Radical Stereochemistry: Accounting for Diastereomers in Kinetic Mechanism Development.

Recent work in combustion and atmospheric chemistry has revealed cases in which diastereomers must be distinguished to accurately model a reacting flow. This paper presents an open-source framework for introducing such stereoisomer resolution into a kinetic mechanism. We detail our definitions and algorithms for labeling and enumerating the stereoisomers of a molecule and then generalize our system to describe the transition state (TS) of a reaction. This allows for the stereospecific enumeration of reactants and products while accounting for "fleeting" stereochemistry that is unique to the TS. We also present the AutoMech Chemical Identifier (AMChI), an InChI-like string identifier that accounts for stereocenters omitted by InChI. This identifier is extended to describe the TSs of reactions, providing a universal lookup key for specific reaction channels. The final piece of our methodology is an analytic formula to remove redundancy from a stereoresolved mechanism when its enantiomers exist as a racemic mixture, making it as compact as possible while fully accounting for the differences between diastereomers. In applying our methodology to two subsets of the NUIGMech1.1 mechanism, we find that our approach reduces the extra species added for large-fuel oxidation from 2231 (133%, full expansion) to 694 (41%, nonredundant expansion). We also find that for pyrolysis more than a quarter of the species in the expanded mechanism cannot be properly described by an InChI string, requiring an AMChI string to communicate their identity. Finally, we find that roughly one-quarter of the large-fuel oxidation reactions and one-third of the pyrolysis reactions include fleeting TS stereochemistry, which may have relevant effects on their kinetics.

Initial detachment of the mouse oocyte from the zona pellucida is mediated by metallopeptidase activity†.

The fully grown mammalian oocyte is tightly attached to its extracellular matrix shell, the zona pellucida (ZP), but the oocyte detaches from the ZP shortly after ovulation is signaled. The mechanism by which the oocyte detaches from the ZP is unknown. Because ZP proteins are initially secreted as transmembrane proteins, we hypothesized that attachment of the oocyte to the ZP is mediated by transmembrane ZP proteins and that detachment occurs when these proteins are cleaved by peptidases. To identify potential candidates for the type of peptidase, we used mouse oocyte transcriptome data sets to identify candidate peptidases localized to the exterior of the oocyte. Screening with a set of small molecule inhibitors that broadly target the families of peptidases represented by the candidates, we found that only inhibitors of the M10 and M12 families of metallopeptidases prevented detachment. Using more selective inhibitors indicated that detachment was prevented by an inhibitor, GI254023X, developed to be selective for ADAM10 in the M12 family but not by those considered selective for the M10 family or for other M12 metallopeptidases expressed in oocytes. Using an antibody that binds to an epitope just distal to the likely cleavage site of murine ZP3 showed that this site was gradually lost from the oocyte surface during the period when detachment occurs and that inhibiting metallopeptidase activity prevented the loss of this epitope. Taken together, these results indicate that detachment of the oocyte from the ZP is mediated by a metallopeptidase.

Acceptability and Feasibility of a Mobile Phone Application to Support HIV Pre-exposure Prophylaxis Among Women with Opioid Use Disorder.

Despite evidence supporting HIV pre-exposure prophylaxis (PrEP) effectiveness, very few women with opioid use disorder (OUD) take PrEP. Interventions that improve medication assisted treatment (MAT) uptake and adherence may also be beneficial for PrEP. The reSET-O mobile phone app is a component of the evidence-based Therapeutic Education System, which improves retention and abstinence for people with OUD. To better understand use of this mobile health tool as a support for PrEP among women with OUD, pre-implementation contextual inquiry is needed. Therefore, we set out to assess target user characteristics, implementation barriers, feasibility, and acceptability of reSET-O. We recruited women with OUD receiving care from a community-based organization in Philadelphia to complete semi-structured interviews. All participants were prescribed reSET-O. We interviewed 20 participants (average age 37 years; 70% white, 15% Hispanic, 5% Black) from 5/2021 to 2/2022. We used an integrated analysis approach combining modified grounded theory and implementation science constructs. Half reported recent injection drug use, and 6 were taking buprenorphine. Mental health symptoms were common, and half described engaging in transactional sex. The majority expressed strong interest in PrEP. Participants reported the app would be highly acceptable for PrEP and MAT adherence support, but only two redeemed the prescription. The most common barriers included phone and internet access. Our findings highlight potential implementation challenges for the use of such an app to support PrEP use in this population. Poor uptake of the app at follow-up indicates that initial prescription redemption is a major barrier to reSET-O implementation.

