Highly Selective Ratiometric Sensors for Pb2+ Based on Luminescent Zn(II)-Coordination Polymers with Thiophenedicarboxylate. Crystal Structures and Spectroscopic Studies.

The development of luminescent coordination polymers for the selective sensing of Pb2+ in water constitutes an active area of research that impacts analytical, environmental, and inorganic chemistry. Herein, two novel water-stable 2D Zn-coordination polymers {[Zn2(H2O)2(tdc)2(bpy)]·(H2O)}n 1 and [Zn(tdc)(tmb)]n 2 (tdc = thiophenedicarboxylate; bpy = 4,4'-bipyridine and tmb = 4,4'-trimethylenebipyridine) were synthesized, structurally determined by single crystal X-ray diffraction, and studied in-depth as luminescent sensors for a series of cations (Ca2+, Mg2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+ Cd2+, Hg2+ and Pb2+) in 20% aqueous ethanol. These Zn-polymers possess photostability in 20% aqueous ethanol with a strong emission at 410 upon excitation at 330 nm and quantum yields of around Φ = 0.09. Under these conditions, Pb+2 can be efficiently sensed with polymer 2 through a fluorescent ratiometric response with selectivity over common interfering metal ions such as Cu2+, Cd2+ and Hg2+ in the micromolar concentration range (detection limit = 1.78 ± 10 µM). Such selectivity/affinity of Pb2+ over Hg2+ for luminescent chemosensors is still rare. On the basis of spectroscopic tools (1H NMR, far ATR-IR, PXRD), the X-ray crystal structure of 2, and Scanning Electron Microscopy with Energy-Dispersive X-ray Spectroscopic analysis, the ratiometric fluorescent response is proposed via an efficient metal-ion exchange driven through interactions between thiophenedicarboxylate rings and Pb2+ ions. The use of flexible luminescent Zn-coordination polymers as sensors for selective and direct detection of Pb2+ in aqueous media has been unexplored until now.

Steady Laminar Flow Decreases Endothelial Glycolytic Flux While Enhancing Proteoglycan Synthesis and Antioxidant Pathways.

Endothelial cells in steady laminar flow assume a healthy, quiescent phenotype, while endothelial cells in oscillating disturbed flow become dysfunctional. Since endothelial dysfunction leads to atherosclerosis and cardiovascular disease, it is important to understand the mechanisms by which endothelial cells change their function in varied flow environments. Endothelial metabolism has recently been proven a powerful tool to regulate vascular function. Endothelial cells generate most of their energy from glycolysis, and steady laminar flow may reduce endothelial glycolytic flux. We hypothesized that steady laminar but not oscillating disturbed flow would reduce glycolytic flux and alter glycolytic side branch pathways. In this study, we exposed human umbilical vein endothelial cells to static culture, steady laminar flow (20 dynes/cm2 shear stress), or oscillating disturbed flow (4 ± 6 dynes/cm2 shear stress) for 24 h using a cone-and-plate device. We then measured glucose and lactate uptake and secretion, respectively, and glycolytic metabolites. Finally, we explored changes in the expression and protein levels of endothelial glycolytic enzymes. Our data show that endothelial cells in steady laminar flow had decreased glucose uptake and 13C labeling of glycolytic metabolites while cells in oscillating disturbed flow did not. Steady laminar flow did not significantly change glycolytic enzyme gene or protein expression, suggesting that glycolysis may be altered through enzyme activity. Flow also modulated glycolytic side branch pathways involved in proteoglycan and glycosaminoglycan synthesis, as well as oxidative stress. These flow-induced changes in endothelial glucose metabolism may impact the atheroprone endothelial phenotype in oscillating disturbed flow.

Pandemic Demand for SARS-CoV-2 Testing Led to Critical Supply and Workforce Shortages in U.S. Clinical and Public Health Laboratories.

