Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial.

AIMS/HYPOTHESIS: Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. METHODS: This study included adults (aged 20-86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. RESULTS: Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: -0.26 ± 0.64 vs -0.17 ± 0.62, p=0.44; GSRS: -0.35 ± 0.62 vs -0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: -0.47 ± 0.78 vs -0.33 ± 0.75, p=0.34; GSRS: -0.46 ± 0.90 vs -0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs -19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated. CONCLUSIONS/INTERPRETATION: Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04143269 FUNDING: The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045).

Early Economic Assessment of Faecal Microbiota Transplantation for Patients with Urinary Tract Infections Caused by Multidrug-Resistant Organisms.

INTRODUCTION: The use of faecal microbiota transplantation (FMT) to eradicate intestinal carriage of multidrug-resistant organisms (MDRO) has been described in case reports and small case series. Although few in numbers, these patients suffer from recurrent infections that may exacerbate both the patients' comorbidities and their healths. In the current study, we hypothesized that FMT for MDRO-related urinary tract infections (UTIs) reduces hospitalisations and associated costs. METHODS: In a cohort of patients referred for FMT from 2015 to 2020, we selected all patients who had consecutively been referred for eradication of MRDO carriage with UTIs. An early economic assessment was performed to calculate hospital-related costs. The overall study cohort was registered at ClinicalTrials, study identifier NCT03712722. RESULTS: We consecutively included five patients with UTIs caused by MDROs. Four of the patients were renal transplant recipients. Patients were followed for median 126 days (range 60-320), where the follow-up duration for each patient was aligned with the number of days from the first UTI to FMT. The median number of UTIs per patient dropped from 4 to 0. Investigating hospital costs, hospital admission days dropped by 87% and monthly hospital costs by 79%. CONCLUSIONS: FMT was effective in reducing the occurrence of UTIs and mediated a marked reduction in hospital costs. We suggest that this strategy is cost-effective. TRIAL REGISTRATION: ClinicalTrials, study identifier NCT03712722.

Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans-A Systematic Review and Treatment Guideline.

In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.

Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Clostridioides difficile infection is an urgent antibiotic-associated health threat with few treatment options. Microbiota restoration with faecal microbiota transplantation is an effective treatment option for patients with multiple recurring episodes of C difficile. We compared the efficacy and safety of faecal microbiota transplantation compared with placebo after vancomycin for first or second C difficile infection. METHODS: We did a randomised, double-blind, placebo-controlled trial (EarlyFMT) at a university hospital in Aarhus, Denmark. Eligible patients were aged 18 years or older with first or second C difficile infection (defined as ≥3 watery stools [Bristol stool chart score 6-7] per day and a positive C difficile PCR test). Patients were randomly assigned (1:1) to faecal microbiota transplantation or placebo administered on day 1 and between day 3 and 7, after they had received 125 mg oral vancomycin four times daily for 10 days. Randomisation was done by investigators using a computer-generated randomisation list provided by independent staff. Patients and investigators were masked to the treatment group. The primary endpoint was resolution of C difficile-associated diarrhoea (CDAD) 8 weeks after treatment. We followed up patients for 8 weeks or until recurrence. We planned to enrol 84 patients with a prespecified interim analysis after 42 patients. The primary outcome and safety outcomes were analysed in the intention-to-treat population, which included all randomly assigned patients. The trial is registered with ClinicalTrials.gov, NCT04885946. FINDINGS: Between June 21, 2021, and April 1, 2022, we consecutively screened 86 patients, of whom 42 were randomly assigned to faecal microbiota transplantation (n=21) or placebo (n=21). The trial was stopped after the interim analysis done on April 7, 2022 for ethical reasons because a significantly lower rate of resolution was identified in the placebo group compared with the faecal microbiota transplantation group (Haybittle-Peto boundary limit p<0·001). 19 (90%; 95% CI 70-99) of 21 patients in the faecal microbiota transplantation group and seven (33%, 95% CI 15-57) of 21 patients in the placebo group had resolution of CDAD at week 8 (p=0·0003). The absolute risk reduction was 57% (95% CI 33-81). Overall, 204 adverse events occurred, with one or more adverse events being reported in 20 of 21 patients in the faecal microbiota transplantation group and all 21 patients in the placebo group. Diarrhoea (n=23 in the faecal microbiota transplantation group; n=14 in the placebo group) and abdominal pain (n=14 in the faecal microbiota transplantation group; n=11 in the placebo group) were the most common adverse events. Three serious adverse events possibly related to study treatment occurred (n=1 in the faecal microbiota transplantation group; n=2 in the placebo group), but no deaths or colectomies during the 8-week follow-up. INTERPRETATION: In patients with first or second C difficile infection, first-line faecal microbiota transplantation is highly effective and superior to the standard of care vancomycin alone in achieving sustained resolution from C difficile. FUNDING: Innovation Fund Denmark.