No difference in survival for primary cutaneous Merkel cell carcinoma after Mohs micrographic surgery and wide local excision.

BACKGROUND: The preferred treatment for clinically node-negative Merkel cell carcinoma (MCC) is surgical excision in conjunction with sentinel lymph node biopsy. There is limited large-scale research on survival outcomes by surgical approach for management of the primary tumor. OBJECTIVE: To compare overall and MCC-specific survival outcomes in clinically and pathologically, node-negative MCC patients treated with wide-local excision (WLE) and Mohs micrographic surgery (MMS) in a nationally representative sample. METHODS: Overall and MCC-specific survival outcomes for primary MCC tumors contained in the SEER (Surveillance, Epidemiology, and End Results)-18 database from 1989 to 2015 were stratified by surgical modality and analyzed via competing risk analysis. RESULTS: A total of 2359 US adults with MCC were included in the analysis. For overall and MCC-specific survival, there was no significant difference in survival outcomes between WLE and MMS on multivariable analysis (hazard ratio, 1.04 [95% CI, 0.88-1.22]; subdistribution hazard ratio, 0.76 [95% CI, 0.53-1.09]). Sentinel lymph node biopsy was associated with improved overall survival and MCC-specific survival. LIMITATIONS: Retrospective design of SEER and the lack of covariates such as comorbidities and immunostaining. CONCLUSION: There is no survival disadvantage for MMS compared to WLE as the surgical modality for primary cutaneous MCC. Sentinel lymph node biopsy should be coordinated prior to MMS.

Evaluating Predictors of Patient Satisfaction With Facial Appearance After Mohs Micrographic Surgery Using the FACE-Q.

BACKGROUND: Although patient satisfaction with reconstructive outcomes after facial skin cancer resection is an important consideration in Mohs surgery, there is limited information evaluating this concern using validated patient-reported outcome tools. OBJECTIVE: To characterize predictors that may be associated with increased postoperative patient satisfaction with facial appearance after Mohs surgery using the FACE-Q/Skin Cancer survey, a patient-reported outcome tool that has been validated in various studies. METHODS: A total of 202 patients who underwent Mohs surgery for facial skin cancer at the Brigham and Women's Faulkner Hospital between April 2017 and November 2021 were included after completing the postoperative Satisfaction with Facial Appearance scale (FACE-Q scale). RESULTS: Male patients were significantly more likely to have higher satisfaction scores compared with female patients (aOR 2.4, 95% CI 1.1-5.1). Increased preoperative facial satisfaction scores was directly correlated with increased postoperative facial satisfaction scores ( p < .01). Patients with tumors on the lower face/neck (aOR 3.88; 95% CI 1.4-10.7) had significantly greater satisfaction scores compared with those with tumors on their nose/nasolabial folds. CONCLUSION: Potential interventions and counseling methods can be tailored toward specific patient populations with lower satisfaction scores to increase their overall satisfaction with reconstructive outcomes.

Dosimetric and feasibility evaluation of a CBCT-based daily adaptive radiotherapy protocol for locally advanced cervical cancer.

