Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Robotic-Assisted Surgery Training (RAST): Assessment of Surgeon Console Ergonomic Skills.

OBJECTIVE: The aim of this study was to evaluate the responsiveness of postgraduate year (PGY) general surgery residents (GSRs) to surgeon console ergonomics within the robotic-assisted surgery training (RAST) program. DESIGN: This was a prospective educational study. GSRs were prepared with a pretraining educational video. Faculty provided one-on-one resident hands-on training and testing. Nine proficiency criteria (emergency stop & recover; left side pod adjustments; touchpad controls; footswitch panel; energy control pedals; camera control & focus; arm swap; master & finger clutch; dual console settings control) were assessed with a 5-point Likert-scale. Responsiveness was defined as change in performance over time. The robotic platform was Da Vinci Xi (Intuitive Surgical, Sunnyvale, CA). The Dundee ready educational environment measure (DREEM) inventory was used by GSRs to assess the educational environment. SETTING: Tertiary care academic teaching institution. PARTICIPANTS: A total of 22 GSRs: 4 PGY 1, 4 PGY 2, 4 PGY 3, 5 PGY 4, 5 PGY 5. RESULTS: From June 2022 to March 2023 the hands-on console time decreased at testing when compared to baseline: median 39.0 (range 37-41) vs 20.1 (range 19-22) minutes, respectively. There was no difference in mean hands-on testing scores stratified by PGY: 4.85±0.4 PGY1; 4.98 ± 0.3 PGY2; 4.86 ± 0.4 PGY3, 4.88 ± 0.2 PGY4, and 4.91 ± 0.1 PGY5 (ANOVA test; p = 0.095). The overall DREEM score was 167.1 ± 16.9 with CAC = 0.908 (excellent internal consistency). CONCLUSIONS: Training in ergonomics on the surgeon console impacted the responsiveness of the GSRs with 51% console time reduction. There were no differences in hands-on testing scores among PGYs. Perception of the educational environment by the GSRs was high.

Diagnostic tools for assessment of urinary dysfunction in MS patients without urinary disturbances.

Many guidelines are available for the management of lower urinary tract symptoms (LUTSs) in multiple sclerosis (MS) patients, but no agreement exists on the best approach for subjects without LUTSs. The objective of this study was to evaluate whether LUTSs can be detected in MS patients asymptomatic for urinary dysfunction, comparing three different tools [measure of post-void residual volume (PRV), bladder diary (BD), a focused questionnaire (IPSS)], and whether disability, disease duration and signs of pyramidal involvement are linked to their subclinical presence. 178 MS patients (118 women) have been included (mean age 41.2 years, mean disease duration 11.3 years, mean EDSS 2.2), and tested with the above-mentioned tools. PRV was abnormal in 14 subjects (7.8%), associated to abnormal findings at IPSS in 3 cases, at BD in 2 cases, at both in 1. BD was abnormal in 37 subjects (20.8%), with concomitant abnormal PRV in 2, abnormal IPSS in 10 cases, abnormal IPSS and BD in 1. IPSS was ≥ 9 in 43 subjects (24.1%). At least one test was abnormal in 76 patients (42.7%): 1 in 57 patients (32.0%), 2 in 17 (9.5%), and 3 tests in 2 (1.1%). Patients with at least one abnormal urinary variable, compared to patients without urinary abnormalities, had a more frequent pyramidal involvement (69.5 vs. 16.8%, χ(2) = 48.6, p < 0.00001), a more frequent occurrence of EDSS ≥2 (83.1 vs. 23.5%, χ(2) = 56.9, p < 0.00001), and a longer disease duration (15.7 ± 7.3 vs. 9.1 ± 7.1, t = 5.7, p < 0.00001). Asymptomatic LUTS were frequent but none of the tests used permitted to better identify asymptomatic patients.

Simulated colonoscopy training using a low-cost physical model improves responsiveness of surgery interns.

