance services in Africa and other regions with similar settings.S1 FileFigure A: Adverse Drug Reactions Form; Figure B: Letter of appreciation in respect of collaborative work to increase adverse drug reactions reporting in Nigeria.(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.S2 Dataset(XLSX)Click here for additional data file.S3 Dataset(XLSX)Click here for additional data file.S4 Dataset(XLSX)Click here for additional data file.S5 Dataset(XLSX)Click here for additional data file.


Advanced renal cell carcinoma accompanied by tumor thrombus in the venous systemis present in up to 10% of cases. Extension of tumor thrombus above thediaphragm or into the right atrium represents level IV disease. Level IV tumorsare typically treated with sterno-laparotomy approach with or without deephypothermic circulatory arrest and veno-venous bypass. In this case report, thesurgical technique for the resection of advanced RCC were described, with theconcomitant use of transesophageal echocardiography for thrombus extractionwithout the veno-venous or cardiopulmonary bypass. Resection of RCC with inferior vena cava (IVC) tumorextension poses a challenge with perioperative morbidity and mortality reaching50%. Complete surgicalremoval remains the only potential hope for a cure. Incomplete resection results in100% 5-year mortality. Extensionof tumor thrombus above the diaphragm or into the right atrium (RA) represents levelIV disease, according to the Mayo Classification system. In this case report, the surgical technique withthe concomitant use of transesophageal echocardiography (TEE) for the resection ofadvanced RCC were described, without the use of venovenous or cardiopulmonarybypass.At the time of diagnosis, renal cell carcinoma (RCC) is accompanied by tumor thrombusin the venous system in up to 10% of casesTwo patients operated at our clinic in January 2018 were a 55-year-old female and61-year-old male who were recently diagnosed with RCC, both with stage T4NxM0 , who were scheduledfor radical right nephrectomy with IVC thrombectomy. All patients werepreoperatively evaluated with routine blood analyses, chest X-ray, transthoracicechocardiography (TTE) computerized tomography (CT) and contrast venacavography.Preoperative CT and TTE revealed the tumor extension into the IVC up to the RA formale patient and supradiaphragmatic portion of IVC in female patient .The operation was performed by our team of vascular surgeons. Cardiac surgery teamwas also assembled assigned to the care of the patient, because the original planwas to do the sterno-laparotomy and partial veno-venous bypass. Following theinduction of general anesthesia, internal jugular central line was inserted. Inaddition, a multiplane TEE probe was placed in the esophagus. Initial TEEexamination of the heart confirmed the normal cardiac structures and functionwithout a patent foramen ovale. TEE study was performed with emphasis on the hepaticveins, IVC, right side of the heart, and pulmonary arteries (PAs). The tumor waswell visualized in the IVC extending proximal into the RA for male patient andsupradiaphragmatic portion of IVC in female patient .Surgery proceeded with median laparotomy and right subcostal incision for femalepatient and bilateral subcostal Chevron incision for male patient. Cardio surgicalteam and cardiopulmonary bypass team were placed on standby. Liver was mobilized,hepatic veins were exposed, and the IVC was isolated . With a ,6. The concept ofresorting to an entirely intra-abdominal approach without cardiopulmonary orveno-venous bypass is the byproduct of this approach. Whereas such techniques avoid the risks ofcardiovascular bypass , the chance for hemodynamiccompromise is increased during vena cava exploration and venous returninterruption.Surgical resection remains treatment mainstay for RCC. The critical factor forsuccessful surgery is mainly management of the IVC, and the important goals are tominimize bleeding and prevent embolism from the thrombus during surgery. Eitherevent often leads to fatal consequences. Over the years, several approaches havebeen developed to aid in the safe removal of these tumors. The improvement insurgical technique has often been due to the application of surgical principles