PURPOSE: Evaluate a cone-beam computed tomography (CBCT)-based daily adaptive platform in cervical cancer for multiple endpoints: (1) physics contouring accuracy of daily CTVs, (2) CTV coverage with adapted plans and reduced PTV margins versus non-adapted plans with standard-of-care (SOC) margins, (3) dosimetric improvements to CTV and organs-at-risk (OARs), and (4) on-couch time. METHODS AND MATERIALS: Using a Varian Ethos™ emulator and KV-CBCT scans, we simulated the doses 15 retrospective cervical cancer patients would have received with/without online adaptation for five fractions. We compared contours and doses from SOC plans (5-15 mm CTV-to-PTV margins) to adapted plans (3 mm margins). Auto-segmented CTVs and OARs were reviewed and edited by trained physicists. Physics-edited targets were evaluated by an oncologist. Time spent reviewing and editing auto-segmented structures was recorded. Metrics from the CTV (D99%), bowel (V45Gy, V40Gy), bladder (D50%), and rectum (D50%) were compared. RESULTS: The physician approved the physics-edited CTVs for 55/75 fractions; 16/75 required reductions, and 4/75 required CTV expansions. CTVs were encapsulated by unadapted, SOC PTVs for 56/75 (72%) fractions-representative of current clinical practice. CTVs were completely covered by adapted 3 mm PTVs for 71/75 (94.6%) fractions. CTV D99% values for adapted plans were comparable to non-adapted SOC plans (average difference of -0.9%), while all OAR metrics improved with adaptation. Specifically, bowel V45Gy and V40Gy decreased on average by 87.6 and 109.4 cc, while bladder and rectum D50% decreased by 37.7% and 35.8%, respectively. The time required for contouring and calculating an adaptive plan for 65/75 fractions was less than 20 min (range: 1-29 min). CONCLUSIONS: Improved dose metrics with daily adaption could translate to reduced toxicity while maintaining tumor control. Training physicists to perform contouring edits could minimize the time physicians are required at adaptive sessions improving clinical efficiency. All emulated adaptive sessions were completed within 30 min however extra time will be required for patient setup, image acquisition, and treatment delivery.

Half-pin Breakage in Multiplanar External Fixators Used for Pediatric Deformity Correction.

BACKGROUND: Pediatric patients with leg length discrepancies and complex deformities may require multiplanar external fixators for correction. We have encountered 4 cases of half-pin breakage with the Orthex hexapod frame. The purpose of this study is to report factors associated with half-pin breakage and compare various deformity correction characteristics between 2 hexapod frames - Taylor Spatial Frame (TSF) and Orthex. METHODS: Pediatric patients with lower extremity deformities treated with an Orthex or TSF at a single tertiary children's hospital between 2012 and 2022 were included for retrospective review. Variables compared between frame groups include frame configuration, half-pin/wire fixation, length achieved, angular correction, and frame time. RESULTS: There were 23 Orthex frames (23 patients) and 36 TSF (33 patients) included. Four Orthex and zero TSF had proximal half-pin breakage. The Orthex group was younger on average (10 vs. 12 y, P =.04*) at the time of frame placement. The majority (52%) of Orthex frames were used for simultaneous lengthening and angular correction, while the majority (61%) of TSF was used for only angular correction. Orthex had more half-pins used for proximal fixation (median 3 vs. 2, P <0.0001*) and more frames with nonstandard configuration (7 (30%) vs. 1 (3%), P =0.004*). Orthex group had a longer total frame time (median 189 vs. 146 days, P =0.012*) and longer time required for regenerate healing (117 vs. 89 d, P =0.02*). There were no significant differences in length gained, angular correction, or healing index between Orthex and TSF. Nonstandard configuration, increased number of proximal half-pins, younger age at index surgery, and increased lengthening were associated with pin breakage. CONCLUSIONS: This is the first study to report half-pin breakage while using multiplanar frames in pediatric lower extremity deformity correction. The Orthex and TSF groups consisted of significantly different patients and frame configurations, making it difficult to identify any specific cause for pin breakage. This study shows that pin breakage is likely caused by multiple factors and is associated with the increased complexity of deformity correction. LEVEL OF EVIDENCE: Level III-Retrospective Comparison Study.

Clinical commissioning of an adaptive radiotherapy platform: Results and recommendations.

