How does sleeve gastrectomy impact long-term eating-related symptoms, distress, and behavior? A cross-sectional study using the BODY-Q patient-reported outcome measures.

BACKGROUND: Patients undergoing sleeve gastrectomy (SG) experience transformative changes in eating-related experiences that include eating-related symptoms, emotions, and habits. Long-term assessment of these endpoints with rigorous patient-reported outcome measures (PROMs) is limited. We assessed patients undergoing SG with the Body-Q Eating Module PROMs. METHODS: All patients evaluated at the Emory Bariatric Center were given the Body-Q Eating Modules questionnaire at preoperative/postoperative clinic visits. Rasch scores and prevalence of relevant endpoints were assessed across six time-points of interest: preoperatively, post-operative months 0-6, 7-12, 12-24, 24-36, and over 36. Student's t-test and Chi-square test were used for analysis. RESULTS: Overall, 1,352 questionnaires were completed pre-operatively and 493 postoperatively. Survey compliance was 81%. Compared to the pre-operative group, the post-operative group had lower BMI (39.7 vs. 46.4, p < 0.001) and higher age (46.3 vs. 44.9, p = 0.019). Beginning one year after SG, patients experience more frequent eating-related pain, nausea and constipation compared to pre-operative baseline (p < 0.05). They also more frequently experience eating-related regurgitation and dumping syndrome-related symptoms beginning post-operative year two (p < 0.05). In the first year after SG, patients more rarely feel eating-related embarrassment, guilt, and disappointment compared to pre-operative baseline (p < 0.05). These improvements disappear one year after SG, after which patients more frequently experience feeling out of control, unhappy, like a failure, disappointed, and guilty (p < 0.05). In the first year after SG, patients experience an increased frequency in positive eating behaviors (ate healthy foods, showed self-control, stopped before full; (p < 0.05). Only two eating-related behavior improvements persist long-term: feeling in control and eating the right amount (p < 0.05). CONCLUSIONS: Patients undergoing SG may experience more frequent eating-related symptoms, distress, and behavior in the long-term. These findings can enhance the pre-operative informed consent and guide development of a more tailored approach to postoperative clinical management such as more frequent visits with the dietician.

Caenorhabditis elegans as a Convenient Animal Model for Microbiome Studies.

Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host-microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host genetics on microbial composition. In the wild, the C. elegans gut contains various microbial species, while in the laboratory it is usually a host for a single bacterial species. There is a potential host-microbe interaction between microbial metabolites, drugs, and C. elegans phenotypes. This mini-review aims to summarize the current understanding regarding the microbiome in C. elegans. Examples using C. elegans to study host-microbe-metabolite interactions are discussed.

Factors Associated with Substance Use Disorder among High-Need Adolescents and Young Adults in North Carolina.

Background: Prevalence of substance use disorders (SUD) is high among adolescents and young adults (AYAs) with complex medical needs. Little is known about risk factors for SUD in this population. Methods: This retrospective cohort study used electronic health record data from a large academic hospital system (2015-2019) to identify adolescents (aged 10-17) and young adults (aged 18-27) with intellectual/developmental disorders, psychiatric conditions, or complex medical conditions. Logistic regression was used to identify demographic, clinical, and neighborhood-level risk factors associated with SUD in this population. Results: A total of 149 adolescents and 536 young adults had a SUD diagnosis (6.7% and 20.6%, respectively). Among adolescents, notable risk factors for SUD included age (adjusted odds ratio [aOR] = 1.42, 95% confidence interval [CI] = [1.31, 1.54]), Hispanic ethnicity (aOR = 2.10, 95% CI = [1.10, 3.99]), additional psychoactive medication classes (aOR = 1.27, 95% CI = [1.11, 1.46]), and living in a "high" child opportunity index (COI) (aOR = 2.06, 95% CI [1.02, 4.14]) or a "very high" COI (aOR = 3.04, 95% CI [1.56,5.95]) area. Among young adults, notable risk factors included being male (aOR = 2.41, 95% CI [1.91, 3.05]), being Black (aOR = 1.64, 95% CI [1.28, 2.09]), and additional non-psychoactive (aOR = 1.07, 95% CI [1.03, 1.11]) or psychoactive medication classes (aOR = 1.17, 95% CI [1.07, 1.28]). Limitations: These descriptive analyses are limited to one large academic hospital system in North Carolina and may not be representative of all high-need AYAs in the state. Conclusions: Several demographic, clinical, and neighborhood risk factors are associated with SUD in high-need AYAs.

