Comparing open and minimally invasive surgical procedures for oesophagectomy in the treatment of cancer: the ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) feasibility study and pilot trial

Localised oesophageal cancer can be curatively treated with surgery (oesophagectomy) but the procedure is complex with a risk of complications, negative effects on quality of life and a recovery period of 6-9 months. Minimal-access surgery may accelerate recovery.The ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) study aimed to establish the feasibility of, and methodology for, a definitive trial comparing minimally invasive and open surgery for oesophagectomy. Objectives were to quantify the number of eligible patients in a pilot trial; develop surgical manuals as the basis for quality assurance; standardise pathological processing; establish a method to blind patients to their allocation in the first week post surgery; identify measures of postsurgical outcome of importance to patients and clinicians; and establish the main cost differences between the surgical approaches.Pilot parallel three-arm randomised controlled trial nested within feasibility work.Two UK NHS departments of upper gastrointestinal surgery.Patients aged ≥ 18 years with histopathological evidence of oesophageal or oesophagogastric junctional adenocarcinoma, squamous cell cancer or high-grade dysplasia, referred for oesophagectomy or oesophagectomy following neoadjuvant chemo(radio)therapy.Oesophagectomy, with patients randomised to open surgery, a hybrid open chest and minimally invasive abdomen or totally minimally invasive access.The primary outcome measure for the pilot trial was the number of patients recruited per month, with the main trial considered feasible if at least 2.5 patients per month were recruited.During 21 months of recruitment, 263 patients were assessed for eligibility; of these, 135 (51%) were found to be eligible and 104 (77%) agreed to participate, an average of five patients per month. In total, 41 patients were allocated to open surgery, 43 to the hybrid procedure and 20 to totally minimally invasive surgery. Recruitment is continuing, allowing a seamless transition into the definitive trial. Consequently, the database is unlocked at the time of writing and data presented here are for patients recruited by 31 August 2014. Random allocation achieved a good balance between the arms of the study, which, as a high proportion of patients underwent their allocated surgery (69/79, 87%), ensured a fair comparison between the interventions. Dressing patients with large bandages, covering all possible incisions, was successful in keeping patients blind while pain was assessed during the first week post surgery. Postsurgical length of stay and risk of adverse events were within the typical range for this group of patients, with one death occurring within 30 days among 76 patients. There were good completion rates for the assessment of pain at 6 days post surgery (88%) and of the patient-reported outcomes at 6 weeks post randomisation (74%).Rapid recruitment to the pilot trial and the successful refinement of methodology indicated the feasibility of a definitive trial comparing different approaches to oesophagectomy. Although we have shown a full trial of open compared with minimally invasive oesophagectomy to be feasible, this is necessarily based on our findings from the two clinical centres that we could include in this small preliminary study.Current Controlled Trials ISRCTN59036820.This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 48. See the NIHR Journals Library website for further project information

IL28B Alleles Exert an Additive Dose Effect When Applied to HCV-HIV Coinfected Persons Undergoing Peginterferon and Ribavirin Therapy

BACKGROUND: Genetic studies have demonstrated a strong association between single nucleotide polymorphisms (SNPs) at IL28B and response to treatment with peginterferon (PEG) and ribavirin (RBV) in HCV monoinfected persons. We sought to test these associations in a prospective PEG / weight based ribavirin (WBR) treatment trial (ACTG A5178) (National Institution of Health registration number NCT00078403) in persons with HCV-HIV coinfection, and to develop a prediction score. METHODS: We selected subjects enrolled in A5178 who completed at least the first 12 weeks of the trial and had DNA available, and genotyped three SNPs at IL28B (rs12979860, rs12980275, rs8099917). We used multivariate logistic regression analysis to evaluate the association between IL28B SNPs and HCV treatment outcomes and to develop the prediction score. RESULTS: 231 HCV/HIV coinfected subjects were included. We observed a strong association between IL28B genotype and response to therapy among those with genotypes 1 or 4 (odds ratio for complete early virologic responses (cEVR) and sustained virologic response (SVR) was 2.98 [1.7-5.3] and 3.4 [1.7-6.9], respectively, for each additional copy of the C allele of rs12979860). Differences in frequency of the responder allele explained some of the discrepancy in HCV treatment outcomes between blacks and whites. A simple pretreatment prediction score that incorporates the IL28B genotype and baseline HCV viral load has a 93% negative predictive value (NPV) for SVR. CONCLUSIONS: IL28B SNPs have an additive allele dose effect in predicting HCV treatment outcomes in HCV/HIV coinfected persons and can be incorporated into a simple pretreatment prediction score that could minimize the risk of exposure to PEG/RBV therapy for persons with unfavorable scores