COVID-19 has brought unprecedented challenges to clinical and public health laboratories. While U.S. laboratories have continued striving to provide quality test results during the pandemic, the uncertainty and lack of supplies became a significant hurdle, hindering day-to-day laboratory operations and the ability to increase testing capacity for both SARS-CoV-2 and non-COVID-19 testing. In addition, long-standing laboratory workforce shortages became apparent, hindering the ability of clinical and public health laboratories to rapidly increase testing. The American Society for Microbiology, the College of American Pathologists, the National Coalition of STD Directors, and the Emerging Infections Network independently conducted surveys in 2020 and early 2021 to assess the capacity of the nation's clinical laboratories to respond to the increase in demand for testing during the COVID-19 pandemic. The results of these surveys highlighted the shortages of crucial supplies for SARS-CoV-2 testing and supplies for other routine laboratory diagnostics, as well as a shortage of trained personnel to perform testing. The conclusions are based on communications, observations, and the survey results of the clinical laboratory, public health, and professional organizations represented here. While the results of each survey considered separately may not be representative of the entire community, when considered together they provide remarkably similar results, further validating the findings and highlighting the importance of laboratory supply chains and the personnel capable of performing these tests for any response to a large-scale public health emergency.

Multiscale modeling of presynaptic dynamics from molecular to mesoscale.

Chemical synapses exhibit a diverse array of internal mechanisms that affect the dynamics of transmission efficacy. Many of these processes, such as release of neurotransmitter and vesicle recycling, depend strongly on activity-dependent influx and accumulation of Ca2+. To model how each of these processes may affect the processing of information in neural circuits, and how their dysfunction may lead to disease states, requires a computationally efficient modelling framework, capable of generating accurate phenomenology without incurring a heavy computational cost per synapse. Constructing a phenomenologically realistic model requires the precise characterization of the timing and probability of neurotransmitter release. Difficulties arise in that functional forms of instantaneous release rate can be difficult to extract from noisy data without running many thousands of trials, and in biophysical synapses, facilitation of per-vesicle release probability is confounded by depletion. To overcome this, we obtained traces of free Ca2+ concentration in response to various action potential stimulus trains from a molecular MCell model of a hippocampal Schaffer collateral axon. Ca2+ sensors were placed at varying distance from a voltage-dependent calcium channel (VDCC) cluster, and Ca2+ was buffered by calbindin. Then, using the calcium traces to drive deterministic state vector models of synaptotagmin 1 and 7 (Syt-1/7), which respectively mediate synchronous and asynchronous release in excitatory hippocampal synapses, we obtained high-resolution profiles of instantaneous release rate, to which we applied functional fits. Synchronous vesicle release occurred predominantly within half a micron of the source of spike-evoked Ca2+ influx, while asynchronous release occurred more consistently at all distances. Both fast and slow mechanisms exhibited multi-exponential release rate curves, whose magnitudes decayed exponentially with distance from the Ca2+ source. Profile parameters facilitate on different time scales according to a single, general facilitation function. These functional descriptions lay the groundwork for efficient mesoscale modelling of vesicular release dynamics.

Imatinib plasma levels in patients with chronic myeloid leukaemia under routine clinical practice conditions.

INTRODUCTION: The addition of imatinib to the therapeutic arsenal for chronic myeloid leukaemia (CML) has changed the natural course of the disease, in such a way that it is now considered a chronic pathology. However, to achieve therapeutic success, it is necessary to reach adequate plasma concentrations to ensure efficacy and safety.In this study, we aimed to evaluate the plasma concentration of imatinib, analysing its influence on effectiveness and safety in patients with CML. METHODS: We performed a descriptive, multicentre study in which imatinib plasma levels from patients diagnosed with CML between 2019-2020 were analysed. An optimal therapeutic range of 750-1500 ng/mL was established for the stratification of patients, according to their minimum plasma concentrations measured at steady state (Cssmin). RESULTS: A total of 28 patients were included, of whom only 39.3% (n = 11) showed Cssmin within the therapeutic range. 100% of patients with Cssmin >750 ng/mL achieved an optimal molecular response, while only 50% of patients with Cssmin <750 ng/mL achieved an optimal molecular response (p = 0.0004). The toxicity rate was 36.4% for patients with Cssmin >1500 ng/mL and 5.9% for those with Cssmin <1500 ng/mL (p = 0.039). CONCLUSIONS: This study aimed to describe the correlation between the toxicity and effectiveness of imatinib according to its Cssmin in routine clinical practice conditions. Based on our findings, it would be certainly justified to monitor patient plasma concentrations of imatinib on a daily routine basis in our hospitals.

