A Novel Nephropsychology Clinic: Partnering With Patients in the Era of Value-Based Care in Nephrology.

CKD and end-stage kidney disease are highly prevalent and complex chronic conditions with a high disease burden that corresponds to a high cost of care. Mental health conditions have a high prevalence in this population and add to the burden of disease, increase the cost of care, and are co-related with worse clinical outcomes. Despite these clear co-relations, mental health disorders remain underdiagnosed and undertreated in this population, secondary to multiple reasons, including patient-specific factors as well as systematic issues, including difficulty in accessing mental health experts. Here we describe a novel collaborative care model for patients with advanced CKD within the nephrology clinic space, in the form of a nephropsychology clinic. We present the details of our clinic, our preliminary findings, and propose that an integrated behavioral health model offers convenience for the patient and improves workflow for the physician, allowing a pathway to timely mental health interventions.

Exploring body morphology, sacral skin microclimate and pressure injury development and risk among patients admitted to an intensive care unit: A prospective, observational study.

OBJECTIVE: To determine the association between body morphology, sacral skin microclimate and their impact on the development and risk of pressure injuries among patients in an intensive care unit. METHODOLOGY: A prospective observational exploratory study was conducted over 30 weeks. Repeat study observations occurred multiple times a week for 28 days or until discharge. Participant inclusion criteria were ≥ 18 years of age, expected intensive care length of stay > 24 h and intact skin over the sacrum region. SETTING: The study was conducted in a 36-bed intensive care unit of a major metropolitan public hospital in Queensland, Australia. OUTCOME MEASURES: Pressure injuries were staged and independently verified according to the international pressure injury classification system. Pressure injury risk was determined by the Braden scale score and subepidermal oedema, using a subepidermal moisture scanner at the sacrum. RESULTS: Of the 93 participants recruited, an inverted triangle body shape (p =.049), a BMI > 25 kg/m2 (p =.008), a standard foam mattress type (p =.017) and increased length of stay (p <.001) were associated with an increased pressure injury risk according to subepidermal oedema. Participants with increased sacral skin temperature (p <.001), mechanical ventilation (p <.001), vasoactive drugs administered (p =.003), increased sequential organ failure assessment score (p =.047), neurovascular diagnosis (p =.031) and increased length of stay (p =.027) were associated with increased pressure injury risk according to the Braden scale score. CONCLUSION: Body morphology and skin microclimate are associated with pressure injury risk during critical illness. IMPLICATIONS FOR CLINICAL PRACTICE: Subepidermal oedema was associated with a patient's shape, body mass index and mattress type, factors that directly influence the pressure loading and the skin, whereas the Braden scale was associated with sacral temperature and clinical measures of critical illness. Consideration of body morphology and skin microclimate in pressure injury risk assessment could lead to more specific prevention strategies targeting high risk patients.

Exploring the Association between Hemochromatosis and Lower-Limb Venous Disease.

OBJECTIVE: Chronic venous disease is a circulatory system dysfunction that has the potential to lead to venous leg ulceration. Although research on the influence of specific gene variants on chronic venous disease has been limited, a few studies have reported an association between hemochromatosis and chronic venous disease. However, no studies have looked at the prevalence of lower-limb venous disease and leg ulcers in people with hemochromatosis. This study aimed to review the existing literature for any association between venous disease and hemochromatosis and investigate the prevalence of venous disease and leg ulcers in people with hemochromatosis. METHODS: Scoping systematic literature review and cross-sectional study surveying people with hemochromatosis. RESULTS: This scoping systematic literature review included nine articles and indicated a link between hemochromatosis and venous disease/leg ulcers, although further studies are needed to support this link. Analysis of survey results from people with hemochromatosis found a 9.2% prevalence of leg ulcers in those with self-reported hemochromatosis, considerably higher than the 1% to 3% expected, suggesting that hemochromatosis gene variants may be associated with the pathogenesis of chronic venous disease and leg ulcers. CONCLUSIONS: This is the first known study to complete a review of the literature regarding hemochromatosis and venous leg ulcers and document the association between hemochromatosis and venous disease/leg ulcers. There is a lack of research in this area and hence limited evidence to guide practice.

Clinical correlates of pain in adults with hard-to-heal leg ulcers: a cross-sectional study.

