Merkel Cell Polyomavirus Antibody Titer Predicts Recurrence-Free Survival.

BACKGROUND: Merkel cell polyomavirus (MCPyV) is associated with the development of Merkel cell carcinoma (MCC). Antibody (MCPyV-Ab) titers may have prognostic implications. This study evaluated the impact of the presence or absence of MCPyV-Ab on the 2-year overall survival (OS) and disease-free survival (DFS) of MCC patients. METHODS: This single-center, IRB-approved, retrospective cohort study evaluated 51 adult patients with MCC from 2014 to 2021 using a prospectively maintained database. Patients were compared by MCPyV-Ab status, and Kaplan-Meier analysis was used to evaluate 2-year OS and DFS. RESULTS: Of the 51 patients, 13 (25.4%) were seropositive, 41 (80.4%) underwent wide excision, 40 (80.0%) received radiotherapy, and 43 (84.3%) received multimodal therapy. The median follow-up period was 15.5 months (range 1-69.5 months). The median 2-year OS of the entire cohort was not reached. The median 2-year OS was not reached for either the seronegative or the seropositive patients. The difference in 2-year OS between the groups was not statistically significant (p = 0.37). Eight patients, all seronegative, were never rendered disease-free and were removed from recurrence analysis. The seropositive patients experienced no recurrences. Of the 30 seronegative patients, 9 (30.0%) experienced recurrence. The median 2-year DFS of the entire cohort was not reached. The median 2-year DFS of the seronegative group was 22.2 months. The 2-year DFS was not reached for the seropositive cohort. Seropositivity conferred a significantly better 2-year DFS than seronegativity (p = 0.04). CONCLUSION: The MCPyV-Ab seropositive patients demonstrated improved 2-year DFS. The seropositive patients showed a strong trend toward improved 2-year OS, although the difference not statistically significant. This study substantiated the value of MCPyV-Ab assessment for MCC.

Alvimopan retains efficacy in patients undergoing colorectal surgery within an established ERAS program.

BACKGROUND: Post-operative ileus and delayed return of gastrointestinal function are complications seen frequently in patients undergoing colorectal surgery. Many enhanced recovery after surgery protocols include alvimopan to inhibit the effects of opiates in the gastrointestinal tract and lidocaine to augment analgesics. Limited data exist regarding alvimopan's efficacy in opiate-sparing regimens. METHODS: This single-center, retrospective cohort analysis was conducted in a randomly selected population of adult patients undergoing colorectal resection between February 2018 and October 2019. Patients meeting inclusion criteria were divided into four groups dependent upon whether or not they received alvimopan (A or a) and/or lidocaine (L or l). The primary endpoint in this study was median time to first bowel movement or discharge, whichever came first. Our secondary endpoint was length of stay. RESULTS: Of the 430 patients evaluated, a total of 192 patients were included in the final evaluation in the following groups: AL (n = 93), Al (n = 34), aL (n = 44), and al (n = 21). A significant difference was found among the groups for the primary outcome of median time to bowel movement or discharge (p = 0.001). Three subsequent pair-wise comparisons resulted in a significant difference in the primary outcome: group AL 39.4 h vs. group aL 54.0 h (p = 0.003), group AL 39.4 h vs. group al 55.4 h (p = 0.001), and group Al 44.9 h vs. group al 55.4 h (p = 0.01). Length of stay was significantly reduced by 1.8 days in groups AL and Al compared to group aL (p < 0.001). CONCLUSION: Treatment with alvimopan resulted in a significant improvement in time to GI recovery and decreased length of stay in an established ERAS program. While lidocaine's reduction in opiates was minimal, the group receiving both alvimopan and lidocaine had the greatest reduction in time to GI recovery and length of stay.

The frequency and impact of undiagnosed benign paroxysmal positional vertigo in outpatients with high falls risk.