Adolescent asthma management self-efficacy and responsibility: impact on asthma control and quality-of-life.

OBJECTIVE: The purpose of this study was to investigate the extent to which adolescent asthma management self-efficacy, outcome expectations, and asthma responsibility were associated with asthma control and quality-of-life. Adolescent self-efficacy and outcome expectations are important components of social cognitive theory, which guided this research. METHODS: English- and Spanish-speaking adolescents ages 11-17 with persistent asthma were recruited at four pediatric clinics. Adolescents were interviewed and parents completed questionnaires. Multiple linear regression was used to analyze the data. RESULTS: Three hundred and fifty-nine adolescents were recruited. Older adolescent age, male gender, and higher adolescent asthma management self-efficacy were significantly associated with higher adolescent responsibility; outcome expectations were not significantly associated with responsibility. Adolescent ratings of their own responsibility were higher than parent ratings of their child's responsibility for almost all asthma management tasks. Adolescents with higher reported asthma management self-efficacy were significantly more likely to have better quality-of-life and controlled asthma. Adolescents with more positive outcome expectations were significantly more likely to have controlled asthma. Being Native American was associated with worse quality-of-life and asthma not being controlled. Being Black was associated with asthma not being controlled. CONCLUSIONS: Parents and providers should work to improve adolescent self-efficacy in managing their asthma because it is associated with asthma responsibility, asthma control, and quality-of-life. Providers need to especially work with Native American and Black adolescents to improve quality-of-life and asthma control.

Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages.

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

Effect of operative times in bariatric surgery on outcomes: a matched analysis of the MBSAQIP database.

BACKGROUND: The implications of operative time (OT) have been studied in different surgical specialties, showing a correlation with higher incidence rates of postoperative complications. However, the impact of OT on bariatric surgery complications is not well elucidated. METHODS: A retrospective review of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database between 2015 and 2019 was performed. A total of 358,382 SG patients and 123,357 RYGB patients were included. The median OT was 68 min (10-720) and 113 min (10-640) for the sleeve gastrectomy (SG) group and the Roux-en-Y gastric bypass group, respectively. The groups were subdivided into two subgroups based on OT in comparison to the median time of each group. The subgroups were compared for surgical complications and outcomes. To reduce selection bias and risk of confounders, we performed a propensity score matching (PSM) for 22 variables. RESULTS: In the PSM-matched cohort, 18,915 SG and 6,495 RYGB patients were included in each subgroup. The SG cohort showed higher rates of Clavien-Dindo Class 1, 2, 3a, 4, and 5 complications as well as higher rates of readmission, reoperation, and reintervention in the longer OT group before matching. After PSM, the subgroup with longer times continued to have higher rates of Clavien-Dindo Class 2 complications and higher rates of readmission and reoperation. Similarly, there were higher rates of all Clavien-Dindo class complications as well as readmission, reoperation, and reintervention in the RYGB group with higher OT. After PSM, there were still higher rates of Clavien-Dindo Class 3a complications as well as readmission and reintervention in the RYGB subgroup with prolonged OT. CONCLUSION: In both SG and RYGB, longer OT was associated with increased rates of complications as well as readmission, reoperation, and reintervention. Surgeons should be cognizant of the increased rates of complications when operative times are longer.

Does the use of a suction calibration system (SCS) reduce stapler load firings and operative time? A randomized controlled trial comparing use of endoscopic calibration vs. SCS in laparoscopic sleeve gastrectomy.