OBJECTIVE: Pain is a complex symptom associated with hard-to-heal (chronic) leg ulcers that is often poorly managed. The objective of this study was to gain greater understanding by investigating relationships between physical and psychosocial factors, and pain severity in adults with hard-to-heal leg ulcers. METHOD: A secondary analysis of data collected for a longitudinal, observational study of adults with hard-to-heal leg ulcers was undertaken. Data were collected over a 24-week period, including variables relating to sociodemographics, clinical variables, medical status, health, ulcer and vascular histories, and psychosocial measures. Multiple linear regression modelling was used to determine the independent influences of these variables on pain severity, as measured with a Numerical Rating Scale (NRS). RESULTS: Of 142 participants who were recruited, 109 met the inclusion criteria for this study, of whom: 43.1% had venous ulcers; 41.3% had mixed ulcers; 7.3% had arterial ulcers; and 8.3% had ulcers from some other cause. The final model explained 37% (adjusted r2=0.370) of the variation in the pain NRS scores. Controlling for analgesic use, salbutamol use (p=0.005), clinical signs of infection (p=0.027) and ulcer severity (p=0.001) were significantly associated with increased pain, while the presence of diabetes (p=0.007) was significantly associated with a decrease in pain. CONCLUSION: Pain is a highly complex and pervasive symptom associated with hard-to-heal leg ulcers. Novel variables were identified as being associated with pain in this population. The model also included wound type as a variable; however, despite being significantly correlated to pain at the bivariate level of analysis, in the final model, the variable did not reach significance. Of the variables included in the model, salbutamol use was the second most significant. This is a unique finding that, to the authors' knowledge, has not been previously reported or studied. Further research is required to better understand these findings and pain in general.

Sleep Profiles of Caregivers for Persons Living with Dementia: A Qualitative Study.

Sleep disturbance is prevalent among caregivers of people living with dementia. However, gaps exist about caregivers' sleep patterns before and during their caregiving trajectory. This exploratory secondary analysis using a qualitative descriptive approach aimed to (1) identify and describe current caregivers' patterns of change in sleep before and during caregiving, and (2) understand caregivers' perceptions of their current sleep compared to their pre-caregiving sleep. We conducted semi-structured interviews with 19 caregivers taking part in a larger randomized controlled trial. Participants were female (n = 11), white (n = 13) and on average 63 years of age. Interview questions focused on caregivers' sleep patterns. The interviews were audio-recorded using a videoconferencing platform and ranged from 20 to 45 minutes. We conducted thematic analysis of the interview transcripts. Three distinct caregiver-sleep profiles emerged from the qualitative data: changed and dissatisfied, changed and satisfied, and unchanged and dissatisfied. Caregivers whose sleep was categorized as changed reported a difference when comparing their current sleep pattern to their pre-caregiving sleep pattern. This was usually a change from good to poor sleep. Caregivers whose sleep was unchanged had poor sleep pre-caregiving and continued to have poor sleep during caregiving. Caregivers also reported being satisfied or dissatisfied with their current sleep pattern, defined in terms of distress and impairment. These three subtypes highlight the heterogeneity of caregivers' sleep experiences and debut a useful clinical framework with which to identify, categorize, and target caregivers at risk for sleep disturbance, many who may be ready to engage in behaviors to improve their sleep. Knowing caregivers' sleep profiles will enable health care providers and researchers to determine caregivers' needs and readiness for interventions then work collaboratively with them to improve their sleep problems.

International validation of a venous leg ulcer risk assessment tool.

OBJECTIVE: To internationally validate a tool for predicting the risk of delayed healing of venous leg ulcers (VLUs). METHOD: A 10-item tool including sociodemographic factors, venous history, ulcer and lower limb characteristics, compression and mobility items to determine the risk of delayed healing of VLUs has previously been developed and validated in Australia. This study prospectively validated this tool using receiver operating characteristic (ROC) methods; using the area under the curve (AUC) to quantify the discriminatory capability of the tool to analyse the international populations of the UK, Austria and New Zealand. RESULTS: The validation of the tool in the UK, Austria and New Zealand has indicated that the model has moderate discrimination and goodness-of-fit with an AUC of 0.74 (95% CI: 0.66-0.82) for the total risk assessment score. CONCLUSION: The international validation of a risk assessment tool for delayed healing of VLUs will allow clinicians globally to be able to determine realistic outcomes from an early assessment and to be able to guide early tailored interventions to address the specific modifiable risk factors and thus promote timely healing.

Clinical indicators of acute deterioration in persons who reside in residential aged care facilities: A rapid review.