Online adaptive radiotherapy platforms present a unique challenge for commissioning as guidance is lacking and specialized adaptive equipment, such as deformable phantoms, are rare. We designed a novel adaptive commissioning process consisting of end-to-end tests using standard clinical resources. These tests were designed to simulate anatomical changes regularly observed at patient treatments. The test results will inform users of the magnitude of uncertainty from on-treatment changes during the adaptive workflow and the limitations of their systems. We implemented these tests for the cone-beam computed tomography (CT)-based Varian Ethos online adaptive platform. Many adaptive platforms perform online dose calculation on a synthetic CT (synCT). To assess the impact of the synCT generation and online dose calculation on dosimetric accuracy, we conducted end-to-end tests using commonly available equipment: a CIRS IMRT Thorax phantom, PinPoint ionization chamber, Gafchromic film, and bolus. Four clinical scenarios were evaluated: weight gain and weight loss were simulated by adding and removing bolus, internal target shifts were simulated by editing the CTV during the adaptive workflow to displace it, and changes in gas were simulated by removing and reinserting rods in varying phantom locations. The effect of overriding gas pockets during planning was also assessed. All point dose measurements agreed within 2.7% of the calculated dose, with one exception: a scenario simulating gas present in the planning CT, not overridden during planning, and dissipating at treatment. Relative film measurements passed gamma analysis (3%/3 mm criteria) for all scenarios. Our process validated the Ethos dose calculation for online adapted treatment plans. Based on our results, we made several recommendations for our clinical adaptive workflow. This commissioning process used commonly available equipment and, therefore, can be applied in other clinics for their respective online adaptive platforms.

Guidelines on the management of ascites in cirrhosis.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time.

HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study.

AIMS/HYPOTHESIS: The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes. METHODS: We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [3H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima-media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2 years; BMI 26.9 ± 0.5 kg/m2) and 100 non-diabetic participants (37.7 ± 1.1 years; 27.1 ± 0.5 kg/m2). RESULTS: Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04 µmol/l [mean difference (MD) -3.32 µmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05 µmol/l [MD +2.37 µmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56 nm [MD +0.38 nm]) (p < 0.05 for all). Total CEC (14.57 ± 2.47%CEC/4 h vs 12.26 ± 3.81%CEC/4 h [MD +2.31%CEC/4 h]) was greater in participants with type 1 diabetes relative to non-diabetic participants. Increased HDL particle size was independently associated with increased total CEC; however, following adjustment for this in multivariable analysis, CEC remained greater in participants with type 1 diabetes. Both components of CEC, ABCA1-dependent (6.10 ± 2.41%CEC/4 h vs 5.22 ± 2.57%CEC/4 h [MD +0.88%CEC/4 h]) and ABCA1-independent (8.47 ± 1.79% CEC/4 h vs 7.05 ± 1.76% CEC/4 h [MD +1.42% CEC/4 h]) CEC, were greater in type 1 diabetes but the increase in ABCA1-dependent CEC was less marked and not statistically significant in multivariable analysis. CIMT was increased in participants with type 1 diabetes but in multivariable analysis it was only associated negatively with age and BMI. CONCLUSIONS/INTERPRETATION: HDL particle size but not HDL-cholesterol level is independently associated with enhanced total CEC. HDL particle size is greater in individuals with type 1 diabetes but even after adjusting for this, total and ABCA1-independent CEC are enhanced in type 1 diabetes. Further studies are needed to understand the mechanisms underlying these effects, and whether they help attenuate progression of atherosclerosis in this high-risk group. Graphical abstract.

Substitution Reactions in the Pyrolysis of Acetone Revealed through a Modeling, Experiment, Theory Paradigm.

The development of high-fidelity mechanisms for chemically reactive systems is a challenging process that requires the compilation of rate descriptions for a large and somewhat ill-defined set of reactions. The present unified combination of modeling, experiment, and theory provides a paradigm for improving such mechanism development efforts. Here we combine broadband rotational spectroscopy with detailed chemical modeling based on rate constants obtained from automated ab initio transition state theory-based master equation calculations and high-level thermochemical parametrizations. Broadband rotational spectroscopy offers quantitative and isomer-specific detection by which branching ratios of polar reaction products may be obtained. Using this technique, we observe and characterize products arising from H atom substitution reactions in the flash pyrolysis of acetone (CH3C(O)CH3) at a nominal temperature of 1800 K. The major product observed is ketene (CH2CO). Minor products identified include acetaldehyde (CH3CHO), propyne (CH3CCH), propene (CH2CHCH3), and water (HDO). Literature mechanisms for the pyrolysis of acetone do not adequately describe the minor products. The inclusion of a variety of substitution reactions, with rate constants and thermochemistry obtained from automated ab initio kinetics predictions and Active Thermochemical Tables analyses, demonstrates an important role for such processes. The pathway to acetaldehyde is shown to be a direct result of substitution of acetone's methyl group by a free H atom, while propene formation arises from OH substitution in the enol form of acetone by a free H atom.

