Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process ...driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis.
BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99.
Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline.
The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.
Abstract
The influence of climate change on civil conflict and societal instability in the premodern world is a subject of much debate, in part because of the limited temporal or disciplinary scope ...of case studies. We present a transdisciplinary case study that combines archeological, historical, and paleoclimate datasets to explore the dynamic, shifting relationships among climate change, civil conflict, and political collapse at Mayapan, the largest Postclassic Maya capital of the Yucatán Peninsula in the thirteenth and fourteenth centuries CE. Multiple data sources indicate that civil conflict increased significantly and generalized linear modeling correlates strife in the city with drought conditions between 1400 and 1450 cal. CE. We argue that prolonged drought escalated rival factional tensions, but subsequent adaptations reveal regional-scale resiliency, ensuring that Maya political and economic structures endured until European contact in the early sixteenth century CE.
Objectives
This study uses osteological and radiocarbon datasets combined with formal quantitative analyses to test hypotheses concerning the character of conflict in the Nasca highlands during the ...Late Intermediate Period (LIP, 950–1450 C.E.). We develop and test osteological expectations regarding what patterns should be observed if violence was characterized by intragroup violence, ritual conflict, intermittent raiding, or internecine warfare.
Materials and methods
Crania (n = 267) were examined for antemortem and perimortem, overkill, and critical trauma. All age groups and both sexes are represented in the sample. One hundred twenty‐four crania were AMS dated, allowing a detailed analysis of diachronic patterns in violence among various demographic groups.
Results
Thirty‐eight percent (102/267) of crania exhibit some form of cranial trauma, a significant increase from the preceding Middle Horizon era. There are distinct trauma frequencies within the three subphases of the LIP, but Phase III (1300–1450 C.E.) exhibits the highest frequencies of all trauma types. Males exhibit significantly more antemortem trauma than females, but both exhibit similar perimortem trauma rates.
Discussion
There was chronic, internecine warfare throughout the Late Intermediate Period with important variations in violence throughout the three temporal phases. Evidence for heterogeneity in violent mortality shows a pattern consistent with social substitutability, whereby any and all members of the Nasca highland population were appropriate targets for lethal and sublethal violence. We argue that by testing hypotheses regarding the targets and types of conflict we are better able to explain the causes and consequences of human conflict.
A typical chullpa tomb in the Nasca highlands.
Background
The purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to ...pancreatoduodenectomy (PD).
Methods
Consecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990–1999, 2000–2004, 2005–2009, 2010–2014) were evaluated and compared.
Results
The average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001).
Conclusions
Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.
A long-standing theory posits that central chemoreception, the CNS mechanism for CO(2) detection and regulation of breathing, involves neurons located at the ventral surface of the medulla oblongata ...(VMS). Using in vivo and in vitro electrophysiological recordings, we identify VMS neurons within the rat retrotrapezoid nucleus (RTN) that have characteristics befitting these elusive chemoreceptors. These glutamatergic neurons are vigorously activated by CO(2) in vivo, whereas serotonergic neurons are not. Their CO(2) sensitivity is unaffected by pharmacological blockade of the respiratory pattern generator and persists without carotid body input. RTN CO(2)-sensitive neurons have extensive dendrites along the VMS and they innervate key pontomedullary respiratory centers. In brainstem slices, a subset of RTN neurons with markedly similar morphology is robustly activated by acidification and CO(2). Their pH sensitivity is intrinsic and involves a background K(+) current. In short, the CO(2)-sensitive neurons of the RTN are good candidates for the long sought-after VMS chemoreceptors.
To evaluate the effects of an enhanced recovery after minimally invasive surgery (MIS-ERAS) protocol on opioid requirements and post-operative pain in patients undergoing minimally invasive ...hysterectomy on a gynecologic oncology service.
For this retrospective study, opioid use (oral morphine equivalents (OME)) and post-operative pain scores were compared between patients undergoing minimally invasive hysterectomy pre and post MIS-ERAS protocol implementation. Patients with chronic opioid use or chronic pain were excluded. Opioid use and pain scores were compared between groups using Wilcoxon Rank Sum, Student's t-test, and multiple linear regression. Compliance and factors associated with opioid use and pain scores were assessed.