AIM: Surgery residents are required to become proficient in colonoscopy before completing training. The aim of this study was to evaluate the responsiveness of surgery interns to simulated colonoscopy training. METHOD: Interns, defined as postgraduate year 1 residents without exposure to endoscopy, underwent training in a physical model including colonoscopy, synthetic anatomy trays with luminal tattoos and a hybrid simulator. After baseline testing and mentored training, final testing was performed using five predetermined proficiency criteria. Content-valid metrics defined by the extent of departure from clinical reality were evaluated by two blinded assessors. Responsiveness was defined as change in performance over time and assessed comparing baseline testing with nonmentored final testing. RESULTS: Twelve interns (eight male, mean age 26, 80% right-handed) performed 48 colonoscopies each over 1 year. Improvement was seen in the overall procedure time (24 min 46 s vs 20 min 54 s; P = 0.03), passing the splenic flexure (20 min 33 s vs 10 min 45 s; P = 0.007), passing the hepatic flexure (23 min 31 s vs 12 min 45 s; P = 0.003), caecal intubation time (23 min 38 s vs 13 min 26 s; P = 0.008), the duration of loss of view of the lumen (75% vs 8.3%; P = 0.023), incomplete colonoscopy (100% vs 33.3%; P = 0.042), colonoscope withdrawal < 6 min (16.7% vs 8.3%; P = 0.052). Tattoo identification time (9 min 16 s vs 12 min 25 s; P = 0.50), colon looped time (2 min 12 s vs 1 min 45 s; P = 0.50) and rate of colon perforation (8.3% vs 8.3%; P = 1) remained unchanged. Interrater reliability was 1.0 for all measures. CONCLUSION: Simulated colonoscopy training in a low-cost physical model improved the performance of surgery interns with decreased procedure time, increased rates of complete colonoscopy and appropriate scope withdrawal.

Hemorrhoidal dearterialization with mucopexy versus hemorrhoidectomy: 3-year follow-up assessment of a randomized controlled trial.

BACKGROUND: A randomized controlled trial showed that patients with grade III or IV internal hemorrhoids had similar symptomatic relief of symptoms up to 3 months following dearterialization with mucopexy or hemorrhoidectomy albeit with less postoperative pain after the former. This study aimed to compare hemorrhoidal recurrence and chronic complications at 3-year follow-up. METHODS: This study was carried out on 40 patients with grade III or IV internal hemorrhoids previously enrolled to a randomized trial comparing dearterialization to hemorrhoidectomy. Recurrence was defined as internal hemorrhoids diagnosed on proctoscopy. Chronic complications were nonresolving adverse events related to surgery. Outcome measures included patient-reported outcomes and quality of life measured by brief pain inventory (BPI), SF-12, and fecal incontinence surveys. RESULTS: At median follow-up of 36 (27-43) months, 13 patients (32.5 %) were lost to follow-up. Patient-reported outcomes suggested no difference between dearterialization and hemorrhoidectomy in persistent symptoms, occurring in 1 (8.3 %) vs. 2 (13.3 %) patients (p = 0.681) and in symptom recurrence, occurring in 6 (50 %) vs. 4 (26.7 %) patients (p = 0.212). On proctoscopy, recurrence was seen in 2 (13.3 %) vs. 1 (6.7 %) patients (p = 0.411), all with index grade IV disease. One patient in each arm required reoperation (p = 0.869). Chronic complications were not seen in the dearterialization arm while they occurred in 2 (13.3 %) hemorrhoidectomy patients (p = 0.189) and included unhealed wound (n = 1), anal fissure (n = 1) and fecal incontinence (n = 1). There was a trend toward more patient reported than actual recurrence on proctoscopy (10 vs. 3, p = 0.259). There was no difference in BPI, SF-12, and fecal incontinence quality of life scores. CONCLUSIONS: Recurrence rates did not differ significantly at 3-year follow-up and occurred in patients with index grade IV hemorrhoids. Chronic complications occurred only after hemorrhoidectomy.

The DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis.

Swallowing problems can be relevant, even if underestimated, in Multiple Sclerosis (MS) patients. However, no specific questionnaire for the assessment of dysphagia in MS is available. We built a questionnaire (DYsphagia in MUltiple Sclerosis, DYMUS) that was administered to 226 consecutive MS patients (168 F, 58 M, mean age 40.5 years, mean disease duration 10.1 years, mean EDSS 3.1) during control visits in four Italian MS Centres. DYMUS was abnormal in 80 cases (35%). The patients who claimed to have swallowing problems had a significantly higher mean DYMUS score that the other patients (p<0.0001). Mean DYMUS scores were significantly higher in the progressive forms (p=0.003). DYMUS values were significantly correlated to EDSS (p=0.0007). DYMUS showed a very good internal consistency (Cronbach's alpha 0.877). Factor analysis allowed us to sub-divide DYMUS in two sub-scales, 'dysphagia for solid' and 'dysphagia for liquid', both of them had a very good internal consistency (Cronbach's alpha 0.852 and 0.870 respectively). DYMUS demonstrated to be an easy and consistent tool to detect dysphagia and its main characteristics in MS. It can be used for preliminary selection of patients to submit to more specific instrumental analyses, and to direct toward programs for prevention of aspiration.

In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis.