BACKGROUND: The frequency and impact of undiagnosed benign paroxysmal positional vertigo (BPPV) in people identified with high falls risk has not been investigated. OBJECTIVE: To determine the frequency and impact on key psychosocial measures of undiagnosed BPPV in adult community rehabilitation outpatients identified with a high falls risk. DESIGN: A frequency study with cross-sectional design. SETTING: A Community Rehabilitation Program in Melbourne, Australia. SUBJECTS: Adult community rehabilitation outpatients with a Falls Risk for Older People in the Community Screen score of four or higher. METHODS: BPPV was assessed in 34 consecutive high falls risk rehabilitation outpatients using the Dix-Hallpike test and supine roll test. Participants were assessed for anxiety, depression, fear of falls, social isolation and loneliness using the Hospital Anxiety and Depression Scale, Falls Efficacy Scale-International and De Jong Gierveld 6-Item Loneliness Scale. RESULTS: A total of 18 (53%; 95% confidence interval: 36, 70) participants tested positive for BPPV. There was no significant difference between those who tested positive for BPPV and those who did not for Falls Risk for Older People in the Community Screen scores (P = 0.555), Hospital Anxiety and Depression Scale (Anxiety) scores (P = 0.627), Hospital Anxiety and Depression Scale (Depression) scores (P = 0.368) or Falls Efficacy Scale-International scores (P = 0.481). Higher scores for the De Jong Gierveld 6-Item Loneliness Scale in participants with BPPV did not reach significance (P = 0.056). CONCLUSIONS: Undiagnosed BPPV is very common and associated with a trend towards increased loneliness in adult rehabilitation outpatients identified as having a high falls risk.

Rehabilitation for people with dementia: a multi-method study examining knowledge and attitudes.

BACKGROUND: People with dementia are not routinely offered rehabilitation services despite experiencing disability associated with the condition and accumulating evidence for therapies such as exercise, occupational therapy, and cognitive or physical rehabilitation. It is important to understand the needs and preferences of people with dementia regarding rehabilitation services. The aim of this study was to explore thoughts and beliefs about rehabilitation amongst people with dementia and their families. METHODS: Interviews with people with dementia and family members regarding their experience of care following diagnosis and their attitudes and beliefs about rehabilitation for dementia. Surveys with older people with cognitive impairment and/or a diagnosis of dementia to determine preferences for services and understanding of rehabilitation programs. RESULTS: Interviews with 13 participants (n = 6 people living with dementia with mean age 60 and n = 7 care partners) revealed gaps in care post diagnosis. People reported having to seek out services and frequently sought out services which were rehabilitative in nature. Survey data (n = 91 participants, average age 82) showed that most people had heard of rehabilitation (92%) or had experience of rehabilitation (49%) at some point. There was a wide range of services identified as being beneficial. Rehabilitative interventions including case management, exercise and memory strategies were considered desirable. CONCLUSIONS: People with dementia report having a wide variety of needs. There are gaps following diagnosis where people with dementia report having to seek out their own services. Some interview participants (who tended to be younger) clearly articulated the need for tailored interventions which maximised independence and quality of life. Survey participants, who were on average older, reported that they would participate in individually applicable rehabilitative therapies if they were available.

The clinical correlation of phosphatase and tensin homolog on chromosome 10, phosphorylation of AKT to an activated state, and odontogenic ameloblast-associated protein in gastrointestinal stromal tumors.

BACKGROUND: Approximately 15% of gastrointestinal stromal tumors (GISTs) will not respond to tyrosine kinase inhibitors and drug resistance can develop over time. For refractory tumors, additional therapies are needed. Odontogenic ameloblast-associated protein (ODAM) is expressed in some epithelial malignancies and can correlate with clinical outcomes. This study evaluated ODAM and its relationship to phosphatase and tensin homolog on chromosome 10 (PTEN) and phosphorylation of AKT to an activated state (pAKT) in GISTs. MATERIALS AND METHODS: Ninety-five distinct tumor specimens from 79 patients were identified. Morphologic features and clinical data were recorded for all tumors. Risk of recurrence was calculated using the Memorial Sloan-Kettering nomogram. Immunohistochemistry was performed using antibodies to ODAM, PTEN, and pAKT. Immunoreactivity was assessed for both cytoplasmic and nuclear expression. Staining patterns were correlated with clinical outcomes. RESULTS: Increasing cytoplasmic ODAM staining correlated with a lower recurrence score (P = 0.002), a lower mitotic rate (P = 0.0001), and smaller tumor size (P = 0.038). Increasing pAKT cytoplasmic staining correlated with a higher recurrence score (P = 0.037) and a higher mitotic rate (P = 0.036). ODAM and pAKT expression in the nucleus was associated with tumor origin. PTEN nuclear expression increased with increasing mitotic rate. pAKT expression increased in the cytoplasm and nucleus in high-risk tumors. CONCLUSIONS: Risk of recurrence correlated with cytoplasmic expression of ODAM and pAKT, whereas nuclear expression did not predict recurrence. The staining pattern for ODAM and pAKT in the cytoplasm may further clarify the risk of recurrence beyond the available nomograms. The increased expression of pAKT in the cytoplasm and nucleus of high-risk tumors suggests a potential target for systemic therapy.