Intercolony variation in reproductive skipping in the African penguin

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data underlying this article are available in the Dryad digital repository: https://doi.org/10.5061/dryad.0rxwdbs3z (Leith et al., 2022).In long-lived species, reproductive skipping is a common strategy whereby sexually mature animals skip a breeding season, potentially reducing population growth. This may be an adaptive decision to protect survival, or a non-adaptive decision driven by individual-specific constraints. Understanding the presence and drivers of reproductive skipping behavior can be important for effective population management, yet in many species such as the endangered African penguin (Spheniscus demersus), these factors remain unknown. This study uses multistate mark-recapture methods to estimate African penguin survival and breeding probabilities at two colonies between 2013 and 2020. Overall, survival (mean ± SE) was higher at Stony Point (0.82 ± 0.01) than at Robben Island (0.77 ± 0.02). Inter-colony differences were linked to food availability; under decreasing sardine (Sardinops sagax) abundance, survival decreased at Robben Island and increased at Stony Point. Additionally, reproductive skipping was evident across both colonies; at Robben Island the probability of a breeder becoming a nonbreeder was ~0.22, versus ~0.1 at Stony Point. Penguins skipping reproduction had a lower probability of future breeding than breeding individuals; this lack of adaptive benefit suggests reproductive skipping is driven by individual-specific constraints. Lower survival and breeding propensity at Robben Island places this colony in greater need of conservation action. However, further research on the drivers of inter-colony differences is needed.Association of Zoos and AquariumsBristol Zoological SocietyDepartment of Forestry, Fisheries, and the EnvironmentEarthwatch InstitutePew Charitable TrustsLeiden Conservation FoundationSANCCOBSan Diego Zoo Wildlife Allianc

Past Tense Formation in Williams Syndrome

It has been claimed that in the language systems of people with Williams syndrome (WS), syntax is intact but lexical memory is impaired. Evidence has come from past tense elicitation tasks with a small number of participants where individuals with WS are said to have a specific deficit in forming irregular past tenses. However, typically developing children also show poorer performance on irregulars than regulars in these tasks, and one of the central features of WS language development is that it is delayed. We compared the performance of 21 participants with WS on two past tense elicitation tasks with that of four typically developing control groups, at ages 6, 8, 10, and adult. When verbal mental age was controlled for, participants in the WS group displayed no selective deficit in irregular past tense performance. However, there was evidence for lower levels of generalisation to novel strings. This is consistent with the hypothesis that the WS language system is delayed because it has developed under different constraints, constraints that perhaps include atypical phonological representations. The results are discussed in relation to dual-mechanism and connectionist computational models of language development, and to the possible differential weight given to phonology versus semantics in WS development

Aspiration therapy for the treatment of obesity: 4-year results of a multicenter randomized controlled trial.