The MIS-ERAS cohort (n = 127) was compared to the historical cohort (n = 99) with no differences in patient demographic, clinical or surgical characteristics observed between groups. Median intra-operative and inpatient post-operative opioid use were lower among the MIS-ERAS cohort (12.0 vs 32.0 OME, p < .0001 and 20.0 vs 35.0 OME, p = .02, respectively). Pain scores among MIS-ERAS patients were also lower (mean 3.6 vs 4.1, p = .03). After controlling for age, BMI, operative time, length of stay, cancer diagnosis, and surgical approach, the MIS-ERAS cohort used 10.43 fewer OME intra-operatively (p < .001), 10.97 fewer OME post-operatively (p = .019) and reported pain scores 0.56 points lower than historical controls (p = .013). Compliance was ≥81% for multimodal analgesia elements and ≥75% overall.
Enhanced recovery after minimally invasive surgery protocol implementation is an effective means to reduce opioid use, both in the intra-operative and post-operative phases of care, among gynecologic oncology patients undergoing minimally invasive hysterectomy.
•An enhanced recovery protocol reduced inpatient post-operative opioid use after minimally invasive hysterectomy.•An enhanced recovery after minimally invasive surgery protocol reduced intra-operative opioid use.•Despite reductions in opioid use, post-operative pain scores were lower after enhanced recovery protocol implementation.•Protocol compliance exceeded 80% for multimodal pain management interventions and was 75% overall.
Predators are frequently victims of wildlife crime due to conflicts with human interests. Where predators are protected, killing may occur covertly and novel methods, including satellite tracking, ...are often required to assess population consequences. Wildlife crime persists in the British uplands, where raptors are illegally killed on moorland managed for Red Grouse Lagopus lagopus scotica shooting. To understand impacts on one such species, the Hen Harrier Circus cyaneus, we analysed data from 148 individuals tracked across Britain between 2014 and 2021. Using remotely sensed land-use data and continuous-time survival methods, we quantified survival rates, contributions of natural causes and illegal killing to mortality, and spatial and temporal associations between mortality and land managed for grouse shooting. Annual survival was low, especially among first-year birds (males: 14 %; females: 30 %), with illegal killing accounting for 27–43 % and 75 % of mortality in first-year and subadult (1-2 years) harriers respectively. Illegal killing is likely attributable to grouse moor management because i) a 10 % increase in grouse moor use resulted in a 43 % increase in mortality risk; ii) a strong overlap existed between mortality and grouse moor extent in 20 km squares, identifying hotspots of illegal killing in northern England and northeast Scotland; iii) death due to natural causes showed different spatial and temporal patterns; and iv) timing of mortality peaked around the shooting season and during breeding territory establishment. Governments have failed to reduce illegal killing of Hen Harriers and other raptors in Britain and our results emphasise that further legislative reform is needed to tackle this enduring criminality.
Background
Primary sclerosing cholangitis is a progressive and fibrotic liver disease. Treatments remain inadequate, and patients with persistent elevations in activity of alkaline phosphatase are at ...greatest risk of disease progression. Studies in patient cohorts have implicated the serum amine oxidase vascular adhesion protein 1 in the pathophysiology of disease, including liver fibrogenesis. We hypothesised that blockade of serum amine oxidase by a monoclonal antibody would result in a reduction in liver fibrosis/injury, as evaluated by serum liver tests and other non-invasive markers of liver injury.
Objectives
To evaluate the open-label effect on liver injury markers of treatment with the anti-vascular adhesion protein 1 monoclonal antibody BTT1023 in patients with primary sclerosing cholangitis over a 78-day treatment period.
Design
A single-arm, two-stage, open-label, multicentre, Phase II clinical trial.
Setting
Ambulatory liver disease practices in tertiary care hospitals.