PURPOSE: To identify the clinical indicators of acute deterioration in residents and the factors that influence residential aged care facility staff's identification of these. DESIGN: Rapid review and narrative synthesis. METHODS: The WHO and Cochrane Rapid Review Methods Group recommendations guided the review processes. CINAHL, Medline, PubMed, and the Cochrane Library were searched from 2000 to January 2022. Data related to clinical indicators of deterioration were categorized using the Airway, Breathing, Circulation, Disability, Exposure assessment framework, and factors influencing detection were grouped as consumer (resident and family), aged care workforce, and organization factors. RESULTS: Twenty publications were included of which 14 informed clinical indicators; nine highlighted factors that influence staff's identification of these and three informed both. Included article were collectively below moderate quality. Most clinical indicators were grouped into the 'Disability' category with altered level of consciousness, behavior, and pain identified most frequently. Few studies reported more traditional indicators of deterioration used in the general population - changes in vital signs. The most common factors influencing the detection of acute deterioration were organizational and workforce-related including resource, knowledge, and confidence deficits. CONCLUSION: Findings suggest subtle changes in resident's health status, rather than focusing primarily on physiologic parameters used in early warning tools for acute care settings, should be recognized and considered in the design of early warning tools for residential aged care facilities. CLINICAL RELEVANCE: Early warning tools sensitive to the unique needs of residents and support for aged care facility staff are recommended to improve the capacity of aged care facility care staff to identify and manage acute deterioration early to avoid hospitalization.

Elements of long-term care that promote quality of life for Indigenous and First Nations Peoples: A mixed methods systematic review.

BACKGROUND AND OBJECTIVES: Little is known about elements of long-term care (LTC) that promote quality of life (QoL) for older Indigenous and First Nations peoples. This systematic review aimed to extend understanding of those deemed most important. RESEARCH DESIGN AND METHODS: Following PRISMA guidelines, systematic database and hand-searching were used to find published and unpublished qualitative studies and textual reports. A convergent integrated approach was used to synthesize data, according to the Joanna Briggs Institute methodology for mixed methods systematic reviews. RESULTS: Included papers (11 qualitative; 7 reports) explored views and experiences of Indigenous residents, families, and LTC staff from North America (8), South Africa (1), Norway (1), New Zealand (1), and Australia (7). Elements of care included: i) co-designing and collaborating with Indigenous and First Nations communities and organizations to promote culturally safe care; ii) embedding trauma-informed care policies and practices, and staff training to deliver culturally safe services; iii) being respectful of individual needs, and upholding cultural, spiritual and religious beliefs, traditional activities and practices; iv) promoting connection to culture and sense of belonging through sustained connection with family, kin and Indigenous and First Nations communities. DISCUSSION AND IMPLICATIONS: This review identifies elements or models of care that promote QoL for Indigenous and First Nations peoples in LTC. While included papers were mostly from the United States and Australia, the congruence of elements promoting QoL was evident across all population groups. Findings may be used to inform standards specific to the care of Indigenous and First Nations peoples.

Promoting Person-Centered Care for Health Baccalaureate Students: Piloting an Interprofessional Education Approach to Wound Management.

OBJECTIVE: To describe and analyze the implementation of a wound management interprofessional education experience for nursing, podiatry, pharmacy, and exercise and nutrition science health baccalaureate students. The disciplines outside of nursing were invited to join the classes of a wound care elective unit in nursing. METHODS: This study included the development and implementation of a wound care program and observation of all students enrolled in the health disciplines where wound management education was relevant. RESULTS: Results indicated an increase in students' recognition of their roles and the roles of others within an interprofessional healthcare team. Facilitators reported that students learned to share information and work collaboratively to plan care for people with wounds. CONCLUSIONS: The outcomes confirm that the structured wound management program of interprofessional education within a Faculty of Health course promoted student recognition of wound management and the essential shared approach to person-centered care.

Risk factors for the recurrence of venous leg ulcers in adults: A systematic review protocol.