BackgroundThe AspireAssist is the first Food and Drug Administration-approved endoluminal device indicated for treatment of class II and III obesity.ObjectivesWe earlier reported 1-year results of the PATHWAY study. Here, we report 4-year outcomes.SettingUnited States-based, 10-center, randomized controlled trial involving 171 participants with the treatment arm receiving Aspiration Therapy (AT) plus Lifestyle Therapy and the control arm receiving Lifestyle Therapy (2:1 randomization).MethodsAT participants were permitted to continue in the study for an additional year up to a maximum of 5 years providing they maintained at least 10% total weight loss (TWL) from baseline at each year end. For AT participants who continued the study, 5 medical monitoring visits were provided at weeks 60, 68, 76, 90, and 104 and thereafter once every 13 weeks up to week 260. Exclusion criteria were a history of eating disorder or evidence of eating disorder on a validated questionnaire. Follow-up weight, quality of life, and co-morbidities were compared with the baseline levels. In addition, rates of serious adverse event, persistent fistula, withdrawal, and A-tube replacement were reported. All analyses were performed using a per-protocol analysis.ResultsOf the 82 AT participants who completed 1 year, 58 continued to this phase of the trial. Mean baseline body mass index of these 58 patients was 41.6 ± 4.5 kg/m2. At the end of first year (at the beginning of the follow-up study), these 58 patients had a body mass index of 34.1 ± 5.4 kg/m2 and had achieved an 18.3 ± 8.0% TWL. On a per protocol basis, patients experienced 14.2%, 15.3%, 16.6%, and 18.7% TWL at 1, 2, 3, and 4 years, respectively (P < .01 for all). Forty of 58 patients (69%) achieved at least 10% TWL at 4 years or at time of study withdrawal. Improvements in quality of life scores and select cardiometabolic parameters were also maintained through 4 years. There were 2 serious adverse events reported in the second through fourth years, both of which resolved with removal or replacement of the A tube. Two persistent fistulas required surgical repair, representing approximately 2% of all tube removals. There were no clinically significant metabolic or electrolytes disorders observed, nor any evidence for development of any eating disorders.ConclusionsThe results of this midterm study have shown that AT is a safe, effective, and durable weight loss alternative for people with class II and III obesity and who are willing to commit to using the therapy and adhere to adjustments in eating behavior

Patient understanding and acceptability of an early lung cancer diagnosis trial: a qualitative study

Background The ELCID (Early Lung Cancer Investigation and Diagnosis) trial was a feasibility randomised controlled trial examining the effect on lung cancer diagnosis of lowering the threshold for referral for urgent chest x-ray for smokers and recent ex-smokers, aged over 60 years with new chest symptoms. The qualitative component aimed to explore the feasibility of individually randomising patients to an urgent chest x-ray or not and to investigate any barriers to patient recruitment and participation. We integrated this within the feasibility trial to inform the design of any future definitive trial, particularly in view of the lack of research exploring symptomatic patients’ experiences of participating in diagnostic trials for possible/suspected lung cancer. Although previous studies contributed valuable information concerning screening for lung cancer and patient participation in trials, this paper is the first to explore issues relating to this specific patient group. Methods Qualitative interviews were conducted with 21 patients, comprising 9 who had been randomised to receive an immediate chest x-ray, 10 who were randomised to receive the standard treatment according to the National Institute for Health and Care Excellence guidelines, and 2 who chose not to participate in the trial. Interviews were analysed using a framework approach. Results The findings of this analysis showed that altruism, personal benefit and the reassurance of not having lung cancer were important factors in patient participation. However, patients largely believed that being in the intervention arm was more beneficial, highlighting a lack of understanding of clinical equipoise. Disincentives to participation in the trial included the stigmatisation of patients who smoked (given the inclusion criteria). Although the majority of patients reported that they were happy with the trial design, there was evidence of poor understanding. Last, for several patients, placing trust in health professionals was preferred to understanding the trial processes. Conclusions The integration of a qualitative study focusing on participant experience as a secondary outcome of a feasibility trial enabled exploration of patient response to participation and recruitment. The study demonstrated that although it is feasible to recruit patients to the ELCID trial, more work needs to be done to ensure an understanding of study principles and also of smoking stigmatisation