BACKGROUND: It is critical to ensure appropriate and consistent sleeve size and orientation during laparoscopic sleeve gastrectomy (LSG). Various devices are used to achieve this, including weighted rubber bougies, esophagogastroduodenoscopy (EGD), and suction calibration systems (SCS). Prior reports suggest that SCSs may decrease operative time and stapler load firings but are limited by single-surgeon experience and retrospective design. We performed the first randomized controlled trial comparing SCS against EGD in patients undergoing LSG to investigate whether the SCS decreases the number of stapler load firings. METHODS: This was a randomized, non-blinded study from a single MBSAQIP-accredited academic center. Appropriate LSG candidates ≥ 18 years of age were randomized to EGD or SCS calibration. Exclusion criteria included prior gastric or bariatric surgery, detection of hiatal hernia before surgery, and intraoperative hiatal hernia repair. A randomized block design was employed controlling for body mass index, gender, and race. Seven surgeons employed a standardized LSG operative technique. The primary endpoint was the number of stapler load firings. Secondary endpoints were operative duration, reflux symptoms, and change in total body weight (TBW). Endpoints were analyzed via t-test. RESULTS: A total of 125 LSG patients (84% female) underwent study enrollment, with an average age of 44 ± 12 years and average BMI of 49 ± 8 kg/m2. Overall, 117 patients were randomized to receive EGD (n = 59) or SCS (n = 58) calibration. No significant differences in baseline characteristics were identified. The mean number of stapler load firings for EGD and SCS groups were 5.43 ± 0.89 and 5.31 ± 0.81, respectively (p = 0.463). The mean operative times for EGD and SCS groups were 94.4 ± 36.5 and 93.1 ± 27.9 min, respectively (p = 0.83). There were no significant differences in post-operative reflux, TBW loss, or complications. CONCLUSION: Use of EGD and SCS resulted in a similar number of LSG stapler load firings and operative duration. Additional research is needed to compare LSG calibration devices in different patients and settings to optimize surgical technique.

The financial impact of the COVID-19 pandemic on sleeve gastrectomy at a major academic institution.

INTRODUCTION: The COVID-19- pandemic significantly impacted metabolic and bariatric surgery (MBS) practices due to large-scale surgery cancellations along with staff and supply shortages. We analyzed sleeve gastrectomy (SG) hospital-level financial metrics before and after the COVID-19 pandemic. METHODS: Hospital cost-accounting software (MicroStrategy, Tysons, VA) was reviewed for revenues, costs, and profits per SG at an academic hospital (2017-2022). Actual figures were obtained, not insurance charge estimates or hospital projections. Fixed costs were obtained through surgery-specific allocation of inpatient hospital and operating-room costs. Direct variable costs were analyzed with sub-components including: (1) labor and benefits, (2) implants, (3) drug costs, and 4) medical/surgical supplies. The pre-COVID-19 period (10/2017-2/2020) and post-COVID-19 period (5/2020-9/2022) financial metrics were compared with student's t-test. Data from 3/2020 to 4/2020 were excluded due to COVID-19-related changes. RESULTS: A total of 739 SG patients were included. Average length of stay (LOS), Center for Medicaid and Medicare Case Mix Index (CMI), and percentage of patients with commercial insurance were similar pre vs. post-COVID-19 (p > 0.05). There were more SG performed per quarter pre-COVID-19 than post-COVID-19 (36 vs. 22; p = 0.0056). Pre-COVID-19 and post-COVID-19 financial metrics per SG differed significantly for, respectively, revenues ($19,134 vs. $20,983) total variable cost ($9457 vs. $11,235), total fixed cost ($2036 vs. $4018), total profit ($7571 vs. $5442), and labor and benefits cost ($2535 vs. $3734; p < 0.05). CONCLUSIONS: The post-COVID-19 period was characterized by significantly increased SG fixed cost (i.e., building maintenance, equipment, overhead) and labor costs (increased contract labor), resulting in precipitous profit decline that crosses the break-even in calendar year quarter (CQ) 3, 2022. Potential solutions include minimizing contract labor cost and decreasing LOS.

Demographic diversity of US-based participants in GSK-sponsored interventional clinical trials.