Assessment of Gastrointestinal Autonomic Dysfunction: Present and Future Perspectives.

The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson's disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals.

AIM: Since GH stimulates lipolysis in vivo after a 2-hr lag phase, we studied whether this involves GH signaling and gene expression in adipose tissue (AT). METHODS: Human subjects (n = 9) each underwent intravenous exposure to GH versus saline with measurement of serum FFA, and GH signaling, gene array, and protein in AT biopsies after 30-120 min. Human data were corroborated in adipose-specific GH receptor knockout (FaGHRKO) mice versus wild-type mice. Expression of candidate genes identified in the array were investigated in 3T3-L1 adipocytes. RESULTS: GH increased serum FFA and AT phosphorylation of STAT5b in human subjects. This was replicated in wild-type mice, but not in FaGHRKO mice. The array identified 53 GH-regulated genes, and Ingenuity Pathway analysis showed downregulation of PDE3b, an insulin-dependent antilipolytic signal, upregulation of PTEN that inhibits insulin-dependent antilipolysis, and downregulation of G0S2 and RASD1, both encoding antilipolytic proteins. This was confirmed in 3T3-L1 adipocytes, except for PDE3B, including reciprocal effects of GH and insulin on mRNA expression of PTEN, RASD1, and G0S2. CONCLUSION: (a) GH directly stimulates AT lipolysis in a GHR-dependent manner, (b) this involves suppression of antilipolytic signals at the level of gene expression, (c) the underlying GH signaling pathways remain to be defined.

The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials.

BACKGROUND: Recent randomised phase III trials have led to the approval of several immune checkpoint inhibitors for unresectable or metastatic melanoma (MM). These trials all employed strict patient selection criteria, and it is currently unknown how large proportion of 'real-world' patients diagnosed with MM is not represented in these trials. PATIENTS AND METHODS: The Danish MM Database contains data on the entire, unselected population of MM within a nationwide geographical area. A total of 276 unselected cases of MM (ocular melanoma excluded), referred for first oncological evaluation in 2014, were included in the analysis. Seven pre-defined eligibility criteria, all used to select patients for enrolment in five recent randomised phase III immunotherapy trials, were analysed. RESULTS: Fifty-five percent of the total population with MM did not meet one or more eligibility criteria ('not eligible' group) at first evaluation. PS ≥ 2 or active/untreated known brain metastases accounted alone for 74% of non-eligibility cases. Median overall survival in the 'not eligible' group was 5.43 months versus 18.3 months for the eligible (p < 0.0001, hazard ratio (HR) 2.44), reflected by significantly worse baseline prognostic features. However, patients treated with immunotherapy had similar survival outcomes regardless of eligibility. CONCLUSION: Over half of the patients evaluated for systemic treatment of MM are not represented in phase III registration immunotherapy trials. The data reveal a huge knowledge gap regarding the usefulness of new immunotherapies in the 'real-world' patient population, and urge additional testing of known regimens in selected poor prognosis cohorts.

Growth Hormone and Insulin Signaling in Acromegaly: Impact of Surgery Versus Somatostatin Analog Treatment.

CONTEXT: Somatostatin analogs (SAs) used in acromegaly to suppress GH secretion and tumor growth also suppress insulin secretion and may impact GH signaling. OBJECTIVE: To compare GH and insulin signaling after iv GH exposure in acromegalic patients controlled by surgery (n = 9) or SA (n = 9). DESIGN: Each patient was studied for 3 hours after an overnight fast (t = -60 to 120 minutes). GH was administered at t = 0 minutes; muscle and fat biopsies were obtained at t = 0 minutes and at t = 30 minutes (muscle) and t = 120 minutes (fat). Interstitial fluid was obtained from skin suction blisters (t = 0 minutes). MAIN OUTCOME MEASURES: GH and insulin signalling in muscle and fat. GH and IGF-1 in serum and interstitial fluid; insulin and free fatty acids in serum. RESULTS: The groups were comparable as regards GH and IGF-1. The SA group exhibited higher free fatty acid and glucose levels; basal suppressor of cytokine signaling protein 1 (SOCS1) mRNA in fat was increased in the SA group and correlated positively with SA dose (r2 = 0.54; P = .04). GH-induced GH signalling (pSTAT5b) in muscle occurred in both groups together with increased expression of SOCS and CISH genes. GH-induced pAKTthr308 was observed in SA patients. In both groups, mRNA expression of phosphatase and tensin homolog, a suppressor of insulin signaling, increased in fat after GH. CONCLUSION: 1) Signatures of GH and insulin signaling differ as a function of acromegaly treatment modality. 2) Extra-pituitary effects of SA may account for this. 3) The clinical implications remain to be investigated.

