Structural cumulative survival models for estimation of treatment effects accounting for treatment switching in randomized experiments.

Treatment switching in a randomized controlled trial occurs when a patient in one treatment arm switches to another arm during follow-up. This can occur at the point of disease progression, whereby patients in the control arm may be offered the experimental treatment. It is widely known that failure to account for treatment switching can seriously bias the estimated treatment causal effect. In this paper, we aim to account for the potential impact of treatment switching in a reanalysis evaluating the treatment effect of nucleoside reverse transcriptase inhibitors (NRTIs) on a safety outcome (time to first severe or worse sign or symptom) in participants receiving a new antiretroviral regimen that either included or omitted NRTIs in the optimized treatment that includes or omits NRTIs trial. We propose an estimator of a treatment causal effect for a censored time to event outcome under a structural cumulative survival model that leverages randomization as an instrumental variable to account for selective treatment switching. We establish that the proposed estimator is uniformly consistent and asymptotically Gaussian, with a consistent variance estimator and confidence intervals given, whose finite-sample performance is evaluated via extensive simulations. An R package 'ivsacim' implementing all proposed methods is freely available on R CRAN. Results indicate that adding NRTIs versus omitting NRTIs to a new optimized treatment regime may increase the risk for a safety outcome.

Physiological effects and subjective tolerability of prone positioning in COVID-19 and healthy hypoxic challenge.

BACKGROUND: Prone positioning has a beneficial role in coronavirus disease 2019 (COVID-19) patients receiving ventilation but lacks evidence in awake non-ventilated patients, with most studies being retrospective, lacking control populations and information on subjective tolerability. METHODS: We conducted a prospective, single-centre study of prone positioning in awake non-ventilated patients with COVID-19 and non-COVID-19 pneumonia. The primary outcome was change in peripheral oxygenation in prone versus supine position. Secondary outcomes assessed effects on end-tidal CO2, respiratory rate, heart rate and subjective symptoms. We also recruited healthy volunteers to undergo proning during hypoxic challenge. RESULTS: 238 hospitalised patients with pneumonia were screened; 55 were eligible with 25 COVID-19 patients and three non-COVID-19 patients agreeing to undergo proning - the latter insufficient for further analysis. 10 healthy control volunteers underwent hypoxic challenge. Patients with COVID-19 had a median age of 64 years (interquartile range 53-75). Proning led to an increase in oxygen saturation measured by pulse oximetry (SpO2) compared to supine position (difference +1.62%; p=0.003) and occurred within 10 min of proning. There were no effects on end-tidal CO2, respiratory rate or heart rate. There was an increase in subjective discomfort (p=0.003), with no difference in breathlessness. Among healthy controls undergoing hypoxic challenge, proning did not lead to a change in SpO2 or subjective symptom scores. CONCLUSION: Identification of suitable patients with COVID-19 requiring oxygen supplementation from general ward environments for awake proning is challenging. Prone positioning leads to a small increase in SpO2 within 10 min of proning though is associated with increased discomfort.

Endovascular treatment of a large iatrogenic popliteal arteriovenous fistula.

A 40-year-old man presented with years of progressive leg swelling and venous varicosities. Lower limb computed tomography angiography and subsequent digital subtraction angiography demonstrated a large popliteal arteriovenous fistula (AVF). This was treated successfully by endovascular technique with a Viabahn stent (W. L. Gore & Associates, Flagstaff, Ariz) in the popliteal artery to exclude the AVF. AVFs of this size and chronicity are rare, and this case demonstrates a successful endovascular method of treatment.

Continuous local anaesthetic wound infusion for postoperative pain after midline laparotomy for colorectal resection in adults.