fromdifferent disciplines. Cardiopulmonary bypass, with or without deep hypothermiccirculatory arrest, is an example of using cardiac surgery tools in an oncologicoperation. However, novel surgical techniques borrowed from liver transplant surgeryhave allowed for exposure and isolation of the IVC during tumor resection therebysparing the use of vascular bypassEighty-five patients were operated because of RCC tumor with extension into the IVCfrom 2007 to 2017 at the Clinic for Vascular and Endovascular Surgery. Out of those,five patients had the level IV tumor extension of RCC tumor. All of these wereoperated with the standard use of sterno-laparatomy approach. The clinicalperioperative data of the five patients are summarized in With this new concept, RCC with tumor thrombus extending to the supradiaphragmaticIVC can be resected while employing a series of clamps in succession on the IVC thatallow for minimal venous return interruption. Once the renal artery is ligated andIVC clamped in infrarenal position and opened, the thrombi are quickly removed withthe help of Fogarty catheter or resected to a position in the IVC below the hepaticveins. After the tumor thrombus removal and nephrectomy the liver inflow and outflowis restored. This partially mitigates the hemodynamic disturbance of impaired lowerabdominal venous return. Using these techniques, both hemodynamic an ischemicconsequences are lessened but still require care from the anesthesiologist in theform of invasive monitors including arterial line, high volume central line, use ofvasopressors, and TEE..Another interesting momment was observed the renal artery ligation and clamping ofthe infrarenal part of IVC. The thrombus subsequently retracted and allowed its saferemoval. This could be explained that the most thrombus are not adherent to IVCwall, and also by the fact that the inflow to the RA is reduced allowing thrombusnot to bee pushed by "full blood flow". This maneuver "simplify" operation when theproximal extent of tumor is near hepatic veins or right atriumTEE has major effects on the decision-making process in surgical and anestheticmanagement. TEE can also demonstrate the tumor mobility, whether it is fragileand/or adherent to the IVC. A fragile tumor has a higher risk of pulmonary embolism,and adherence of the tumor to the IVC wall may result in an incomplete resection ofthe tumor or vascular injury when using an occlusion balloon catheter. TEE imagingcan determine whether it will be possible to bring the thrombus down with theballoon or not, and also provide information about the precise location and size ofthe balloon. Because TEE visualized a mobile and oscillating thrombus, we decided toremove it by using an occlusion balloon catheter. We removed the thrombussuccessfully by this simple technique with minimum hepatic mobilization for thethrombectomy. It should be also monitored by the operators directly on the surgicalfield. Intraoperative real-time TEE monitoring can be provided by anesthesiologistswithout interruption of the surgical procedure, and we regard this as one of themost important advantages of TEE monitoring. Most importantly, the real-time TEEmonitoring allowed us to perform this intervention safely. Fortunately, no evidenceof pulmonary embolism was found in our two cases. Nevertheless real-time TEE canprovide rapid recognition of massive pulmonary embolism. TEE can reveal the suddendisappearance of the tumor head, presence of the thrombus in the pulmonary artery,or any sign of right heart dysfunction. Intraoperative TEE is also useful inanesthetic management to evaluate the left ventricular volume (LV) and function.Massive bleeding and decreased venous return due to the IVC clamp can be immediatelytreated with volume loading according to the LV volume assessed by TEE.Our preliminary experience suggest that the advantages of intraoperative TEE,including verification of the level of IVC involvement, confirmation of completeremoval of the IVC thrombus, and intervention using catheters to assist inthrombectomy. This would help with earlier detection and management ofcomplications, which will probably contribute to a decrease in the morbidity andmortality associated with the management of those high-risk patients.