Evaluation of Public Interest in Mohs Surgery and Other Elective Surgical Procedures During the COVID-19 Pandemic.

BACKGROUND: The reallocation of health care resources to focus on the acute care needs of COVID-19 patients leads to a delay and deferral of outpatient surgical procedures such as Mohs surgery. OBJECTIVE: Planning for the resumption of regular outpatient surgical care and preparing for future surges in COVID-19 cases requires identifying surrogate markers of health care demand. MATERIALS AND METHODS: United States national and state-based Google search data for "Mohs surgery" and other common elective surgical and cosmetic procedures were evaluated. These were compared with national and state-wide COVID-19 case number and death data from the Johns Hopkins University. Pearson correlation coefficients were generated to assess the association between COVID-19 cases and deaths with Google search trends. RESULTS: Search volume for "Mohs surgery" and other elective surgical and cosmetic procedures significantly decreased as the number of new deaths from COVID-19 increased. Statistically significant inverse correlation was noted between "Mohs surgery" search volume and new COVID-19 deaths on a national and state-based level. CONCLUSION: Search metric analysis may be used as part of a big data model to help predict health care demand during the reopening phase of the COVID-19 pandemic.

A Non-Surgical and Cost-Effective Treatment Approach Employing Topical Imiquimod, 5-Fluorouracil, and Tretinoin for Primary Non-Melanoma Skin Cancers.

BACKGROUND: Minimally invasive alternative approaches to treat non-melanoma skin cancers remain limited and unproven. OBJECTIVE: We aim to assess the efficacy of varying combinations of anti-tumor agents—imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream—with brief cryotherapy in treating non-melanoma skin cancers. METHODS: This retrospective study included 690 cases of non-melanoma skin cancers in 480 patients who received a diagnosis of a basal cell carcinoma or squamous cell carcinoma during a ten-year period. During treatment period, patients applied 30 applications of one of three combinations (imiquimod/tretinoin, 5-fluorouracil/tretinoin, or imiquimod/5-fluorouracil/tretinoin) and had cryotherapy every 2 weeks. Each patient had a clinical examination at least three years post-treatment or documented treatment failure. Clearance was defined by a lack of persistence or recurrence for 3 years following the completion of treatment. The likelihood of lesion clearance was evaluated using multivariable logistic regression analysis. RESULTS: A total of 186 cases (97; basal cell carcinoma and 89; squamous cell carcinoma) in 133 patients [37% women and 63% men; median (interquartile range) age, 77 (69, 83) years] met the inclusion criteria. Multivariable logistic regression analysis adjusting for clinical and lesion variables demonstrated that, relative to the imiquimod/5-fluorouracil/tretinoin treatment approach, imiquimod/ tretinoin (odds ratio, 0.05; 95% confidence interval, 0.00-0.99) and 5-fluorouracil/tretinoin (0.02; 0.00–0.45) were associated with lower likelihoods of lesion clearance. Likewise, morpheaform basal cell carcinoma had a lower probability of clearance (0.05; 0.00–0.72). CONCLUSIONS: The combination of imiquimod/5-fluorouracil/tretinoin with cryotherapy had high clearance rates and was the most effective treatment regimen. J Drugs Dermatol. 2021;20(3):260-267. doi:10.36849/JDD.5427.

Continuing patient care to underserved communities and medical education during the COVID-19 pandemic through a teledermatology student-run clinic.

A virtual pediatric dermatology student-run clinic was initiated during the COVID-19 pandemic, when in-person educational opportunities were limited. The clinic's aim is to provide high-quality dermatologic care to a diverse, underserved pediatric patient population while teaching trainees how to diagnose and manage common skin conditions. In our initial eight sessions, we served 37 patients, predominantly those with skin of color, and had a low no-show rate of 9.8%. This report describes the general structure of the clinic, goals, and the patient population to provide an overview of our educational model for those interested in similar efforts.