BACKGROUND: Demographic diversity among clinical trials is required for representing the real-world populations intended for treatment and disease prevention. Moreover, genetic and environmental differences between ethnic and racial groups necessitate appropriately powered trials for relevant subgroups. We investigate the racial and ethnic demographic diversity of US-based participants in GSK-sponsored interventional trials. We also assess the evaluation of demographic diversity against US Census and epidemiologic data. METHODS: GSK-sponsored interventional phase I-IV clinical trials conducted from 2002 to 2019 across three areas were analyzed: pharmaceutical (includes therapeutic medicines except for vaccines and human immunodeficiency virus (HIV)), vaccine (includes prophylactic and therapeutic vaccines), and ViiV (includes HIV therapies). A total of 1005 global trials encompassing 460,707 global participants were identified, of which 495 had US-based sites with a total of 108,261 (23.5% of global) US participants (pharmaceutical, n = 357 trials; vaccine, n = 45 trials; and ViiV, n = 93 trials). We evaluated how GSK US-based trial recruitment compares with US Census (in line with previously published studies from other groups) and with epidemiologic data. RESULTS: GSK participant data for race and ethnicity combined across areas were generally similar to US Census levels (e.g. GSK versus census: White, 76.5% versus 76.3%; Black or African American, 15.1% versus 13.4%; Asian, 1.8% versus 5.9%; Hispanic or Latino, 14.0% versus 18.5%; Non-Hispanic White, 63.5% versus 60.1%). However, this was not the case for the individual pharmaceutical, vaccine, and ViiV data sets; least represented groups were Asian individuals for pharmaceutical and ViiV trials and American Indian or Alaskan Native individuals for vaccine trials (6.2%, 11.8%, and 11.1% of trials met/exceeded census level representation, respectively). The percentage of trials reaching/exceeding census levels also varied per trial phase for race and ethnicity. Furthermore, disparities in the percentage of trials reaching/exceeding census levels versus epidemiology-based prevalence levels have revealed opportunities to improve industry success metrics; in HIV trials, the proportion of Black or African American individuals (35.1%) exceeded census (13.4%) but not epidemiologic levels (55.3%). CONCLUSION: Further work is required to achieve demographic diversity across clinical trials. We conclude that US Census data are an inappropriate universal benchmark. A shift to epidemiology benchmarking will enable the consideration of global participants into US analyses for highly intrinsic (i.e. influenced by ancestry) diseases and more firm requirements for US-based participants into US analyses for extrinsic (i.e. influenced by location or culture) diseases. Benchmarking in line with epidemiologic data will allow us to set better trial enrollment goals, with the aim of conducting more demographically balanced, diverse, and representative clinical trials and enabling a better understanding of drug safety and efficacy per demographic group.

A Quality Improvement Innovation for Reproductive Health Planning in the Time of COVID.

OBJECTIVES: To see if an outreach approach with telehealth is feasible and acceptable to patients to talk about their reproductive health; and as a secondary outcome, capture data on time spent on the visit and what kind of information was discussed. METHODS: A registry was created from three family physicians' panels of all adult patients with anticipated ability to become pregnant ages 18-45 who had not had a documented reproductive health discussion in the previous 6 months. Using that registry, outreach was performed to schedule a telehealth visit to discuss their reproductive health with their primary care provider. The visit was standardized using the One Key Question approach. For patients who agreed to participate in the research, the patient completed a survey about their experience. The provider also completed a survey on the time spent and the issues addressed. RESULTS: Two hundred and six patients were called. Ninety patients (44%) could not be reached. Of the remaining patients, 34 scheduled either a telehealth or in-person visit and 7 also agreed to participate in the survey. New information was uncovered in the visit in 86% of participants. The most common need uncovered during the visit was unrelated medical needs (71%), followed by preconception health education/advice (43%) and contraception needs/counseling (29%). Most participants found the telehealth visit valuable. CONCLUSIONS: An outreach methodology can uncover unmet health needs, both reproductive and otherwise. We found that people who had the visit often needed something, but a majority of patients declined the visit saying that they did not think they needed it. It is possible that patients are not aware of the value of reproductive health discussions, and therefore clinicians need to take every opportunity to have these discussions whenever possible, whether through outreach or inreach (during already scheduled visits).