BACKGROUND: Colorectal resection through a midline laparotomy is a commonly performed surgical procedure to treat various bowel conditions. The typical postoperative hospital stay after this operation is 6 to 10 days. The main factors hindering early recovery and discharge are thought to include postoperative pain and delayed return of bowel function.Continuous infusion of a local anaesthetic into tissues surrounding the surgical incision via a multi-lumen indwelling wound catheter placed by the surgeon prior to wound closure may reduce postoperative pain, opioid consumption, the time to return of bowel function, and the length of hospital stay. OBJECTIVES: To evaluate the efficacy and adverse events of continuous local anaesthetic wound infusion for postoperative pain after midline laparotomy for colorectal resection in adults. SEARCH METHODS: We searched the CENTRAL, MEDLINE and Embase databases to January 2019 to identify trials relevant to this review. We also searched reference lists of relevant trials and reviews for eligible trials. Additionally, we searched two clinical trials registers for ongoing trials. SELECTION CRITERIA: We considered randomised controlled trials (including non-standard designs) or quasi-randomised controlled trials comparing continuous wound infusion of a local anaesthetic versus a placebo or a sham after midline laparotomy for colorectal resection in adults. We did not compare continuous local anaesthetic wound infusion to other techniques, such as transverse abdominis plane block or thoracic epidural analgesia. We allowed non-randomised analgesic co-interventions carried out equally in the intervention and control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials for inclusion and assessed their quality using the Cochrane 'Risk of bias' tool. We extracted data using standardised forms, including pain at rest and on movement (10-point scale), opioid consumption via a patient-controlled analgesia (PCA) system (mg morphine equivalent), postoperative opioid-related adverse events, the time to rescue analgesia, the time to first flatus and to first bowel movement, the time to ambulation, the length of hospital stay, serious postoperative adverse events, and patient satisfaction. We quantitatively synthesised the data by meta-analysis. We summarised and graded the certainty of the evidence for critical outcomes using the GRADEpro tool and created a 'Summary of findings' table. MAIN RESULTS: This review included six randomised controlled trials that enrolled a total of 564 adults undergoing elective midline laparotomy for colorectal resection comparing continuous wound infusion of a local anaesthetic to a normal saline placebo. Due to 23 post-randomisation exclusions, a total of 541 participants contributed data to the analysis of at least one outcome (local anaesthetic 268; control 273). Most participants were aged 55 to 65 years, with normal body mass index and low to moderate anaesthetic risk (American Society of Anesthesiologists class I-III). Random sequence generation, allocation concealment, and blinding were appropriately carried out in most trials. However, we had to downgrade the certainty of the evidence for most outcomes due to serious study limitations (risk of bias), inconsistency, indirectness, imprecision and reporting bias.Primary outcomesOn postoperative day 1, pain at rest (mean difference (MD) -0.59 (from 3.1), 95% confidence interval (CI) -1.12 to -0.07; 5 studies, 511 participants; high-certainty evidence), pain on movement (MD -1.1 (from 6.1), 95% CI -2.3 to -0.01; 3 studies, 407 participants; low-certainty evidence) and opioid consumption via PCA (MD -12 mg (from 41 mg), 95% CI -20 to -4; 6 studies, 528 participants; moderate-certainty evidence) were reduced in the local anaesthetic group compared to the control group.Secondary outcomesThere was a reduction in the time to first bowel movement (MD -0.67 from 4.4 days, 95% CI -1.17 to -0.17; 4 studies, 197 participants; moderate-certainty evidence) and the length of hospital stay (MD -1.2 from 7.4 days, 95% CI -2.0 to -0.3; 4 studies, 456 participants; high-certainty evidence) in the local anaesthetic group compared to the control group.There was no evidence of a difference in any serious postoperative adverse events until hospital discharge (RR 1.04, 95% CI 0.68 to 1.58; 6 studies, 541 participants; low-certainty evidence) between the two study groups. AUTHORS' CONCLUSIONS: After elective midline laparotomy for colorectal resection, continuous wound infusion of a local anaesthetic compared to a normal saline placebo reduces postoperative pain at rest and the length of hospital stay, on the basis of high-certainty evidence. This means we are very confident that the effect estimates for these outcomes lie close to the true effects. There is moderate-certainty evidence to indicate that the intervention probably reduces opioid consumption via PCA and the time to first bowel movement. This means we are moderately confident that effect estimates for these outcomes are likely to be close to the true effects, but there is a possibility that they are substantially different. The intervention may reduce postoperative pain on movement, however, this conclusion is based on low-certainty evidence. This means our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. There is low-certainty evidence to indicate that the intervention may have little or no effect on the rates of any serious postoperative adverse events until hospital discharge. High-quality randomised controlled trials to evaluate the intervention with a focus on important clinical and patient-centred outcomes are needed.