Participants
Patients with primary sclerosing cholangitis at risk of disease progression, based on elevated activity of serum alkaline phosphatase, and without evidence of infection, liver failure or advanced disease.
Intervention
Seven intravenous infusions of BTT1023 (8 mg/kg of timolumab) over a 78-day treatment period. The intervention was split into a dose-confirmatory stage (to confirm pharmacokinetics), followed by a confirmed expansion cohort stage.
Main outcome measures
Our primary outcome measure was patient response to treatment at day 99, measured by a reduction in activity of serum alkaline phosphatase of ≥ 25% from baseline to day 99. Secondary markers of efficacy were assessed based on evaluation of changes in markers of liver injury and liver fibrosis. Safety assessments were performed throughout.
Results
Thirty-five patients were consented and screened for eligibility. Twenty-three patients were treated across the two stages of the trial. Interim assessment demonstrated a failure to meet the primary end point, leading to trial discontinuation on the grounds of futility. Multiple exploratory markers were evaluated in a final cohort of 22 patients (modified intention-to-treat analysis). No treatment-related effects were evident. No new safety concerns were seen.
Conclusions
No preliminary evidence for disease modification was demonstrated.
Limitations
It is clear that this study is limited in its design. Even if there were a better biomarker of fibrosis turnover that could be considered the ‘gold standard’, the design and duration would have had real-world resource limitations. With limited opportunity to test a new agent in large numbers of patients over a prolonged period, it was necessary to aim to see efficacy in a small cohort over a short period. Given the absence of any proven biochemical surrogate of disease activity in primary sclerosing cholangitis, alkaline phosphatase was chosen as an end point. This remains a difficult end point (yet one that does capture biliary injury) and, therefore, despite limitations, this study did demonstrate short-term safety.
Future work
Future research will require attention to an ongoing debate regarding the optimal end points for assessing efficacy, as well as consideration of duration of treatment, even in early-phase studies. This raises the challenge of how to fund early experimental trials with ‘high risk of failure’ adequately to ensure that clearer results (negative or positive) arise by the end of the study.
Trial registration
Current Controlled Trials ISRCTN11233255, EudraCT 2014-002393-37 and NCT02239211.
Funding
This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in
Efficacy and Mechanism Evaluation
; Vol. 9, No. 1. See the NIHR Journals Library website for further project information.
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Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic ...preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular antiviral activity. This structure–activity relationship (SAR) exploration was guided by the use of calculated hydration site thermodynamic maps (WaterMap) to drive potency via displacement of waters from high-energy sites. Thousands of diverse compounds were designed to target these high-energy hydration sites and then prioritized for synthesis by physics- and structure-based Free-Energy Perturbation (FEP+) simulations, which accurately predicted biochemical potencies. This approach ultimately led to the rapid discovery of lead compounds with unique SAR that exhibited potent enzymatic and cellular activity with excellent pan-coronavirus coverage.
Intraoperative electrocochleography (ECOG) is performed using a single low-frequency acoustic stimulus (e.g., 500 Hz) to monitor cochlear microphonics (CM) during cochlear implant (CI) electrode ...insertion. A decrease in CM amplitude is commonly associated with cochlear trauma and is used to guide electrode placement. However, advancement of the recording electrode beyond the sites of CM generation can also lead to a decrease in CM amplitude and is sometimes interpreted as cochlear trauma, resulting in unnecessary electrode manipulation and increased risk of cochlear trauma during CI electrode placement. In the present study, multi-frequency ECOG was used to monitor CM during CI electrode placement. The intraoperative CM tracings were compared with electrode scan measurements, where CM was measured for each of the intracochlear electrodes. Comparison between the peak CM amplitude measured during electrode placement and electrode scan measurements was used to differentiate between different mechanisms for decrease in CM amplitude during CI electrode insertion. Analysis of the data shows that both multi-frequency electrocochleography and electrode scan could potentially be used to differentiate between different mechanisms for decreasing CM amplitude and providing appropriate feedback to the surgeon during CI electrode placement.