Body Mass Index and Perioperative Complications After Esophagectomy for Cancer.

BACKGROUND: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after esophagectomy for cancer. METHODS: From our comprehensive esophageal cancer database consisting of 510 patients, we identified 166 obese (BMI ≥30), 176 overweight (BMI 25-29), and 148 normal-weight (BMI 20-24) patients. Malnourished patients (BMI of <20) were excluded. Incidence of preoperative risk factors and perioperative complications in each group were analyzed. RESULTS: The patient group consists of 420 men and 70 women with a mean age at time of surgery were 64 years (range 28-86 years). The categories of patients (obese, overweight, and normal-weight) were similar in terms of demographics and comorbidities, with the exception of a younger age (62.5 years vs 66.2 years vs 65.3 years, P = 0.002), and a higher incidence of diabetes (23.5% vs 11.4% vs 10.1%, P = 0.001) and hiatal hernia (28.3% vs 14.8% vs 20.3%, P = 0.01) for obese patients. More patients with BMI >24 were found with adenocarcinoma, compared with the normal-weight group (90.8% vs 90.9% vs 82.5%, P = 0.03). Despite similar preoperative stage, obese patients were less likely to receive neoadjuvant treatment (47.6% vs 54.5% vs 66.2%, P = 0.004). The type of surgery performed, overall blood loss, extent of lymphadenectomy, rate of resections with negative margins, and postoperative complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, BMI did not affect number of harvested lymph-nodes, rates of negative margins, and morbidity and mortality after esophagectomy for cancer. In our experience, esophagectomy could be performed safely and efficiently in mildly obese patients.

Dorsiflexion assist orthosis reduces the physiological cost and mitigates deterioration in strength and balance associated with walking in people with multiple sclerosis.

OBJECTIVE: To evaluate the effect of wearing a dorsiflexion assist orthosis (DAO) on walking distance, physiological cost, fatigue, and strength and balance measures after a modified 6-minute walk test (6MWT) in people with multiple sclerosis (MS). DESIGN: Randomized crossover trial. SETTING: Hospital Movement Laboratory. PARTICIPANTS: People with moderate MS and Expanded Disability Status Scale score of 3.7±0.7 (N=34; 26 women). INTERVENTIONS: Modified 6MWT with and without a DAO worn on the weaker leg. MAIN OUTCOME MEASURES: Distance walked, perceived fatigue, and the physiological cost of walking were compared between walking conditions. Pre- and postwalk changes in knee extensor and ankle dorsiflexor isometric strength and standing postural sway with eyes open and closed were compared between walking conditions. RESULTS: There were no differences in distance walked or perceived fatigue between the 2 walking conditions. However, there was a reduced physiological cost of walking (P<.05), a smaller reduction in knee extensor strength (P<.05), and a smaller increase in standing postural sway with eyes open (P<.01) after walking while wearing the DAO compared with walking without wearing the DAO. CONCLUSIONS: Despite not increasing walking distance or reducing perceived fatigue, the DAO reduced the physiological cost of walking and maintained knee strength and standing balance, which may have important implications for physical rehabilitation in people with MS. Further trials are required to determine whether the beneficial effects of wearing a DAO found here are maintained for longer periods.

Is the TNM staging system for breast cancer still relevant in the era of biomarkers and emerging personalized medicine for breast cancer - an institution's 10-year experience.