In patients with primary progressive (PP) multiple sclerosis, brain MRI lesion activity and burden are low, despite the presence of severe neurological impairment. On the contrary, the degree of cord atrophy and diffuse tissue damage in the brain and cervical cord have been found to be associated with clinical disability. Against this background, this study aimed at providing an in vivo indirect assessment of brain and cervical cord pathology in a large cohort of PP multiple sclerosis patients, using conventional MRI and magnetization transfer imaging (MTI). Ninety-one PP multiple sclerosis patients, 36 secondary progressive (SP) multiple sclerosis patients and 30 healthy controls underwent brain and cervical cord MRI scans, using dual echo (brain) or fast short-tau inversion recovery (cervical cord) MTI and T(1)-weighted sequences. For the brain, T(2) hyperintense and T(1) hypointense lesion volumes were calculated and the volume of the whole of the brain tissue measured. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed. MTI scans were post-processed and analysed to obtain magnetization transfer ratio (MTR) histograms from the whole of the brain and cervical cord tissue and from the normal-appearing brain tissue in isolation. In PP multiple sclerosis patients, brain, normal-appearing brain tissue and cervical cord MTR histogram-derived metrics revealed the presence of diffuse tissue damage whose characteristics did not significantly differ from those of SP multiple sclerosis patients, even though SP multiple sclerosis patients had higher MRI-visible lesion burdens. None of the correlations between MRI or MTI measures obtained from the brain and the cord were significant. PP multiple sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of cervical cord tissue. Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP multiple sclerosis patients, whose extent seems to match that of SP multiple sclerosis patients with similar levels of disability. They also suggest that the severity of multiple sclerosis pathology in the cervical cord is one of the factors contributing to neurological impairment in PP multiple sclerosis.

Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis.

With the aid of a Bayesian statistical model of the natural course of relapsing remitting Multiple Sclerosis (MS), we identify short-term clinical predictors of long-term evolution of the disease, with particular focus on predicting onset of secondary progressive course (failure event) on the basis of patient information available at an early stage of disease. The model specifies the full joint probability distribution for a set of variables including early indicator variables (observed during the early stage of disease), intermediate indicator variables (observed throughout the course of disease, prefailure) and the time to failure. Our model treats the intermediate indicators as a surrogate response event, so that in right-censored patients, these indicators provide supplementary information pointing towards the unobserved failure times. Moreover, the full probability modelling approach allows the considerable uncertainty which affects certain early indicators, such as the early relapse rates, to be incorporated in the analysis. With such a model, the ability of early indicators to predict failure can be assessed more accurately and reliably, and explained in terms of the relationship between early and intermediate indicators. Moreover, a model with the aforementioned features allows us to characterize the pattern of disease course in high-risk patients, and to identify short-term manifestations which are strongly related to long-term evolution of disease, as potential surrogate responses in clinical trials. Our analysis is based on longitudinal data from 186 MS patients with a relapsing-remitting initial course. The following important early predictors of the time to progression emerged: age; number of neurological functional systems (FSs) involved; sphincter, or motor, or motor-sensory symptoms; presence of sequelae after onset. During the first 3 years of follow up, to reach EDSS> or =4 outside relapse, to have sphincter or motor relapses and to reach moderate pyramidal involvement were also found to be unfavourable prognostic factors.

Usefulness of Bayesian graphical models for early prediction of disease progression in multiple sclerosis.

Previous studies of possible prognostic indicators for multiple sclerosis have been based on "classic" Cox's proportional hazards regression model, as well as on equivalent or simpler approaches, restricting their attention to variables measured either at disease onset or at a few points during follow-up. The aim of our study was to analyse the risk of reaching secondary progression in MS patients with a relapsing-remitting initial course, using two different statistical approaches: a Cox's proportional-hazards model and a Bayesian latent-variable model with Markov chain Monte Carlo methods of computation. In comparison with a standard statistical approach, our model is advantageous because, exploiting all the information gleaned from the patient as it is gradually made available, it is capable to detect even small prognostic effects.

Immediately recognizable benefits and drawbacks after laparoscopic colon resection for benign disease.