BACKGROUND: Venous leg ulcers are slow to heal, and recurrence is frequent. Living with venous leg ulcers can affect physical and psychological health, and result in financial burden for individuals. Physiological and psychosocial factors are associated with venous leg ulcer recurrence. As over 50% of venous leg ulcers will recur within 12 months of healing, a comprehensive knowledge of holistic risk factors associated with recurrence is required by health professionals involved in the care of the person with venous leg ulcers. AIM: To develop a systematic review protocol to determine the risk factors for recurrence of venous leg ulcers in adults. METHOD AND ANALYSIS: This protocol was developed according to the Preferred Reporting Items Form Systematic Review and Meta-Analysis Protocols (PRISMA-P). The inclusion criteria will be based on the PICOS mnemonic-adults with a history of venous leg ulcer/s (participants), risk factor/s under physiological (general/medical), clinical, demographics, psychosocial categories (I (intervention) or E (exposure), venous leg ulcer non-recurrence (comparison group), venous leg ulcer recurrence (outcomes to be measured) and will include study designs of original qualitative, quantitative and mixed method studies (study designs to be included). Methodological quality will be assessed using the Mixed Methods Appraisal Tool. This Systematic Review Protocol was registered in PROSPERO [CRD42021279792]. RESULTS: If meta-analysis is not possible, a narrative review of results will be presented. CONCLUSIONS: This systematic review on recurrence of venous leg ulcers can provide evidence-based information for preventive strategies for recurrence of a healed venous leg ulcer. The standardised approach outlined in this systematic review protocol offers a rigorous and transparent method to conduct the review.

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Randomized Trial of Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Long-Term Results of the ORATOR Trial.

PURPOSE: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking. METHODS: We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial. RESULTS: Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time (P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years (P = .015). Dry mouth scores were higher in RT patients over time (P = .041). CONCLUSION: On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355).

Understanding Skin Failure: A Scoping Review.

OBJECTIVE: To map the use of the term "skin failure" in the literature over time and enhance understanding of this term as it is used in clinical practice. DATA SOURCES: The databases searched for published literature included PubMed, Embase, the Cumulative Index for Nursing and Allied Health Literature, and Google Scholar. The search for unpublished literature encompassed two databases, Open Gray and ProQuest Dissertation and Theses. STUDY SELECTION: Search terms included "skin failure," "acute skin failure," "chronic skin failure," and "end stage skin." All qualitative and quantitative research designs, editorial, opinion pieces, and case studies were included, as well as relevant gray literature. DATA EXTRACTION: Data collected included author, title, year of publication, journal name, whether the term "skin failure" was mentioned in the publication and/or in conjunction with other skin injury, study design, study setting, study population, sample size, main focus of the publication, what causes skin failure, skin failure definition, primary study aim, and primary outcome. DATA SYNTHESIS: Two main themes of skin failure were identified through this scoping review: the etiology of skin failure and the interchangeable use of definitions. CONCLUSIONS: Use of the term "skin failure" has increased significantly over the past 30 years. However, there remains a significant lack of empirical evidence related to skin failure across all healthcare settings. The lack of quality research has resulted in multiple lines of thinking on the cause of skin failure, as well as divergent definitions of the concept. These results illustrate substantial gaps in the current literature and an urgent need to develop a globally agreed-upon definition of skin failure, as well as a better understanding of skin failure etiology.

Exploring the prevalence and management of wounds for people with dementia in long-term care.

The prevalence of wounds and comorbidities such as dementia increase with age. With an ageing population, the likelihood of overlap of these conditions is strong. This study aimed to determine the prevalence of wound types and current management strategies of wound care for people with dementia in long-term care (LTC). A scoping literature review, a cross-sectional observational and chart audit study of residents in dementia specific facilities in LTC were conducted. The scoping review indicated that people with dementia/cognitive impairment are often excluded from wound related studies andof the nine studies included in this review, none looked at the prevalence of types of wounds other then pressure injuries. In the skin audit, skin tears were noted as the most common wound type with some evidence-based practice strategies in place for residents. However, documentation of current wound occurred in less than a third of residents with wounds. This is the first study to note the prevalence of different wound types in people with dementia and current management strategies being used across two dementia-specific facilities and a lack of research in this area limits evidence in guiding practice.

DMEK in Super-Seniors: Clinical Outcomes of Descemet Membrane Endothelial Keratoplasty Performed in Patients ≥ 90 Years Old.

PURPOSE/AIMS OF THE STUDY: To evaluate the clinical outcomes of Descemet membrane endothelial keratoplasty (DMEK) performed in the "oldest old" patients, i.e. ≥ 90 years. MATERIALS AND METHODS: Between the years of 2009 and 2019, 20 consecutive eyes of 17 patients aged ≥ 90 underwent DMEK for endothelial dysfunction. Best corrected visual acuity (BCVA), central corneal thickness (CCT), endothelial cell density (ECD), graft survival, and intra- and postoperative complications were assessed. RESULTS: Except in one case in which the DMEK surgery could not be completed, all operated eyes experienced an improvement in BCVA, although only 50% achieved ≥ 20/40 (0.5) by 1 year postoperatively. One year after surgery, median CCT had declined from 641(±161) µm to 480 (±34) µm, and median endothelial cell density was reduced by 53%, from 2574 (±286) to 1226 (±404) cells/mm2. Six of 19 eyes receiving DMEK grafts (32%) developed partial graft detachments requiring re-bubbling. One eye experienced a secondary graft failure at 6 months and underwent repeat endothelial keratoplasty. CONCLUSION: DMEK is technically feasible in the oldest old patients and may yield significant visual improvements, although an elevated risk of some postoperative complications including graft detachment with corresponding need for re-bubbling may be anticipated.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Efficient and Highly Specific Gene Transfer Using Mutated Lentiviral Vectors Redirected with Bispecific Antibodies.