Predictive value of patency capsule and magnetic resonance enterography for capsule endoscopy retention in patients with established Crohn's disease.

INTRODUCTION: retention is the most common adverse event of the small bowel capsule endoscopy procedure. Patency capsule (Medtronic, Dublin, Ireland) and magnetic resonance enterography are two diagnostic methods that can prevent small bowel capsule endoscopy retention. The aim of this study was to evaluate the predictive value of these two diagnostic methods. MATERIAL AND METHODS: a prospective, comparative and observational study was performed in patients with established Crohn's disease. All patients had undergone magnetic resonance enterography and patency capsule procedures. If the patency capsule was not retained, the patient underwent a small bowel capsule endoscopy; otherwise, double balloon enteroscopy was performed to locate the stenosis. Magnetic resonance enterography predictive criteria for retention were analyzed in all cases. Sensitivity, specificity, positive predictive value and negative predictive value of the patency capsule and magnetic resonance enterography compared to small bowel capsule endoscopy or double balloon enteroscopy were calculated. RESULTS: forty patients were included (24 female, 55 ± 13 years old). Retention criteria with capsule endoscopy or double balloon enteroscopy were found in six patients, agreeing in five cases with patency capsule and in three cases with magnetic resonance enterography. Sensitivity, specificity, positive predictive value, negative predictive value and Kappa coefficient for predicting retention with the patency capsule were 83 %, 100 %, 100 % and 97 %, respectively, and 50 %, 91 %, 50 % and 91 %, respectively, with magnetic resonance enterography. CONCLUSIONS: patency capsule has a higher sensitivity and positive predictive value than magnetic resonance enterography for preventing small bowel capsule endoscopy retention in Crohn's disease patients.

Will Polycrystalline Platinum Tip Sliding on a Gold(111) Surface Produce Regular Stick-Slip Friction?

Friction measurements by an atomic force microscope (AFM) frequently showed regular stick-slip friction signals with atomic-scale resolutions. Typically, for an AFM metal tip sliding on a metal crystal surface, the microstructure of the tip made from the thermally evaporated metal coating on a silicon cantilever was polycrystalline. Our detailed molecular dynamics(MD) simulations of a polycrystalline Pt tip (R = 10 nm in radius) sliding on an Au(111) surface revealed how the geometry of the polycrystalline tip took effect on the friction behavior at the contact interface. We found that the apex of the Pt tip with multiple grains near the edge of contact could induce severe plastic deformations of the gold substrate, leading to irregular stick-slip frictions upon sliding. Simulation results showed that in order to achieve a clear stick-slip friction signal with single atomic slips, the apex of the Pt tip must adopt a single crystalline protrusion without any neighboring grains involved in the metal contact. We showed that such a single crystalline protrusion, which presumably could be achieved during initial run-in or wear-out of high-energy Pt atoms in the neighboring grains, was passivated by a large number of gold atoms due to metal adhesion in the contact periphery. Using such a crystalline protrusion tip, we demonstrated that the stick-slip friction produced was very "tolerant" to the adhesion of a large number of gold atoms on the tip apex. We further showed that AFM tip mass used in MD simulations also played an important role in determining the transition between friction regimes, which could be well explained by the Prandtl-Tomlinson thermal activation model.

Anti-drug antibodies anti-trastuzumab in the treatment of breast cancer.

INTRODUCTION: Trastuzumab is a monoclonal antibody which could induce the activation of a humoral immune response generating anti-drug antibodies (ADAs). Such response depends of the protein nature and the route of administration (intravenous or subcutaneous). The formation of these antibodies could block the action of trastuzumab (ADA-Tras) and forming immune complexes which decrease its efficacy, so it would be interesting to determine the presence of ADA-Tras in patients treated with trastuzumab. MATERIAL AND METHODS: The blood samples were centrifuged to separate the plasma. The presence of ADA-Tras in plasma was determined using an ELISA-type automated immunoassay. RESULTS: Fifty-one women with non-metastatic HER2-positive breast cancer treated with trastuzumab were included. Two groups were studied: patients treated intravenously and subcutaneously. In neither case was there any presence of ADA-Tras. DISCUSSION: This study may be the first ever conducted under usual clinical practice conditions to detect the presence of ADA-Tras in patients with non-metastatic HER2-positive breast cancer. We have wanted to show the antibodies anti-trastuzumab determination as a possible tool that would enable comparison of potential differences in immunogenic behavior between trastuzumab and its biosimilars.