We have previously demonstrated that TNM status and age were significant predictors of overall survival (OS) in our study population of Caucasian patients with invasive breast carcinoma (2000-2004 study period). However, estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) biomarker expression was not predictive of OS when using the five-group ER/PR/HER2 subtype classification system recommended by St. Gallen International Consensus Panel in 2011. The current study reassessed the relevance of tumor biomarkers (ER/PR/HER2) in our study population using a recently proposed biologic TNM (bTNM) classification system in which the inclusion of triple negative ER/PR/HER2 phenotype (TNP) could improve the prognostic accuracy of TNM for staging, prognosis and treatment of breast cancer patients. Seven hundred eighty-two Caucasian women diagnosed with invasive ductal carcinoma from 1998 to 2008 were grouped according to their TNM stage and TNP versus non-TNP ER/PR/HER2 phenotype. OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis. TNM stage (Stage II = HR 1.41, 95% CI 1.01-1.97; Stage III = HR 3.96, 95% CI 2.68-5.88; Stage IV = HR 27.25, 95% CI 16.84-44.08), and age (HR 1.05, 95% CI 1.04-1.06) were significant predictors of OS. TNP significantly worsened prognosis/survival only in higher TNM stages (Stage III = HR 3.08, 95% CI 1.88-5.04, Stage IV = HR 24.36, 95% CI 13.81-42.99), but not in lower stages (I and II). Our data support the traditional TNM staging as a continued relevant predictive tool for breast cancer outcomes and show that biomarkers primarily improve the accuracy of TNM staging in advanced stages of breast cancer. We suspect that type of ER/PR/HER2 classification system(s) (St. Gallen, TNP, etc.), characteristics of populations studied (Caucasians, minorities, etc.), and the time period chosen for a study are major factors that determine impact of biomarkers on the prognostic accuracy of TNM. We propose systematic analyses of these factors before biomarkers are fully incorporated into the TNM staging system (bTNM).

The role of the physiotherapist in concussion.

In the last decade, concussion research has exploded in multiple fields of scientific research. This has helped to clarify what causes, influences, and perpetuates human concussion, and displays the integral role physiotherapists play in concussion management. In this article we discuss the latest research relevant to the key role of physiotherapy in concussion management. A narrative review of the literature on concussion was conducted. The current review analyses how concussion has influenced physiotherapy in several categories: assessment, treatment, management, research rigour and building the profile of the profession. Scientific concussion research has largely converged in support of the role of physiotherapists utilising specific components including: (1) autonomic, (2) cervicogenic, (3) vestibulo-ocular and (4) psychological approaches to management. Latest research supports the critical role of physiotherapy in concussion care in the assessment, management, and prevention of concussion with scope for further interdisciplinary collaborations. Clinical implications: Concussion is complex. A basic mental health, Vestibular Ocular Motor Screening (VOMS) and four key components relating to concussion management (autonomic, cervicogenic, vestibular oculomotor, and psychological approaches to management) should be included in the undergraduate and postgraduate curriculum. This will aid clinical physiotherapists to support their patients. A call to advance more intradisciplinary physiotherapy teamwork should be encouraged as valuable knowledge sharing is potentially lost within the framework of 'specialisation'. If needed, the skills of a greater interdisciplinary team are imperative to facilitate patient management and recovery from this multi-faceted injury.

Further Distance From Treating Facility is Associated With Advanced Colon Cancer at Presentation and Increased Mortality.

BACKGROUND: Colon cancer outcomes in the United States have improved over the last thirty years. However, there remain significant outcome disparities, especially in rural regions. It is unclear if distance to the treating facility has an independent effect on colon cancer mortality and outcomes. We sought to evaluate whether distance from a treating facility impacts stage at diagnosis and mortality. METHODS: The National Cancer Database (NCDB) was utilized to identify a cohort of adult patients with colon cancer between the years 2013 and 2017 in all regions of the United States. Outcomes measured included colon cancer TNM stage, time to surgery, time to chemotherapy, and overall survival. RESULTS: A total of n = 356,189 patients met inclusion criteria. When controlling for race, education status, insurance status, comorbidities, and income, distance from the treating facility was a significant predictor of stage at presentation with more advanced clinical TNM stage as distance increased (AORs 1.12-1.62, P < .001 for all groups). Longer distance significantly increased the time to surgery (between 5.06 and 14.46 days, P < .001) and overall mortality (HR 1.11-1.28, P < .001). Median survival was 82.4 months for the closest group, versus 75.1 months for the farthest group (P < .001). CONCLUSIONS: Increased distance from the treating facility resulted in a significantly higher stage at presentation, increased time to surgery, and increased mortality. These results suggest that there are significant disparities in access to cancer care for patients who live in rural areas. Targeted interventions by treating facilities are needed to improve screening and timely treatment for rural colon cancer patients.

The impact of age on morbidity and mortality following esophagectomy for esophageal cancer.