Evasive Malware via Identifier Implanting

To cope with the increasing number of malware attacks that organizations face, anti-malware appliances and sandboxes have become an integral security defense. In particular, appliances have become the de facto standard in the fight against targeted attacks. Yet recent incidents have demonstrated that malware can effectively detect and thus evade sandboxes, resulting in an ongoing arms race between sandbox developers and malware authors. We show how attackers can escape this arms race with what we call customized malware, i.e., malware that only exposes its malicious behavior on a targeted system. We present a web-based reconnaissance strategy, where an actor leaves marks on the target system such that the customized malware can recognize this particular system in a later stage, and only then exposes its malicious behavior. We propose to implant identifiers into the target system, such as unique entries in the browser history, cache, cookies, or the DNS stub resolver cache. We then prototype a customized malware that searches for these implants on the executing environment and denies execution if implants do not exist as expected. This way, sandboxes can be evaded without the need to detect artifacts that witness the existence of sandboxes or a real system environment. Our results show that this prototype remains undetected on commercial malware security appliances, while only exposing its real behavior on the targeted system. To defend against this novel attack, we discuss countermeasures and a responsible disclosure process to allow appliances vendors to prepare for such attacks

The effect of multiple host species on a keystone parasitic plant and its aphid herbivores

1. The exploitation of shared resources by diverse organisms underpins the structure of ecological communities. Hemiparasitic plants and the insect herbivores feeding on them both rely, directly and indirectly, on the resources supplied by the parasite's host plant. Therefore, the identity and number of host plant species providing these resources is likely to be critical for parasite and herbivore performance. 2. We tested the effect of single and multiple host species on the biomass of the generalist parasitic plant Rhinanthus minor and the abundance of its aphid (Aphis gossypii) herbivores. 3. Parasite biomass was proportional to the number of haustorial connections to host roots and was determined by host species identity rather than host functional group. Host species identity was also an important influence on aphid population size, and parasites attached to Lotus corniculatus experienced a considerable reduction in aphid herbivory. 4. The effects on the parasite attaching to multiple hosts depended on the combination of species present. However, host mixtures generally benefitted aphids by diluting the negative effects of particular host species. 5. Our findings suggest that the specificity of host attachment alters the impact of this keystone parasitic plant on its own herbivores and, potentially, on the wider plant and herbivore community

Hiatal Hernia Repair With Transoral Incisionless Fundoplication Versus Nissen Fundoplication for Gastroesophageal Reflux Disease: A Retrospective Study

Background and study aims  Concomitant hiatal hernia (HH) repair with transoral incisionless fundoplication (TIF) is a therapeutic option for patients with HH \u3e 2 cm and gastroesophageal reflux disease (GERD). Data comparing this approach with laparoscopic Nissen fundoplication (LNF) are lacking. We performed an exploratory analysis to compare these two approaches\u27 adverse events (AEs) and clinical outcomes. Patients and methods  This was a multicenter retrospective cohort study of HH repair followed by LNF versus HH repair followed by TIF in patients with GERD and moderate HH (2–5 cm). AEs were assessed using the Clavien-Dindo classification. Symptoms (heartburn/regurgitation, bloating, and dysphagia) were compared at 6 and 12 months. Results  A total of 125 patients with HH repair with TIF and 70 with HH repair with LNF were compared. There was no difference in rates of discontinuing or decreasing proton pump inhibitor use, dysphagia, esophagitis, disrupted wrap, and HH recurrence between the two groups ( P  \u3e 0.05). The length of hospital stay (1 day vs. 2 days), 30-day readmission rate (0 vs. 4.3 %), early AE rate (0 vs. 18.6 %), and early serious AE rate (0 vs. 4.3 %) favored TIF (all P  \u3c 0.05). The rate of new or worse than baseline bloating was lower in the TIF group at 6 months (13.8 % vs. 30.0 %, P  = 0.009). Conclusions  Concomitant HH repair with TIF is feasible and associated with lower early and serious AEs compared to LNF. Further comparative efficacy studies are warranted