Extended enzymatic stability of reconstituted lyophilized PEG-asparaginase in vials.

Asparaginase (ASNase) use as a tumour-inhibitor drug has changed completely the natural course of paediatric acute lymphoblastic leukaemia (ALL) in such a way that it represents a paradigm shift in ALL management. ASNase treatment emergence has significantly improved pathologic responses and increased survival rates of ALL patients. Although different ASNase forms are currently available, only the pegylated form (PEG-ASNase) is recommended by relevant clinic guides. PEG-ASNase form shows longer elimination half-life, reducing the number of administrations, along with an enhanced safety profile. In spite of all of these advantages, PEG-ASNase elevated cost limits enormously its use. PEG-ASNase is commercialised as a lyophilised powder which according to the manufacturer it is stable for 24 hours once reconstituted, as a result, the leftover is usually discarded. In this study we analysed the enzymatic stability of reconstituted PEG-ASNase after conservation in three different temperature conditions for 5 and 14 days, aiming to take advantage of the remaining leftover for the subsequent administration. Our results have shown that PEG-ASNase is stable at 4°C, -20°C and -80°C for at least 14 days, retaining the 95% from the initial enzymatic activity in all three storage temperatures. According to our results, it is feasible to reuse the remaining content of PEG-ASNase vial after reconstitution, which means a 50% reduction of its cost for paediatric patient treatment and, consequently, removes the main barrier to use this drug in a wider population.

Predictors of patients' choice of hospitals under universal health coverage: a case study of the Nicaraguan capital.

BACKGROUND: This study looks at the factors that can shape patients' choice of healthcare providers. Understanding this process can help with making high quality healthcare more accessible for all. We focus on distance, patient's health status, (perceived) quality of healthcare facility, and referrals to investigate how these factors compete in shaping patients' choice of hospitals. METHODS: This study was carried out in Managua, the capital of Nicaragua. Utilizing an exit-survey, patients were interviewed across five public hospitals in 2017 and then six in 2019 when a new highly-equipped hospital was added to the system. We used a multinomial logit model to investigate patients' preference of a specific hospital over the rest within each wave. RESULTS: Our results show that being referred to a hospital is the strongest predictor and in some cases, it can increase the relative risk ratio of choosing a facility by a factor of 49 (p < 0.01; 95% CI: 27.39-87.17). For the remaining factors, the hierarchy of importance was less clear-cut yet all these factors remained significantly important at various levels. CONCLUSIONS: Overall, our results highlight the importance of referral systems in making quality healthcare more equitable. Moreover, with distance also being a key predictor and in the absence of an organized referral system, those with low-income would either be further deprived by having to settle with locally available healthcare (regardless of its quality) or face high amounts of out-of-pocket expenditure when seeking help from the private sector.

Feedforward Thalamocortical Connectivity Preserves Stimulus Timing Information in Sensory Pathways.

Reliable timing of cortical spikes in response to visual events is crucial in representing visual inputs to the brain. Spikes in the primary visual cortex (V1) need to occur at the same time within a repeated visual stimulus. Two classical mechanisms are employed by the cortex to enhance reliable timing. First, cortical neurons respond reliably to a restricted set of stimuli through their preference for certain patterns of membrane potential due to their intrinsic properties. Second, intracortical networking of excitatory and inhibitory neurons induces lateral inhibition that, through the timing and strength of IPSCs and EPSCs, produces sparse and reliably timed cortical neuron spike trains to be transmitted downstream. Here, we describe a third mechanism that, through preferential thalamocortical synaptic connectivity, enhances the trial-to-trial timing precision of cortical spikes in the presence of spike train variability within each trial that is introduced between LGN neurons in the retino-thalamic pathway. Applying experimentally recorded LGN spike trains from the anesthetized cat to a detailed model of a spiny stellate V1 neuron, we found that output spike timing precision improved with increasing numbers of convergent LGN inputs. The improvement was consistent with the predicted proportionality of [Formula: see text] for n LGN source neurons. We also found connectivity configurations that maximize reliability and that generate V1 cell output spike trains quantitatively similar to the experimental recordings. Our findings suggest a general principle, namely intra-trial variability among converging inputs, that increases stimulus response precision and is widely applicable to synaptically connected spiking neurons.SIGNIFICANCE STATEMENT The early visual pathway of the cat is favorable for studying the effects of trial-to-trial variability of synaptic inputs and intra-trial variability of thalamocortical connectivity on information transmission into the visual cortex. We have used a detailed model to show that there are preferred combinations of the number of thalamic afferents and the number of synapses per afferent that maximize the output reliability and spike-timing precision of cortical neurons. This provides additional insights into how synchrony in thalamic spike trains can reduce trial-to-trial variability to produce highly reliable reporting of sensory events to the cortex. The same principles may apply to other converging pathways where temporally jittered spike trains can reliably drive the downstream neuron and improve temporal precision.