Psychological safety and accountability in longitudinal integrated clerkships: a dual institution qualitative study.

BACKGROUND: Psychological safety and accountability are frameworks to describe relationships in the workplace. Psychological safety is a shared belief by members of a team that it is safe to take interpersonal risks. Accountability refers to being challenged and expected to meet expectations and goals. Psychological safety and accountability are supported by relational trust. Relational continuity is the educational construct underpinning longitudinal integrated clerkships. The workplace constructs of psychological safety and accountability may offer lenses to understand students' educational experiences in longitudinal integrated clerkships. METHODS: We performed a qualitative study of 9 years of longitudinal integrated clerkship graduates from two regionally diverse programs-at Harvard Medical School and the University of North Carolina School of Medicine. We used deductive content analysis to characterize psychological safety and accountability from semi-structured interviews of longitudinal integrated clerkship graduates. RESULTS: Analysis of 20 graduates' interview transcripts reached saturation. We identified 109 discrete excerpts describing psychological safety, accountability, or both. Excerpts with high psychological safety described trusting relationships and safe learning spaces. Low psychological safety included fear and frustration and perceptions of stressful learning environments. Excerpts characterizing high accountability involved increased learning and responsibility toward patients. Low accountability included students not feeling challenged. Graduates' descriptions with both high psychological safety and high accountability characterized optimized learning and performance. CONCLUSIONS: This study used the workplace-based frameworks of psychological safety and accountability to explore qualitatively longitudinal integrated clerkship graduates' experiences as students. Graduates described high and low psychological safety and accountability. Graduates' descriptions of high psychological safety and accountability involved positive learning experiences and responsibility toward patients. The relational lenses of psychological safety and accountability may inform faculty development and future educational research in clinical medical education.

Feasibility of a best-worst scaling exercise to set priorities for autism research.

BACKGROUND: The preferences of autism stakeholders regarding the top priorities for future autism research are largely unknown. OBJECTIVE: This study had two objectives: First, to examine what autism stakeholders think new research investments should be and the attributes of investment that they consider important, and second, to explore the feasibility, acceptability and outcomes of two prioritization exercises among autism stakeholders regarding their priorities for future research in autism. DESIGN: This was  a prospective stakeholder-engaged iterative study consisting of best-worst scaling (BWS) and direct prioritization exercise. SETTING AND PARTICIPANTS: A national snowball sample of 219 stakeholders was included: adults with autism, caregivers, service providers and researchers. MAIN OUTCOME MEASURES: The main outcomes measures were attributes that participants value in future research investments, and priority research investments for future research. RESULTS: Two hundred and nineteen participants completed the exercises, of whom 11% were adults with autism, 58% were parents/family members, 37% were service providers and 21% were researchers. Among stakeholders, the BWS exercises were easier to understand than the direct prioritization, less frequently skipped and yielded more consistent results. The proportion of children with autism affected by the research was the most important attribute for all types of stakeholders. The top three priorities among future research investments were (1) evidence on which child, family and intervention characteristics lead to the best/worst outcomes; (2) evidence on how changes in one area of a child's life are related to changes in other areas; and (3) evidence on dietary interventions. Priorities were similar for all stakeholder types. CONCLUSIONS: The values and priorities examined here provide a road map for investigators and funders to pursue autism research that matters to stakeholders. PATIENT OR PUBLIC CONTRIBUTION: Stakeholders completed a BWS and direct prioritization exercise to inform us about their priorities for future autism research.

Acceptance of a Pre-visit Intervention to Engage African American Glaucoma Patients during Visits.