BACKGROUND: A prospective assessment of the impact of laparoscopic colon resection (LCR) was carried out in order to quantify immediately recognizable benefits and limitations of this approach. METHODS: Elective LCR was attempted in 95 selected patients (mean age 64 years, range 39-81 years) presenting with benign disease of the colon. A completely intracorporeal approach was adopted. Results were compared with a control group of 90 patients who had previously undergone open colectomy (OC) by the same surgeons at the same institution. RESULTS: There were no perioperative deaths. Intraoperative complications included difficult extraction of accidentally detached anvil (n = 1), air leak at colonoscopy (n = 2), and conversion to OC (n = 1). Operating time was significantly longer after LCR compared with OC (180 +/- 10.3 vs 116 +/- 97, p < 0.001). Passage of flatus (3.5 +/- 1.2 days vs 4.4 +/- 1.4, p < 0.5) and morbidity (4 vs 3, p = 0.48) were not significantly different in the two groups. Hospital stay was significantly shorter after LCR (5.2 +/- 1.3 days vs 12.2 +/- 1.9 days, p < 0.001). Theater and ward costs were, respectively, significantly increased ($2,829.6 +/- 340 vs $1,422 +/- 318, p < 0.001) and decreased ($2,600 +/- 366 vs $6,022 +/- 916, p < 0.001) in LCR patients compared with the OC group. There was no significant difference in total hospital costs ($10,929 +/- 369 vs $9,944 +/- 1,014). CONCLUSIONS: LCR does not appear to offer any immediately recognizable advantages.

Accuracy of self-assessment of the minimal record of disability in patients with multiple sclerosis.

We tested the validity of a self-administered version of the minimal record of disability (MRD) for multiple sclerosis (MS) by measuring the agreement level between patients' self-assessment and neurologists' independent ratings. 96 MS patients and 4 neurologists took part in the experiment; the agreement level was measured in terms of the intraclass correlation coefficient (ICC). On the Kurtzke functional system (FS) the ICC ranged from 0.26 in the sensory to 0.69 in the pyramidal function; a high concordance (ICC = 0.84) was found on the expanded disability status scale (EDSS). The ICC values were above 0.70 for most of the incapacity status scale (ISS) and environmental status scale (ESS) items. A modified, self-administered version of the MRD may represent a reliable instrument for obtaining a comprehensive profile of patients' abilities.

Neuropsychological assessment in MS: clinical, neurophysiological and neuroradiological relationships.

We assessed cognitive performance and its relationship with clinical and anatomic disease severity in MS with mild to moderate handicap; 34 definite MS and 18 healthy subjects matched for age and education were submitted to a neuropsychological test battery. Both groups were examined for anxiety. MS patients underwent magnetic resonance imaging examination. MS performed worse than controls on all WAIS-P subtests and had learning, short- and long-term verbal memory impairment. Cognitive deficits were not related to abnormal emotional states, but were found to be associated with attentional process and information-processing speed impairment. Cognitive impairment did not correlate with severity of physical disability. The most severe memory deficits were found in patients with extensive periventricular damage.

Progress in the assessment of lymphatic spread in rectal cancer. Rectal endoscopic lymphoscintigraphy.

Rectal endoscopic lymphoscintigraphy was performed in 10 control subjects and in a series of 85 patients with adenocarcinoma of the rectum as a prospective study to evaluate lymphatic drainage of the rectum and lymphatic spread in rectal cancer. Complete cranial drainage was demonstrated in all control subjects, and internal iliac nodes were also visible in 50 percent of cases. Results were correlated with histologic node examination in all patients operated upon for rectal cancer. Rectal endoscopic lymphoscintigraphy was assessed for sensitivity (85 percent), specificity (68 percent), overall accuracy (76 percent), positive predictive value (71 percent), and negative predictive value (83 percent). False-negative and false-positive results are discussed. Rectal endoscopic lymphoscintigraphy represents the only method currently available for evaluation of lymphatic spread in rectal cancer.

Brainstem impairment in multiple sclerosis: an assessment by multimodal evoked potentials.

The usefulness of multimodal evoked potentials for the diagnosis of Multiple Sclerosis (MS) is established. Our purpose was to try to set of 3 EPs (BAEP, median SEP and trigeminal SEP) in the evaluation of brainstem dysfunction. 53 definite and probable MS patients have been examined; they were allotted to 3 groups according to the duration of the disease. Our results showed that median SEP is the most sensitive investigation, while BAEP and trigeminal SEP were abnormal in a smaller number of cases. The combined use of median and trigeminal SEPs supplied sufficient information on brainstem function, without using the complete set of EPs. No significant relation between EP abnormalities and duration of the disease was found.

A prospective study of current diagnostic procedures for assessment of hepatic metastases in colorectal cancers.

In a prospective study of 305 patients with colorectal cancers, we assessed the diagnostic value of ultrasonography and laboratory tests. In each case laparotomy was carried out and the presence of liver metastases was established in 47 patients. The results show that the laboratory tests alone are not sufficiently accurate to detect liver metastases. Additional accuracy can be obtained by the combined use of a single liver imaging test (echography) and selected laboratory tests (C.E.A., gamma GT, Alkaline Phosphatase).