BACKGROUND: In patients with esophageal cancer, treatment decisions often involve a balance between a high-risk procedure and the chance for long-term benefit. The decision can be additionally challenging for elderly patients since some studies have reported an increased incidence of morbidity and mortality in this age group, and data are not clear on the overall benefit of multimodality therapy. METHODS: To investigate the management and outcomes associated with esophagectomy in elderly patients with esophageal cancer, we performed a review of the literature as well as an analysis of our own institutional data, with a focus on the impact of age on surgical outcomes. We examined type of surgery, neoadjuvant and adjuvant therapy, postoperative complications, length of hospitalization, and mortality as variables in elderly patients with esophageal cancer. RESULTS: When assessing the impact of age on the success of esophagectomy, several studies have concluded that advanced age itself is not a predictor of outcomes as much as associated comorbidities are. Our own experience suggests that age is not associated with adverse outcomes when controlling for patient comorbidities. This finding is similar to data reported elsewhere. CONCLUSIONS: When considering treatment for patients of advanced age, the risks of treatment should be compared with the survival benefits of the therapy prescribed, taking into account additional factors such as poor performance status, existing comorbidities, and residual tumor following neoadjuvant therapy. Many reports, as well as our own experience, have concluded that when adjusted for comorbidities, patient age does not significantly affect outcomes.

Concussion Rehabilitation and the Application of Ten Movement Training Principles.

Concussion awareness continues to grow in all aspects of healthcare, including the areas of prevention, acute care, and ongoing rehabilitation. Most of the concussion research to date has focussed on the challenges around screening and diagnosing what can be a complex mix of brain impairments that overlay with additional pre-existing comorbidities. While we expect further progress in concussion diagnosis, progress also continues to be made around proactive rehabilitation, with the emergence of interventions that can enhance the recovery process, maximise function and independence with a return to study, work, and play. Traditionally, optimal multimodal assessments of concussion have treated the physical, cognitive, and psychological domains of brain injury separately, which supports diagnosis, and informs appropriate follow-up care. Due to the complex nature of brain injury, multimodal assessments direct care toward professionals from many different disciplines including medicine, physiotherapy, psychology, neuropsychology, ophthalmology, and exercise physiology. In addition, these professionals may work in different fields such as sports, neurorehabilitation, vestibular, musculoskeletal, community, vocational, and general practice clinical settings. Rehabilitation interventions for concussions employed in practice are also likely to use a blend of theoretical principles from motor control, cognitive, and psychological sciences. This scale of diversity can make information dissemination, collaboration, and innovation challenging. The Ten Movement Training Principles (MTPs) have been proposed as a usable and relevant concept to guide and support clinical reasoning in neurorehabilitation. When applied to concussion rehabilitation, these same 10 principles provide a comprehensive overview of key rehabilitation strategies for current and future practice. Future collaborations can use these training principles to support clinical and research innovations including the rapid rise of technologies in this growing field of rehabilitation practice.

When to Consider Lynch Syndrome in Non-Colon and Non-Endometrial Malignancies.

Lynch syndrome (LS) is a common genetic syndrome characterized by pathogenic mutations of DNA mismatch repair genes resulting in a hereditary predisposition to cancer. While typically associated with colonic and endometrial cancer, LS additionally influences the development of many other malignancies. The Amsterdam II and Revised Bethesda Guidelines are the established clinical criteria for diagnosing LS. These guidelines are based on the most general characteristics of LS and do not address specific characteristics of the less commonly LS-associated malignancies. For individuals that present initially with a non-colon and non-endometrial malignancy, recommendations and guidelines on when to consider screening for LS are limited. Therefore, it is essential that clinicians are familiar with distinct LS-associated patient- and tumor-specific characteristics, especially of the less common LS-associated cancers, so that LS's diagnosis is not missed. In this review article, we focus on extra-colonic and extra-endometrial LS-associated cancers, paying particular attention to any established or currently investigated cancer features that help raise suspicion for LS and potentially lead to its earlier diagnosis. This review will also discuss current guidelines specific to each LS-associated malignancy.

A Novel Preoperative Patient Survey Predicts Adverse Patient Outcomes-Implementation and Preliminary Results of the Tennessee Preoperative Assessment Tool.

BACKGROUND: Accurate preoperative risk stratification remains elusive. Existing tools are often missing important patient-reported and functional factors. We sought to implement a novel tool, with dynamic functional data and comorbidity variables, to define factors which predict postoperative outcomes. MATERIALS AND METHODS: We expanded a previously validated functional questionnaire to create the Tennessee Preoperative Assessment Tool (TPAT). Unique elements included change in functional status, usual and best activity tolerance, and development of new conditions. The survey was administered to all new patients seen in several surgery clinics from July 2021 to June 2022. RESULTS: A total of 1950 patients completed the survey. Of the completed surveys, 197 patients underwent an elective, inpatient, abdominal surgery and were included in the study. Several patient-reported factors were associated with poor postoperative outcomes. For example, decrease in functional activity in the previous 60 days (n = 50; 25.4%) was a strong predictor of poor postoperative outcomes including readmission (30-day: 8.8% vs .0%; P = .034), wound dehiscence (12.0% vs 3.4%; P = .022), blood transfusion (6.0% vs .0%; P = .003), sepsis (4.0% vs .0%; P = .015), and wound infection (18.0% vs 6.8%; P = .076). DISCUSSION: In this preliminary implementation study, patients undergoing elective, inpatient, abdominal surgery, utilization of a novel, patient-reported survey tool proactively identifies patients at risk of clinically relevant postoperative outcomes. Patient-reported decreased activity in the 60 days prior to surgeon evaluation was associated with several adverse postoperative outcomes. Additionally, this study demonstrates that the TPAT can be seamlessly integrated into the usual clinical workflow and is hypothesis generating for future interventional studies.

Dementia lifestyle coach pilot program.

OBJECTIVES: This study aimed to conduct a feasibility pilot of the Dementia Lifestyle Coach program; an individual coaching and counselling program for people recently diagnosed with dementia, to help them to adjust to the diagnosis and live well. METHODS: A randomised controlled pilot trial (n = 11) with wait-list control group was undertaken over 12 months. Intervention group participants received immediate personalised counselling from a registered psychologist and monthly support (face-to-face or by telephone) from a trained peer mentor living with dementia. The wait-listed control group commenced treatment 6 months after baseline. RESULTS: Recruitment and delivery of the Dementia Lifestyle Coach program was highly feasible. The program was acceptable, with nine of the 11 participants describing benefits including informational and emotional support, improving their outlook and mood, and family relationships. The planned program was adapted to participants' individual needs. CONCLUSIONS: This small pilot showed that it is feasible to recruit for and deliver a counselling and peer mentoring program for people recently diagnosed with dementia. A larger hybrid implementation randomised control trial should be conducted to evaluate efficacy and effectiveness.

Pathologic nonresponders after neoadjuvant chemoradiation for esophageal cancer demonstrate no survival benefit compared with patients treated with primary esophagectomy.

BACKGROUND: Neoadjuvant chemoradiation (NCRT) has become the preferred treatment for patients with locally advanced esophageal cancer. Survival often is correlated to degree of pathologic response; however, outcomes in patients who are found to be pathologic nonresponders (pNR) remain uninvestigated. This study was designed to evaluate survival in pNR to NCRT compared with patients treated with primary esophagectomy (PE). METHODS: Using our comprehensive esophageal cancer database, we identified patients treated with NCRT and deemed pNR along with patients who proceeded to PE. Clinical and pathologic data were compared using Fisher's exact and χ(2), whereas Kaplan-Meier estimates were used for survival analysis. RESULTS: We identified 63 patients treated with NCRT and were found to have a pNR, and 81 patients who underwent PE. Disease-free (DFS) and overall survival (OS) were significantly decreased in the pNR group compared with those treated with PE (10 vs. 50 months (0-152), P < 0.001 and 13 vs. 50 months (0-152), P < 0.001, respectively). For patients with stage II disease, DFS and OS were similarly decreased in pathologic nonresponders (13 vs. 62 months (0-120), P < 0.001 and 31 vs. 62 months (0-120), P = 0.024, respectively). There were no differences in DFS or OS for patients with stage III disease (10 vs. 14 months (0-152), P = 0.29 and 10 vs. 19 months (0-152), P = 0.16, respectively). CONCLUSIONS: Pathologic nonresponders to NCRT for esophageal cancer receive no benefit in DFS or OS compared with patients treated with PE. For patients with stage II disease, DFS and OS are, in fact, significantly decreased in the pNR.

Effect of wearing a dorsiflexion assist orthosis on mobility, perceived fatigue and exertion during the six-minute walk test in people with multiple sclerosis: a randomised cross-over protocol.