Abdominal Aortic Aneurysm Screening: A Systematic Review and Meta-analysis of Efficacy and Cost.

BACKGROUND: Abdominal aortic aneurysms (AAA) can cause significant mortality when ruptured but are often undiagnosed before this time. Population screening of high-risk individuals and early intervention may mitigate AAA-related mortality. Large trials have demonstrated a mortality benefit for AAA screening, but adoption is not ubiquitous. This study sought to systematically review and consolidate the most recent randomized trial evidence on AAA screening in men and its cost-effectiveness. METHODS: Randomized trials and cost-effectiveness analyses (CEAs) of AAA screening in men were identified from searching Medline, Embase, CENTRAL, and relevant citation lists. Data were extracted as hazard ratios or raw event rates. Meta-analysis was conducted using a random-effects, inverse variance weighted model for continuous variables and Mantel-Haenszel weighting for event data. Cost estimates of screening were adjusted for inflation and reported as $US/quality-adjusted life year. RESULTS: Five studies were identified totaling 175,085 participants (age, 64-83 years) with a mean 10.6 years of follow-up (4.4-13.1). The AAA detection ranged from 3.3 to 7.7%. Screening significantly reduced all-cause mortality (hazard ratio, 0.97; 95% confidence interval, 0.96-0.99; P = 0.002), AAA-related mortality (0.65; 95% confidence interval, 0.48-0.89; P = 0.008), and emergent AAA repair (relative risk, 0.64; 95% confidence interval, 0.46-0.91; P = 0.02). The number needed to screen to prevent 1 AAA-related death per 10 years ranged from 209 to 769 individuals. Sixteen CEAs found a mean 16,854 $/QALY (range, 266-73,369). CONCLUSIONS: Wider implementation of population-based AAA screening programs in elderly men should be considered as it demonstrates a significant and cost-effective reduction in all-cause mortality as well as AAA-related mortality.

Two-stage residual inclusion for survival data and competing risks-An instrumental variable approach with application to SEER-Medicare linked data.

Instrumental variable is an essential tool for addressing unmeasured confounding in observational studies. Two-stage predictor substitution (2SPS) estimator and two-stage residual inclusion (2SRI) are two commonly used approaches in applying instrumental variables. Recently, 2SPS was studied under the additive hazards model in the presence of competing risks of time-to-events data, where linearity was assumed for the relationship between the treatment and the instrument variable. This assumption may not be the most appropriate when we have binary treatments. In this paper, we consider the 2SRI estimator under the additive hazards model for general survival data and in the presence of competing risks, which allows generalized linear models for the relation between the treatment and the instrumental variable. We derive the asymptotic properties including a closed-form asymptotic variance estimate for the 2SRI estimator. We carry out numerical studies in finite samples and apply our methodology to the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database comparing radical prostatectomy versus conservative treatment in early-stage prostate cancer patients.

Circadian and Brain State Modulation of Network Hyperexcitability in Alzheimer's Disease.

Network hyperexcitability is a feature of Alzheimer' disease (AD) as well as numerous transgenic mouse models of AD. While hyperexcitability in AD patients and AD animal models share certain features, the mechanistic overlap remains to be established. We aimed to identify features of network hyperexcitability in AD models that can be related to epileptiform activity signatures in AD patients. We studied network hyperexcitability in mice expressing amyloid precursor protein (APP) with mutations that cause familial AD, and compared a transgenic model that overexpresses human APP (hAPP) (J20), to a knock-in model expressing APP at physiological levels (APPNL/F). We recorded continuous long-term electrocorticogram (ECoG) activity from mice, and studied modulation by circadian cycle, behavioral, and brain state. We report that while J20s exhibit frequent interictal spikes (IISs), APPNL/F mice do not. In J20 mice, IISs were most prevalent during daylight hours and the circadian modulation was associated with sleep. Further analysis of brain state revealed that IIS in J20s are associated with features of rapid eye movement (REM) sleep. We found no evidence of cholinergic changes that may contribute to IIS-circadian coupling in J20s. In contrast to J20s, intracranial recordings capturing IIS in AD patients demonstrated frequent IIS in non-REM (NREM) sleep. The salient differences in sleep-stage coupling of IIS in APP overexpressing mice and AD patients suggests that different mechanisms may underlie network hyperexcitability in mice and humans. We posit that sleep-stage coupling of IIS should be an important consideration in identifying mouse AD models that most closely recapitulate network hyperexcitability in human AD.