Endocuff Vision Reduces Inspection Time Without Decreasing Lesion Detection: A Clinical Randomized Trial.

BACKGROUND & AIMS: Mucosal exposure devices improve detection of lesions during colonoscopy and have reduced examination times in uncontrolled studies. We performed a randomized trial of Endocuff Vision vs standard colonoscopy to compare differences in withdrawal time (the primary end point). We proposed that Endocuff Vision would allow complete mucosal inspection in a shorter time without impairing lesion detection. METHODS: Adults older than 40 years undergoing screening or surveillance colonoscopies were randomly assigned to the Endocuff group (n=101, 43.6% women) or the standard colonoscopy group (n=99; 57.6% women). One of 2 experienced endoscopists performed the colonoscopies, aiming for a thorough evaluation of the proximal sides of all haustral folds, flexures, and valves in the shortest time possible. Inspection time was measured with a stopwatch and calculated by subtracting washing, suctioning, polypectomy and biopsy times from total withdrawal time. RESULTS: There were significantly fewer women in the Endocuff arm (P = .0475) but there were no other demographic differences between groups. Mean insertion time with Endocuff was 4.0 min vs 4.4 min for standard colonoscopy (P = .14). Mean inspection time with Endocuff was 6.5 min vs 8.4 min for standard colonoscopy (P < .0001). Numbers of adenomas detected per colonoscopy (1.43 vs 1.07; P = .07), adenoma detection rate (61.4% vs 52%; P = .21), number of sessile serrated polyps per colonoscopy (0.27 vs 0.21; P = .12), and sessile serrated polyp detection rate (19.8% vs 11.1%; P = .09) were all higher with Endocuff Vision. Results did not differ significantly when we controlled for age, sex, or race. CONCLUSION: In a randomized trial, we found inclusion of Endocuff in screening or surveillance colonoscopies to decrease examination time without reducing lesion detection. ClinicalTrials.gov, Number: NCT03361917.

Lactobacilli spp.: real-time evaluation of biofilm growth.

BACKGROUND: Biofilm is a fundamental bacterial survival mode which proceeds through three main generalized phases: adhesion, maturation, and dispersion. Lactobacilli spp. (LB) are critical components of gut and reproductive health and are widely used probiotics. Evaluation of time-dependent mechanisms of biofilm formation is important for understanding of host-microbial interaction and development of therapeutic interventions. Time-dependent LB biofilm growth was studied in two systems: large biofilm output in continuous flow system (microfermenter (M), Institute Pasteur, France) and electrical impedance-based real time label-free cell analyzer (C) (xCELLigence, ACEA Bioscience Inc., San Diego, CA). L. plantarum biofilm growth in M system was video-recorded, followed by analyses using IMARIS software (Bitplane, Oxford Instrument Company, Concord, MA, USA). Additionally, whole genome expression and analyses of attached (A) and dispersed (D) biofilm phases at 24 and 48 h were performed. RESULTS: The dynamic of biofilm growth of L. plantarum was similar in both systems except for D phases. Comparison of the transcriptome of A and D phases revealed, that 121 transcripts differ between two phases at 24 h. and 35 transcripts - at 48 h. of M growth. The main pathways, down-regulated in A compared to D phases after 24 h. were transcriptional regulation, purine nucleotide biosynthesis, and L-aspartate biosynthesis, and the upregulated pathways were fatty acid and phospholipid metabolism as well as ABC transporters and purine nucleotide biosynthesis. Four LB species differed in the duration and amplitude of attachment phases, while growth phases were similar. CONCLUSION: LB spp. biofilm growth and propagation area dynamic, time-dependent processes with species-specific and time specific characteristics. The dynamic of LB biofilm growth agrees with published pathophysiological data and points out that real time evaluation is an important tool in understanding growth of microbial communities.