SIGNIFICANCE: The glaucoma question prompt list/video intervention was well received by patients. Eighty-seven percent of patients recommended that other patients should watch the educational video before their visits, and 89% said that other patients should complete the question prompt list before visits. PURPOSE: The objectives of this study were to (a) describe patient feedback on a glaucoma question prompt list/video intervention designed to motivate African American patients to be more engaged during visits and (b) examine patient demographics associated with acceptance of the intervention. METHODS: We are conducting a randomized controlled trial of a glaucoma question prompt list/video intervention. African American patients with glaucoma were enrolled and assigned to a control group or an intervention group where they watched a video emphasizing the importance of asking questions and received a prompt list to complete before visits. All patients were interviewed after visits and are being followed up for 12 months. RESULTS: One hundred eighty-nine African American patients with glaucoma were enrolled into the larger trial. Of the 93 patients randomized to the intervention group, 89% said that patients should complete the prompt lists before visits, and 87% recommended that patients should watch the video before visits. Older patients were significantly less likely to believe that other patients should watch the video before their visits (t = -3.7, P = .04). Patients with fewer years of education were significantly more likely to rate the video as being more useful than patients with more years of education (Pearson correlation, -0.27; P = .01). Patients who reported being less adherent on the visual analog scale were more likely to rate the video as being more useful (Pearson correlation, -0.23; P = .03). CONCLUSIONS: This study demonstrates that the question prompt list/video was accepted by the majority of African American patients who received the intervention.

North Carolina community pharmacists' buprenorphine dispensing practices and attitudes.

BACKGROUND: Many barriers, including stocking behaviors and pharmacist attitudes, can limit access to buprenorphine in pharmacy settings. OBJECTIVES: To assess North Carolina (NC) pharmacists' (1) buprenorphine stocking behaviors, (2) awareness and interpretation of federal and state policy regarding buprenorphine, (3) perceptions about changes in buprenorphine demand, and (4) reasons for not dispensing buprenorphine, including attitudes. METHODS: A convenience sample of currently practicing community pharmacists was recruited to participate in a 10-minute online survey. The survey included demographic questions and assessed pharmacists' buprenorphine ordering, stocking, and dispensing behaviors. Descriptive statistics were calculated, and logistic regressions examined associations with whether pharmacists (1) had ever refused to fill a buprenorphine prescription and (2) perceived buprenorphine dispensing limits. RESULTS: The majority (96%) of respondents (n = 646, completion rate = 5.5%) kept buprenorphine in stock regularly or ordered it as needed, with generic formulations being stocked most often. Many pharmacists (62%) had refused to fill a buprenorphine prescription. Pharmacists with more negative buprenorphine attitudes were more likely to refuse to fill a buprenorphine prescription. Many pharmacists (31%) believed there were buprenorphine ordering limits, with wholesalers most commonly being perceived as the source. Pharmacists with more negative buprenorphine attitudes were more likely to perceive buprenorphine ordering limits, while pharmacists who worked at national chain, grocery or regional chains, and other pharmacy types were less likely to perceive ordering limits than independent pharmacies. CONCLUSION: Although most pharmacies stocked buprenorphine products, pharmacists' refusal to dispense and perceived ordering limits could limit patient access. Refusal and perceived ordering limits were associated with pharmacist attitudes and pharmacy type. Training that addresses logistical and attitudinal barriers to dispensing buprenorphine may equip pharmacists to address buprenorphine access barriers.

Co-design with aboriginal and torres strait islander communities: A journey.

AIM: This paper explores the principles of co-design with Aboriginal and Torres Strait Islander communities by reflecting on the literature, learning from experiences of allied health professionals, and considering how co-design can be applied in rural and remote allied health practice. CONTEXT: This paper has been authored by a working group from Services for Rural and Remote Allied Health (SARRAH). SARRAH is a member-based allied health organisation, working to improve health outcomes for rural and remote Australians. SARRAH has been representing and supporting allied health professionals in rural and remote Australia for over 20 years, with a member base that includes students, practitioners, programme managers, policy makers and academics. As a non-Indigenous organisation, SARRAH works in partnership and receives guidance from the peak organisation, Indigenous Allied Health Australia (IAHA). APPROACH: Over a period of 3 months, a group of eleven SARRAH members and staff came together to review available literature, seek member perspectives and share their experiences and understandings of co-design. Working group discussions were grounded in the knowledge and experiences shared by two Aboriginal and Torres Strait Islander group members. CONCLUSION: This paper proposes that successful co-design with Aboriginal and Torres Strait Islander communities places legitimate value on different knowledge systems, is built on strong and trusting relationships, promotes inclusive involvement and requires authentic partnerships. Using these principles, SARRAH will engage with members and stakeholders to influence meaningful change in allied health practice in rural and remote Australia.