Metabolic liver function after stereotactic body radiation therapy for hepatocellular carcinoma.

Purpose The time course of changes of the liver function after stereotactic body radiotherapy (SBRT) was analyzed in patients treated for non-resectable hepatocellular carcinoma (HCC). Patients and methods Twenty-six patients with non-resectable HCC treated with SBRT were included in this study. Clinical, biochemical and treatment-related parameters were retrospectively collected. S-albumin, s-bilirubin, s-alkaline phosphatase (AP) and s-alanine transaminase (ALAT) at 0, 3, 6, and 12 months after radiotherapy were analyzed. Results Seventeen and nine patients were Child-Pugh class A and B, respectively. The liver was exposed to relatively high radiation doses with mean doses of 1.9-26 Gy. None of the patients developed classic radiotherapy-induced liver disease (RILD), but two patients developed non-classic RILD. Two patients developed grade 3 ascites and no grade 4-5 toxicities were observed. Six patients declined in Child-Pugh class. The s-albumin decreased significantly from a pretreatment median of 37.4-34.36 g/l at three months after SBRT and stabilized thereafter. S-bilirubin, s-AP and s-ALAT did not change significantly over the study period. Conclusion Despite the fact that patients received high radiation dose to the liver, there was only moderate morbidity related to the treatment. The s-albumin decreases over three months after SBRT reflecting minor to moderate hepatic toxicity. S-albumin should be observed in the follow-up of HCC patients treated with SBRT.

Bowel function after laparoscopic posterior sutured rectopexy versus ventral mesh rectopexy for rectal prolapse: a double-blind, randomised single-centre study.

BACKGROUND: Laparoscopic ventral mesh rectopexy for rectal prolapse has been widely used over the past decade to reduce postoperative functional bowel disorders. We aimed to compare changes in functional outcome 12 months after laparoscopic ventral mesh rectopexy versus laparoscopic posterior sutured rectopexy in patients with rectal prolapse. METHODS: In this double-blind, randomised trial, consecutive patients aged 18 years or older at a single centre in Denmark with full-thickness rectal prolapse were randomly assigned (1:1) to either laparoscopic ventral mesh rectopexy or laparoscopic posterior sutured rectopexy by drawing numbers from opaque envelopes, in blocks of four for patients with or without preoperative constipation. Functional assessment was done preoperatively and 12 months postoperatively. The primary outcome was preoperative-to-postoperative change in obstructed defecation syndrome (ODS) score. Patients and those assessing the outcomes were masked to the procedure. The primary analysis was done in the per-protocol population. Safety outcomes were assessed in the entire cohort. The trial is registered with ClinicalTrials.gov, number NCT00946205. FINDINGS: From Nov 1, 2006, to Jan 31, 2014, 75 consecutive patients were assigned to laparoscopic posterior sutured rectopexy (n=37) or laparoscopic ventral mesh rectopexy (n=38). Eight patients withdrew consent to follow-up, leaving 34 patients in the posterior sutured rectopexy group and 33 in the ventral mesh rectopexy groups for the primary analysis. The preoperative-to-postoperative reduction in ODS score was 1·97 (95% CI 0·01 to 3·93) in patients who received ventral mesh rectopexy and 2·18 (-0·14 to 4·49) in those who received posterior sutured rectopexy (difference -0·21 [-3·19 to 2·78]; p=0·890). Postoperative surgical complications of Clavien-Dindo grade II or worse were reported in one (3%) of 38 patients in the ventral mesh rectopexy group (ureteral injury resulting in urine leakage, and a psoas abscess) and one (3%) of 37 patients in the posterior sutured rectopexy group (haematoma and pelvic abscess). Two (5%) patients in the posterior sutured rectopexy group developed recurrence within 12 months compared with none in the ventral mesh rectopexy group (p=0·305). INTERPRETATION: Functional outcome measured by preoperative-to-postoperative change in ODS score was not significantly superior in patients who underwent ventral mesh rectopexy compared with those who had posterior sutured rectopexy. Additional, large, randomised, multicentre studies with long-term outcomes are warranted. FUNDING: None.