Single cell heterogeneity: why unstable genomes are incompatible with average profiles.

Multi-level heterogeneity is a fundamental but underappreciated feature of cancer. Most technical and analytical methods either completely ignore heterogeneity or do not fully account for it, as heterogeneity has been considered noise that needs to be eliminated. We have used single-cell and population-based assays to describe an instability-mediated mechanism where genome heterogeneity drastically affects cell growth and cannot be accurately measured using conventional averages. First, we show that most unstable cancer cell populations exhibit high levels of karyotype heterogeneity, where it is difficult, if not impossible, to karyotypically clone cells. Second, by comparing stable and unstable cell populations, we show that instability-mediated karyotype heterogeneity leads to growth heterogeneity, where outliers dominantly contribute to population growth and exhibit shorter cell cycles. Predictability of population growth is more difficult for heterogeneous cell populations than for homogenous cell populations. Since "outliers" play an important role in cancer evolution, where genome instability is the key feature, averaging methods used to characterize cell populations are misleading. Variances quantify heterogeneity; means (averages) smooth heterogeneity, invariably hiding it. Cell populations of pathological conditions with high genome instability, like cancer, behave differently than karyotypically homogeneous cell populations. Single-cell analysis is thus needed when cells are not genomically identical. Despite increased attention given to single-cell variation mediated heterogeneity of cancer cells, continued use of average-based methods is not only inaccurate but deceptive, as the "average" cancer cell clearly does not exist. Genome-level heterogeneity also may explain population heterogeneity, drug resistance, and cancer evolution.

Ultrathin gold nanowire-functionalized carbon nanotubes for hybrid molecular sensing.

Carbon nanotubes (CNTs) have shown great potential as sensing component in the electrochemical field effect transistor and optical sensors, because of their extraordinary one-dimensional electronic structure, thermal conductivity, and tunable and stable near-infrared emission. However, the insolubility of CNTs due to strong van der Waals interactions limits their use in the field of nanotechnology. In this study, we demonstrate that noncovalent ultrathin gold nanowires functionalized multiwalled carbon nanotube (GNW-CNT) hybrid sensing agents show highly efficient and selective immune molecular sensing in electrochemical and near-infrared photoacoustic imaging methods. A detection limit of 0.01 ng/mL for the alpha-fetoprotein (AFP) antigen with high selectivity is shown. The extraordinary optical absorption, thermal, and electric conductivity of hybrid GNW-CNTs presented in this study could be an effective tactic to integrate imaging, sensing, and treatment functionalities.

Highly sensitive and selective colorimetric genotyping of single-nucleotide polymorphisms based on enzyme-amplified ligation on magnetic beads.

Herein we report a new strategy for highly sensitive and selective colorimatric assay for genotyping of single-nucleotide polymorphisms (SNPs). It is based on the use of a specific gap ligation reaction, horseradish peroxidase (HRP) for signal amplification, and magnetic beads for the easy separation of the ligated product. Briefly, oligonucleotide capture probe functionalized magnetic beads are first hybridized to a target DNA. Biotinylated oligonucleotide detection probes are then allowed to hybridize to the already captured target DNA. A subsequent ligation at the mutation point joins the two probes together. The introduction of streptavidin-conjugated HRP and a simple magnetic separation allow colorimetric genotyping of SNPs. The assay is able to discriminate one copy of mutant in 1000 copies of wild-type KRAS oncogene at 30 picomolar. The detection limit of the assay is further improved to 1 femtomolar by incorporating a ligation chain reaction amplification step, offering an excellent opportunity for the development of a simple and highly sensitive diagnostic tool.