Drosophila melanogaster discovered a conserved molecular machinery that controls epithelial polarity. Recent findings suggest that the textbook Drosophila-based paradigm of the control of epithelial polarity may not be as universal as previously assumed.Multicellular animals face the principle challenge to deal with two distinct compartments: the internal organismal compartment and the external environment. This challenge is met by the differentiation of cell sheets into epithelia, which provide a dynamic barrier in tissues, organs, and organisms. Cell polarity is key to all functions of epithelia, and compromising polarity causes many severe diseases. Within the past 20 years, research on  This Primer discusses recent research showing that the midgut epithelium of the adult fruit fly differs dramatically from the canonical modes of epithelial cell polarity in main features of its cytoarchitecture and its molecular control mechanisms. Drosophila melanogaster, has been one of the most influential model systems in the discovery of the molecular mechanisms that establish and maintain epithelial polarity. The key polarity regulators discovered in the fly turned out to be evolutionarily conserved and often serve similar functions in organisms as diverse as worms and mammals. Despite the similarities, the requirements of these conserved regulators for epithelial polarity are variable in the context of whole organisms. In the present issue of PLOS Biology, Chen and colleagues demonstrate that the conserved polarity machinery of Drosophila epithelia is dispensable in the Drosophila adult midgut epithelium and provide evidence for alternative pathways during polarization of epithelial cells [Epithelial cells are the main building blocks of most organs in our body. Individual epithelial cells are characterized by a profound apical–basal polarity, which is central to their functions and the homoeostasis of tissues and organs.  type and septate junctions (SJs) (Drosophila epithelia contain either pleated SJs (pSJs) or smooth SJs (sSJs). The difference between these two types of SJs is their ultrastructural appearance and their occurrence in distinct epithelial tissues. pSJs are typical for epithelia of ectodermal origin such as the hypodermis, the hindgut, and the trachea, while sSJs are present in epithelia of endodermal origin, like the midgut. The Malpighian tubules, despite being of ectodermal origin, also possess sSJs. Recently, three sSJ-specific proteins were identified: Snakeskin (Ssk), Mesh, and Tetraspanin 2A (Tsp2A) [Drosophila epithelia is very similar to the mammalian epithelial ZA in both its structural features, its molecular composition, and its functions [Drosophila.The cytoarchitecture of invertebrate epithelial cell junctions is diverse among different species and exhibits distinct subtypes and compositions of intercellular junctions . Within ns (SJs) . The SJs (Tsp2A) . The ZA unctions . DesmosoDrosophila epithelia is the localization of the intercellular junctions along the lateral cell interface of adjacent cells. While the ZO is apical to the ZA in mammals, in the fly, the ZA is apical to the SJ. Many epithelia in flies also exhibit a special cytocortical domain at the interface of the ZA and the apical membrane domain called the subapical region (SR) . The SR does not have specific ultrastructural features but contains polarity protein complexes, like the Crumbs (Crb)/Stardust (Sdt) complex and the Partitioning defective (Par)/atypical protein kinase C (aPKC) complex, which are crucial in the controlling of epithelial polarity in embryogenesis [A major difference in mammalian epithelial compared to ogenesis .Drosophila epithelia, the adherens junctions (ZA) are positioned apically to the occluding junction (SJ), while in mammals the occluding junction (tight junction or ZO) is positioned apically to the ZA  via receptors of the integrin family . Chen anNematostella vectensis [crb and do not form apical adherens junctions [Why is the adult midgut epithelium so different in its structure and molecular control to other epithelia in the fly? One reason may be that the midgut epithelium is derived from the endoderm while most other epithelia in the fly are derived from the ectoderm that ultimately originate from the blastoderm epithelium. A germ layer–specific regulation of epithelial polarity has recently been discovered in the diploblastic cnidarian ectensis . This opectensis , migrateunctions , 20. Theunctions –24. HoweWhat is the origin of the adult midgut? The adult midgut is derived from progenitor cells, called adult midgut progenitors (AMPs), that are set aside from the midgut primordia during late embryonic development , 25. TheChen and colleagues target their mutational analysis to the integration of ISCs into the established midgut epithelium. Therefore, one possible explanation of the principle difference in the epithelial polarity of the midgut could be that the mechanism applies exclusively to the ISC-to-enterocyte differentiation. This raises the question whether this way of polarization during differentiation of epithelial stem cell progenies is conserved. It has been known for a long time that basal cues are important for epithelial polarization and the orientation of the apical–basal axis in mammalian epithelial cells . In cult