Despite their exceptional potencies, the broad tropism of most commonly used lentivirus (LV) vectors limits their use for targeted gene delivery in vivo We hypothesized that we could improve the specificity of LV targeting by coupling (i) reduction of their binding to off-target cells with (ii) redirection of the vectors with a bispecific antibody (bsAb) that binds both LV and receptors on target cells. As a proof of concept, we pseudotyped nonreplicating LV using a mutated Sindbis envelope (mSindbis) with ablated binding to native receptors, while retaining the capacity to facilitate efficient fusion and endosomal escape. We then evaluated the transduction potencies of the mSindbis LV for HER2-positive (HER2+) (SKBR3) breast and HER2-negative (HER2-) (A2780) cells when redirected with different bsAbs. mSindbis LV alone failed to induce appreciable green fluorescent protein (GFP) expression in either cell. When mixed with HER2-targeting bsAb, mSindbis LV was exceptionally potent, transducing 12% to 16% of the SKBR3 cells at a multiplicity of infection (MOI [ratio of viral genome copies to target cells]) of 3. Transduction was highly specific, resulting in ∼50-fold-greater selectivity toward SKBR3 cells versus A2780 cells. Redirecting mSindbis LV led to a 10-fold improvement in cell-specific targeting compared to redirecting wild-type Sindbis LV with the same bsAb, underscoring the importance of ablating native virus tropism in order to maximize targeting specificity. The redirection of mutated LV using bsAb represents a potent and highly versatile platform for targeted gene therapy.IMPORTANCE The goal of gene therapy is specific delivery and expression of therapeutic genes to target cells and tissues. Common lentivirus (LV) vectors are efficient gene delivery vehicles but offer little specificity. Here, we report an effective and versatile strategy to redirect LV to target cells using bispecific antibodies (bsAbs) that bind both cell receptors and LV envelope domains. Importantly, we ablated the native receptor binding of LV to minimize off-target transduction. Coupling bsAb specificity and ablated native LV tropism synergistically enhanced the selectivity of our targeted gene delivery system. The modular nature of our bsAb-based redirection enables facile targeting of the same LV to diverse tissues/cells. By abrogating the native broad tropism of LV, our bsAb-LV redirection strategy may enable lentivirus-based gene delivery in vivo, expanding the current use of LV beyond ex vivo applications.

Stigmatization and knowledge of anorexia nervosa.

PURPOSE: To further understand the stigma, attitudes towards, and recognition of Anorexia Nervosa (AN), the current study utilized both stigma and mental health literacy methodology. This study also included another psychological disorder, major depressive disorder (MDD) and a normal, lonely female (C) as comparison conditions. METHODS: Male (291) and female (576) undergraduate students read a vignette describing one of the conditions. Participants then rated the vignettes on general personality characteristics, condition recognition, perceived seriousness and need for treatment. RESULTS: Many of the participants could not correctly identify AN. However, both AN and MDD were stigmatized. Although AN was rated as being very driven and disciplined, there was recognition that treatment was warranted. Familiarity with the conditions did not impact ratings. CONCLUSIONS: Continued efforts to reduce the stigma of AN and subsequent treatment seeking are warranted. The normal, lonely condition also being rated somewhat negatively highlights the need to include comparison conditions in stigma studies. LEVEL OF EVIDENCE: Level II, comparative study.

Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial.

BACKGROUND: Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment. METHODS: The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 (≤4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1-2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting. FINDINGS: 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median follow-up was 25 months (IQR 20-33) for the radiotherapy group and 29 months (23-43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86·9 (SD 11·4) in the radiotherapy group versus 80·1 (13·0) in the TORS plus neck dissection group (p=0·042). There were more cases of neutropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five [15%]), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS. INTERPRETATION: Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options. FUNDING: Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant.