Anal dysplasia and anal cancer screening practices among liver transplant centers in the United States: Results of an online survey.

BACKGROUND: Solid organ transplant recipients are at an increased risk for anogenital Human Papillomavirus (HPV)-related disease, including anal high-grade squamous intraepithelial lesions (HSIL) and anal squamous cell cancer (ASCC). Guidelines for ASCC screening in transplant recipients are limited. Our aim was to understand current practice of ASCC screening in adult liver transplant (LT) candidates and recipients at transplant centers across the United States. METHODS: We surveyed medical directors of 113 LT centers across the United States which had publicly available contact information. The survey evaluated center perceptions on cancer and HPV disease risk in transplant populations, ASCC screening, barriers and facilitators for ASCC screening and HPV vaccination practices. RESULTS: We received 26/113 (23%) responses, of which 24 were complete and included in the analysis. Eleven of 24 (46%) centers reported screening for ASCC and 3/24 (12.5%) centers reported having formal guidelines. Centers who perform ASCC screening were more likely to perform transplants in people living with HIV and were more aware of the burden of HPV disease in transplant populations. All respondents believed that additional data on the impact of screening on ASCC incidence would support screening decisions. Increased access to specialists for screening/high-resolution anoscopy was also perceived as a facilitator. Only 7/24 (29%) centers regularly evaluated HPV vaccination status of their patients. CONCLUSION: This national survey of LT centers reveals non-standardized ASCC screening practices, and identified data, educational and resource needs to improve prevention of ASCC in this population.

Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis-related fatigue.

BACKGROUND: Fatigue is the most common symptom of MS and has no effective pharmacotherapy. OBJECTIVE: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. METHODS: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models. RESULTS: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (-0.10 point; 95% confidence interval (CI): -0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (-5.2 points; 95% CI: -10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (-13.5 point; 95% CI: -25.0, -1.98; p = 0.04). CONCLUSIONS: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.

BACKGROUND: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. METHODS: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. FINDINGS: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). INTERPRETATION: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. FUNDING: Patient-Centered Outcomes Research Institute.

The importance of anal cancer screening and high-resolution anoscopy to gastroenterology practice.

PURPOSE OF REVIEW: Although human papillomavirus (HPV)-related anal squamous cell cancer (ASCC) is rare, its incidence has been rising and in high-risk populations exceeds the incidence of cancers for which screening programs are implemented. Therefore, targeted screening techniques are being evaluated with high-resolution anoscopy (HRA) as the current gold standard because of its ability to detect anal intraepithelial dysplasia (AIN) and premalignant high-grade squamous intraepithelial lesions (HSILs). However, a scarcity of trained providers presents a barrier to screening. RECENT FINDINGS: ASCC incidence is rising especially in elderly women and young black men. Premalignant HSIL may not only progress to ASCC but also regress. Biomarkers such as HPV type, p16 immunostaining and DNA methylation markers may emerge as predictors of disease progression.HRA with acetic acid and Lugol's iodine staining can be used to detect HSIL and ASCC. Recent studies suggest that anal cancer screening may have an impact on the stage of ASCC at diagnosis and the incidence of anal cancer.The Anal Cancer HSIL Outcomes Research (ANCHOR) study is underway to determine whether treating HSIL effects ASCC incidence. SUMMARY: Although there are no consensus screening guidelines for anal cancer, it is reasonable to screen high-risk populations with physical examination, anal cytology and HRA. Gastroenterologists can support anal cancer screening programmes through identifying patients at risk, performing noninvasive screening and considering to incorporate endoscopic techniques to examine the anal canal. VIDEO ABSTRACT: http://links.lww.com/COG/A32.

Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence.

Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a Gq-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.

Advance care planning in residential aged care facilities.

A person's right to self-determination in health care is now a fundamental principle of health care provision. As a consequence Advance Care Planning (ACP) is a critical issue in health care including palliative care as it is seen as a way of ensuring a person's right to participate not only in future health care choices but in end of life decision making. To date there have been few reports of successful ACP programs. In 2004 and 2005 a program of advance care planning, known as Respecting Patient Choices was introduced in 17 residential aged care facilities in metropolitan Melbourne, Australia. This program consisted of a system-wide approach that included education for aged care staff; information for residents and families as well as changes to organisational processes to ensure that residents have opportunity for self-determination in their future health care. This paper will report on the lessons learnt from this implementation and identify strategies which foster sustainability of ACP.