Adequate tacrolimus exposure modulates the impact of HLA class II molecular mismatch: a validation study in an American cohort.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus <6 ng/ml versus >8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.

Blunted sweating does not alter the rise in core temperature in people with multiple sclerosis exercising in the heat.

The purpose of this study is to determine whether thermoregulatory capacity is altered by multiple sclerosis (MS) during exercise in the heat. Sixteen MS participants (EDSS: 2.9 ± 0.9; 47 ± 8 yr; 77.6 ± 14.0 kg) and 14 healthy control (CON) participants (43 ± 11 yr; 78.6 ± 17.0 kg) cycled at a heat production of 4 W·kg-1 for 60 min at 30°C, 30% relative humidity (RH) (Warm). A subset of eight MS (EDSS: 2.6 ± 0.5; 44 ± 8 yr; 82.3 ± 18.2 kg) and 8 CON (44 ± 12 yr; 81.2 ± 21.1 kg) also exercised at 35°C, 30% RH (Hot). Rectal temperature (Tre), mean skin (Tsk) temperature, and local sweat rate (LSR) on the upper back (LSRback) and forearm (LSRarm) were measured. All CON, and only 9 of 16 and 7 of 8 MS participants completed 60 min of exercise in Warm and Hot trials, respectively. All MS participants who were unable to complete exercise stopped with a ΔTre between 0.2 and 0.5°C. The time to reach a ΔTre of 0.2°C was similar (MS: 28 ± 15 min, CON: 32 ± 18 min; P = 0.51). For MS participants, completing 60-min of exercise in Warm, ΔTre (P = 0.13), ΔTsk (P = 0.45), LSRback (P = 0.69), and LSRarm (P = 0.54) was similar to CON, but ΔTb (body temperature) (MS: 0.16 ± 0.13°C, CON: 0.07 ± 0.06°C; P = 0.02) and onset time (MS: 16 ± 10 min, CON: 8 ± 5 min; P = 0.02) for sweating were greater in MS. Similarly, in Hot, ΔTre (P = 0.52), ΔTsk (P = 0.06), LSRback (P = 0.59), and LSRarm (P = 0.08) were similar, but ΔTb (MS: 0.19 ± 0.16°C, CON: 0.06 ± 0.04°C; P = 0.04) and onset time (MS: 13 ± 7 min, CON: 6 ± 3 min; P = 0.02) for sweating were greater in MS. Even at 35°C, a delayed sweating onset did not alter heat loss to sufficiently affect exercise-induced rises in core temperature. Heat intolerance with MS does not seem attributable to thermoregulatory impairments.

Clinically relevant dual probe difference specimen imaging (DDSI) protocol for freshly resected breast cancer specimen staining.

BACKGROUND: Re-excision rates following breast conserving surgery (BCS) remain as high as ~ 35%, with positive margins detected during follow-up histopathology. Additional breast cancer resection surgery is not only taxing on the patient and health care system, but also delays adjuvant therapies, increasing morbidity and reducing the likelihood of a positive outcome. The ability to precisely resect and visualize tumor margins in real time within the surgical theater would greatly benefit patients, surgeons and the health care system. Current tumor margin assessment technologies utilized during BCS involve relatively lengthy and labor-intensive protocols, which impede the surgical work flow. METHODS: In previous work, we have developed and validated a fluorescence imaging method termed dual probe difference specimen imaging (DDSI) to accurately detect benign and malignant tissue with direct correlation to the targeted biomarker expression levels intraoperatively. The DDSI method is currently on par with touch prep cytology in execution time (~ 15-min). In this study, the main goal was to shorten the DDSI protocol by decreasing tissue blocking and washing times to optimize the DDSI protocol to < 10-min whilst maintaining robust benign and malignant tissue differentiation. RESULTS: We evaluated the utility of the shortened DDSI staining methodology using xenografts grown from cell lines with varied epidermal growth factor receptor (EGFR) expression levels, comparing accuracy through receiver operator characteristic (ROC) curve analyses across varied tissue blocking and washing times. An optimized 8-min DDSI methodology was developed for future clinical translation. CONCLUSIONS: Successful completion of this work resulted in substantial shortening of the DDSI methodology for use in the operating room, that provided robust, highly receptor specific, sensitive diagnostic capabilities between benign and malignant tissues.