Prospects for daily online adaptive radiotherapy via ethos for prostate cancer patients without nodal involvement using unedited CBCT auto-segmentation.

PURPOSE:  Implementing new online adaptive radiation therapy technologies is challenging because extra clinical resources are required particularly expert contour review. Here, we provide the first assessment of Varian's Ethos™ adaptive platform for prostate cancer using no manual edits after auto-segmentation to minimize this impact on clinical efficiency. METHODS: Twenty-five prostate patients previously treated at our clinic were re-planned using an Ethos™ emulator. Clinical target volumes (CTV) included intact prostate and proximal seminal vesicles. The following clinical margins were used: 3 mm posterior, 5 mm left/right/anterior, and 7 mm superior/inferior. Adapted plans were calculated for 10 fractions per patient using Ethos's auto-segmentation and auto-planning workflow without manual contouring edits. Doses and auto-segmented structures were exported to our clinical treatment planning system where contours were modified as needed for all 250 CTVs and organs-at-risk. Dose metrics from adapted plans were compared to unadapted plans to evaluate CTV and OAR dose changes. RESULTS: Overall 96% of fractions required auto-segmentation edits, although corrections were generally minor (<10% of the volume for 70% of CTVs, 88% of bladders, and 90% of rectums). However, for one patient the auto-segmented CTV failed to include the superior portion of prostate that extended into the bladder at all 10 fractions resulting in under-contouring of the CTV by 31.3% ± 6.7%. For the 24 patients with minor auto-segmentation corrections, adaptation improved CTV D98% by 2.9% ± 5.3%. For non-adapted fractions where bladder or rectum V90% exceeded clinical thresholds, adaptation reduced them by 13.1% ± 1.0% and 6.5% ± 7.3%, respectively. CONCLUSION:  For most patients, Ethos's online adaptive radiation therapy workflow improved CTV D98% and reduced normal tissue dose when structures would otherwise exceed clinical thresholds, even without time-consuming manual edits. However, for one in 25 patients, large contour edits were required and thus scrutiny of the daily auto-segmentation is necessary and not all patients will be good candidates for adaptation.

A practical method to quantify knowledge-based DVH prediction accuracy and uncertainty with reference cohorts.

The adoption of knowledge-based dose-volume histogram (DVH) prediction models for assessing organ-at-risk (OAR) sparing in radiotherapy necessitates quantification of prediction accuracy and uncertainty. Moreover, DVH prediction error bands should be readily interpretable as confidence intervals in which to find a percentage of clinically acceptable DVHs. In the event such DVH error bands are not available, we present an independent error quantification methodology using a local reference cohort of high-quality treatment plans, and apply it to two DVH prediction models, ORBIT-RT and RapidPlan, trained on the same set of 90 volumetric modulated arc therapy (VMAT) plans. Organ-at-risk DVH predictions from each model were then generated for a separate set of 45 prostate VMAT plans. Dose-volume histogram predictions were then compared to their analogous clinical DVHs to define prediction errors V c l i n , i - V p r e d , i (ith plan), from which prediction bias µ, prediction error variation σ, and root-mean-square error R M S E pred ≡ 1 N ∑ i V c l i n , i - V p r e d , i 2 ≅ σ 2 + µ 2 could be calculated for the cohort. The empirical R M S E pred was then contrasted to the model-provided DVH error estimates. For all prostate OARs, above 50% Rx dose, ORBIT-RT µ and σ were comparable to or less than those of RapidPlan. Above 80% Rx dose, µ < 1% and σ < 3-4% for both models. As a result, above 50% Rx dose, ORBIT-RT R M S E pred was below that of RapidPlan, indicating slightly improved accuracy in this cohort. Because µ ≈ 0, R M S E pred is readily interpretable as a canonical standard deviation σ, whose error band is expected to correctly predict 68% of normally distributed clinical DVHs. By contrast, RapidPlan's provided error band, although described in literature as a standard deviation range, was slightly less predictive than R M S E pred (55-70% success), while the provided ORBIT-RT error band was confirmed to resemble an interquartile range (40-65% success) as described. Clinicians can apply this methodology using their own institutions' reference cohorts to (a) independently assess a knowledge-based model's predictive accuracy of local treatment plans, and (b) interpret from any error band whether further OAR dose sparing is likely attainable.