Pharmacokinetics of Trastuzumab After Subcutaneous and Intravenous Administration in Obese Patients.

Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient's body weight dose) on the initial minimum plasma concentration (Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight-adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.

Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial.

BACKGROUND: Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment. METHODS AND FINDINGS: We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course. CONCLUSIONS: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01960257.

BRCA mutations: is everything said?

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes constitute a risk factor for breast cancer development. BRCA mutation research has been an active field since the discovery of the genes, and new mutations in both genes are constantly described and classified according to several systems. AIM: We intend to provide an overview of the current state of BRCA1 and BRCA2 mutation description and classification. We wanted to know whether there was a trend towards a more frequently described mutation type and what the proportion of pathogenic mutations was. RESULTS: We found that, although new mutations are described each year as reflected in current database records, very few of them are reported in papers. Classification systems are highly heterogeneous and a consensus among them is still under development. Regarding their function, a large number of mutations are yet to be analyzed, a very complex task, due to the great number of possible variations and their diverse effect in the BRCA gene functions. After individual analysis, many variants of unknown significance turn out to be pathogenic, and many can disrupt interactions with other proteins involved in mechanisms such as DNA damage repair pathways. Recent data suggest that looking for mutation patterns or combinations would shed a wider light on BRCA-derived cancer susceptibility in the upcoming years.

Comparing adenoma and polyp miss rates for total underwater colonoscopy versus standard CO2: a randomized controlled trial using a tandem colonoscopy approach.

BACKGROUND AND AIMS: Although water exchange may improve adenoma detection compared with CO2, it is unclear whether water is a better medium to fill the lumen during withdrawal and visualize the mucosa. Total underwater colonoscopy (TUC) involves the use of water exchange with the air valve off during insertion followed by the inspection of the mucosa under water. Our goal was to compare miss rates for TUC with standard CO2 for polyps and adenomas using a tandem colonoscopy design. METHODS: We randomized participants to undergo tandem colonoscopies using TUC or CO2 first. In TUC, water exchange was performed during insertion, and withdrawal was performed under water. For the CO2 colonoscopy, both insertion and withdrawal were performed with CO2. The main outcomes were miss rates for polyps and adenomas for the first examination calculated as the number of additional polyps/adenomas detected during the second examination divided by the total number of polyps/adenomas detected for both examinations. Inspection times were calculated by subtracting the time for polypectomy, and care was taken to keep the times equal for both examinations. RESULTS: A total of 121 participants were randomized with 61 having CO2 first. The overall miss rate for polyps was higher for the TUC-first group (81/237; 34%) compared with the CO2-first cohort (57/264; 22%) (P = .002). In addition, the overall miss rate for all adenomas was higher for the TUC-first group (52/146; 36%) compared with the CO2 group (37/159; 23%) (P = .025). However, 1 of the 3 endoscopists had higher polyp/adenoma miss rates for CO2, but these were not statistically significant differences. The insertion time was longer for TUC than for CO2. After adjusting for times, participant characteristics, and bowel preparation, the miss rate for polyps was higher for TUC than for CO2. CONCLUSIONS: We found that TUC had an overall higher polyp and adenoma miss rate than colonoscopy performed with CO2, and TUC took longer to perform. However, TUC may benefit some endoscopists, an issue that requires further study. (Clinical trial registration number: NCT03231917.).

A comparison of 2 distal attachment mucosal exposure devices: a noninferiority randomized controlled trial.