Dynamic prediction based on variability of a longitudinal biomarker.

BACKGROUND: Tacrolimus is given post-kidney transplant to suppress the immune system, and the amount of drug in the body is measured frequently. Higher variability over time may be indicative of poor drug adherence, leading to more adverse events. It is important to account for the variation in Tacrolimus, not just the average change over time. METHODS: Using data from the University of Colorado, we compare methods of assessing how the variability in Tacrolimus influences the hazard of de novo Donor Specific Antibodies (dnDSA), an early warning sign of graft failure. We compare multiple joint models in terms of fit and predictive ability. We explain that the models that account for the individual-specific variability over time have the best predictive performance. These models allowed each patient to have an individual-specific random error term in the longitudinal Tacrolimus model, and linked this to the hazard of dnDSA model. RESULTS: The hazard for the variance and coefficient of variation (CV) loading parameter were greater than 1, indicating that higher variability of Tacrolimus had a higher hazard of dnDSA. Introducing the individual-specific variability improved the fit, leading to more accurate predictions about the individual-specific time-to-dnDSA. CONCLUSIONS: We showed that the individual's variability in Tacrolimus is an important metric in predicting long-term adverse events in kidney transplantation. This is an important step in personalizing the dosage of TAC post-transplant to improve outcomes post-transplant.

Random survival forests for dynamic predictions of a time-to-event outcome using a longitudinal biomarker.

BACKGROUND: Risk prediction models for time-to-event outcomes play a vital role in personalized decision-making. A patient's biomarker values, such as medical lab results, are often measured over time but traditional prediction models ignore their longitudinal nature, using only baseline information. Dynamic prediction incorporates longitudinal information to produce updated survival predictions during follow-up. Existing methods for dynamic prediction include joint modeling, which often suffers from computational complexity and poor performance under misspecification, and landmarking, which has a straightforward implementation but typically relies on a proportional hazards model. Random survival forests (RSF), a machine learning algorithm for time-to-event outcomes, can capture complex relationships between the predictors and survival without requiring prior specification and has been shown to have superior predictive performance. METHODS: We propose an alternative approach for dynamic prediction using random survival forests in a landmarking framework. With a simulation study, we compared the predictive performance of our proposed method with Cox landmarking and joint modeling in situations where the proportional hazards assumption does not hold and the longitudinal marker(s) have a complex relationship with the survival outcome. We illustrated the use of the RSF landmark approach in two clinical applications to assess the performance of various RSF model building decisions and to demonstrate its use in obtaining dynamic predictions. RESULTS: In simulation studies, RSF landmarking outperformed joint modeling and Cox landmarking when a complex relationship between the survival and longitudinal marker processes was present. It was also useful in application when there were several predictors for which the clinical relevance was unknown and multiple longitudinal biomarkers were present. Individualized dynamic predictions can be obtained from this method and the variable importance metric is useful for examining the changing predictive power of variables over time. In addition, RSF landmarking is easily implementable in standard software and using suggested specifications requires less computation time than joint modeling. CONCLUSIONS: RSF landmarking is a nonparametric, machine learning alternative to current methods for obtaining dynamic predictions when there are complex or unknown relationships present. It requires little upfront decision-making and has comparable predictive performance and has preferable computational speed.