BACKGROUND: Fatigue in combination with gait and balance impairments can severely limit daily activities in people with multiple sclerosis (PWMS). Generalised fatigue has a major impact on walking ability, with moderately disabled PWMS experiencing difficulty in walking extended distances. Localised motor fatigue in the ankle dorsiflexors can lead to foot drop, further reducing functional ambulation. The aim of this study is to evaluate the effect of a simple dynamic dorsiflexion assist orthosis on walking-induced fatigue, gait, balance and functional mobility in PWMS. METHODS: A randomised cross-over trial will be conducted with 40 community dwelling PWMS with mild to moderate mobility disability. Participants will initially be screened for disease severity, balance, strength, depression and fatigue at the South Australian Motion Analysis Centre. On two non-consecutive occasions, within two weeks, participants will undergo either the 6-minute walk test (6MWT) or the 6MWT while wearing a dorsiflexion ankle orthosis (with a randomised condition order). Distance walked, perceived exertion, perceived fatigue and the physiological cost of walking (the primary outcome measures) will be compared between the two walking conditions. Additional pre- and post-6MWT assessments for the two conditions will include tests of strength, reaction time, gait and balance. DISCUSSION: This study will increase our understanding of motor fatigue on gait and balance control in PWMS and elucidate the effect of a Dynamic Ankle Orthosis on fatigue-related balance and gait in PWMS. It will also examine relationships between mobility and balance performance with perceived fatigue levels in this group. TRIAL REGISTRATION NUMBER: ACTRN12612000218897.

Impact of the COVID-19 pandemic on patients with pre-existing mood disorders.

OBJECTIVES: To examine the psychological and social impact of the COVID-19 pandemic on patients with established mood disorders during a period of stringent mandated social restrictions. METHODS: Semi-structured interviews were conducted with 36 individuals attending the Galway-Roscommon Mental Health Services with an International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10) diagnosis of either Bipolar Affective Disorder (BPAD) (n = 20) or Emotionally Unstable Personality Disorder (EUPD) (n = 16) in this cross-sectional study. We determined the impact of the COVID-19 restrictions on anxiety and depressive symptoms, impulsivity, thoughts of self-harm, social and occupational functioning and quality of life. RESULTS: The COVID-19 pandemic deleteriously impacted mental health (56.3% v. 15.0%, χ2 = 7.42, p = 0.02), and mood (75.0% v. 20.0%, χ2 = 11.17, p = 0.002) to a greater extent in the EUPD compared to the bipolar disorder cohort, with 43.8% of individuals with EUPD reporting an increase in suicidal ideation. Psychometric rating scales [Beck Anxiety Inventory (BAI), Beck Depression Scale (BDS), Beck Hopelessness Scale (BHS), Barratt Impulsivity Scale (BIS)] and Likert scales for anxiety, mood and quality of life noted significantly higher levels of psychopathology in the EUPD cohort (p < 0.01). Qualitative analysis reflected quantitative data with themes of the employment of maladaptive coping mechanisms and reduced mental health supports notable. CONCLUSIONS: Individuals with EUPD are experiencing significant mental health difficulties related to the COVID-19 pandemic. The provision and recommencement of therapeutic interventions to this cohort, in particular, are warranted given the significant distress and symptoms being experienced.

Pyruvate kinase M1 regulates butyrate metabolism in cancerous colonocytes.

Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate. M1 and M2 are alternatively spliced isoforms of the Pkm gene. The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. We hypothesize that the PKM isoforms are involved in the shift away from butyrate oxidation towards glycolysis in CRC cells. Here, we find that PKM2 is increased and PKM1 is decreased in human colorectal carcinomas as compared to non-cancerous tissue. To test whether PKM1/2 alter colonocyte metabolism, we created a knockdown of PKM2 and PKM1 in CRC cells to analyze how butyrate oxidation and glycolysis would be impacted. We report that butyrate oxidation in CRC cells is regulated by PKM1 levels, not PKM2. Decreased butyrate oxidation observed through knockdown of PKM1 and PKM2 is rescued through re-addition of PKM1. Diminished PKM1 lowered mitochondrial basal respiration and decreased mitochondrial spare capacity. We demonstrate that PKM1 suppresses glycolysis and inhibits hypoxia-inducible factor-1 alpha. These data suggest that reduced PKM1 is, in part, responsible for increased glycolysis and diminished butyrate oxidation in CRC cells.

Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex.

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.