BACKGROUND AND AIMS: Endocuff (Arc Medical Design, Leeds, UK) and Endocuff Vision (Arc Medical Design, Leeds, UK) are effective mucosal exposure devices for improving polyp detection during colonoscopy. AmplifEYE (Medivators Inc, Minneapolis, Minn, USA) is a device that appears similar to the Endocuff devices but has received minimal clinical testing. METHODS: We performed a randomized controlled clinical trial using a noninferiority design to compare Endocuff Vision with AmplifEYE. RESULTS: The primary endpoint of adenomas per colonoscopy was similar in AmplifEYE at 1.63 (standard deviation 2.83) versus 1.51 (2.29) with Endocuff Vision (P = .535). The 95% lower confidence limit was 0.88 for ratio of means, establishing noninferiority of AmplifEYE (P = .008). There was no difference between the arms for mean insertion time, and mean inspection time (withdrawal time minus polypectomy time and time for washing and suctioning) was shorter with AmplifEYE (6.8 minutes vs 6.9 minutes, P = .042). CONCLUSIONS: AmplifEYE is noninferior to Endocuff Vision for adenoma detection. The decision on which device to use can be based on cost. Additional comparisons of AmplifEYE with Endocuff by other investigators are warranted. (Clinical trial registration number: NCT03560128.).

SIC-8000 versus hetastarch as a submucosal injection fluid for EMR: a randomized controlled trial.

BACKGROUND AND AIMS: Viscous solutions provide a superior submucosal cushion for EMR. SIC-8000 (Eleview; Aries Pharmaceuticals, La Jolla, Calif) is a commercially available U.S. Food and Drug Administration-approved solution, but hetastarch is also advocated. We performed a randomized trial comparing SIC-8000 with hetastarch as submucosal injection agents for colorectal EMR. METHODS: This was a single-center, double-blinded, randomized controlled trial performed at a tertiary referral center. Patients were referred to our center with flat or sessile lesions measuring ≥15 mm in size. The primary outcome measures were the Sydney resection quotient (SRQ) and the rate of en bloc resections. Secondary outcomes were total volume needed for a sufficient lift, number of resected pieces, and adverse events. RESULTS: There were 158 patients with 159 adenomas (SIC-8000, 84; hetastarch, 75) and 57 serrated lesions (SIC-8000, 30; hetastarch, 27). SRQ was significantly better in the SIC-8000 group compared with hetastarch group (9.3 vs 8.1, P = .001). There was no difference in the proportion of lesions with en bloc resections. The total volume of injectate was significantly lower with SIC-8000 (14.8 mL vs 20.6 mL, P = .038). CONCLUSIONS: SIC-8000 is superior to hetastarch for use during EMR in terms of SRQ and total volume needed, although the absolute differences were small. (Clinical trial registration number: NCT03350217.).

Risk of cancer in 10 - 19 mm endoscopically detected colorectal lesions.

BACKGROUND: Recent data indicate that the risk of cancer in colorectal lesions < 10 mm is lower than previously reported, possibly reflecting improved detection of flat, low-volume lesions with a low risk of cancer. Few studies have examined the prevalence of cancer in colorectal lesions 10 - 19 mm in size. METHODS: We reviewed a prospectively collected database of all colorectal lesions removed at a single endoscopy center in order to identify lesions of 10 - 19 mm in size and review their histology. Lesions ≥ 20 mm were evaluated as a control group. We reviewed photographs of cancerous lesions to determine the frequency of endoscopic features of cancer. RESULTS: A total of 5093 lesions ≥ 10 mm were removed from 4020 patients (mean age 63.2 years, 34.4 % female). Among 3068 lesions 10 - 19 mm in size, 28 (0.9 %) had adenocarcinoma, including 1.2 % of conventional adenomas and 0.3 % of serrated class lesions. These rates were lower than the 6.9 % and 2.0 % rates of cancer found in conventional adenomatous lesions and serrated lesions ≥ 20 mm, respectively. Cancer was suggested by endoscopic features in 52.0 % of malignancies 10 - 19 mm in size compared with 79.2 % of lesions ≥ 20 mm. CONCLUSIONS: The prevalence of cancer in 10 - 19 mm colorectal lesions was much lower than previously reported. The cancer risk was higher in conventional adenomas than in serrated lesions. Cancer was endoscopically evident prior to resection in slightly more than half of colorectal lesions 10 - 19 mm in size.