Role of Terlipressin and Albumin for Hepatorenal Syndrome in Liver Transplantation.

Hepatorenal syndrome (HRS) is one of the most ominous complications of portal hypertension in patients with decompensated cirrhosis and ascites. It is associated with very high mortality on the wait list. Liver transplantation (LT) is the most successful therapeutic option for patients with HRS. However, not all the LT candidates with HRS are able to receive a deceased donor allograft in a timely manner because it is a scarce resource and patients may need alternative best supportive treatment with systemic splanchnic vasoconstrictors and albumin as a bridge to transplant. The combination of terlipressin and albumin is efficacious in the reversal of HRS and is used worldwide. More recently, the multicenter, randomized, placebo-controlled double-blind study to confirm efficacy and safety of terlipressin in subjects with hepatorenal syndrome type 1 (the CONFIRM study) trial demonstrated the efficacy of terlipressin and albumin in the reversal of HRS in a North American cohort. The aim of this article is to review the role of terlipressin and albumin in LT candidates with HRS in the United States.

Assessing the Viability of the Methylsulfinyl Radical-Ozone Reaction.

Although integral to remote marine atmospheric sulfur chemistry, the reaction between methylsulfinyl radical (CH3 SO) and ozone poses challenges to theoretical treatments. The lone theoretical study on this reaction reported an unphysically large barrier of 66 kcal mol-1 for abstraction of an oxygen atom from O3 by CH3 SO. Herein, we demonstrate that this result stems from improper use of MP2 with a single-reference, unrestricted Hartree-Fock (UHF) wavefunction. We characterized the potential energy surface using density functional theory (DFT), as well as multireference methodologies employing a complete active-space self-consistent field (CASSCF) reference. Our DFT PES shows, in contrast to previous work, that the reaction proceeds by forming an addition adduct [CH3 S(O3 )O] in a deep potential well of 37 kcal mol-1 . An O-O bond of this adduct dissociates via a flat, low barrier of 1 kcal mol-1 to give CH3 SO2 +O2 . The multireference computations show that the initial addition of CH3 SO+O3 is barrierless. These results provide a more physically intuitive and accurate picture of this reaction than the previous theoretical study. In addition, our results imply that the CH3 SO2 formed in this reaction can readily decompose to give SO2 as a major product, in alignment with the literature on CH3 SO reactions.

Distortion losses of high-speed single-photon avalanche diode optical receivers approaching quantum sensitivity.

The high internal gain of single-photon avalanche diodes (SPADs) operating in Geiger mode allows the quantum limit of detection to be approached. This offers a significantly improved sensitivity for optical communication over existing photodiodes. A fully integrated CMOS SPAD array receiver (RX) is presented which achieves 500 Mb s-1 four-level pulse amplitude modulation in a visible light communication link within 15.2 dB of the quantum limit. However, SPAD dead time induces around 5.7 dB of transient distortion which restricts error performance and data rate. We propose a model describing a discrete photon counting system which exhibits this nonlinear behaviour and compare it to practical measurements with the RX. A unipolar intensity modulated optical signal is considered, as opposed to bipolar electric fields in conventional radio frequency wireless systems. Intermodulation between the DC and harmonic components of the data-carrying waveform is investigated, and the resulting degradation of signal-to-noise-and-distortion ratio and bit error rate is evaluated. The model is developed as a tool for understanding distortion to ultimately allow rectification through RX architecture, modulation scheme, coding and equalization techniques. This article is part of the theme issue 'Optical wireless communication'.

Pheromone Odorant Receptor Responses Reveal the Presence of a Cryptic, Redundant Sex Pheromone Component in the European Corn Borer, Ostrinia nubilalis.

Two odorant receptors (ORs), OnubOR3 and OnubOR6, in the sex pheromone communication systems of E- and Z-strain European corn borers, Ostrinia nubilalis, were broadly receptive to analogs of their pheromone components. In addition to responding to their natural 14-carbon pheromone components, (Z)-11- and (E)-11-tetradecenyl acetates (Z11- and E11-14:OAc), these pheromone ORs responded to the longer-chain compounds, (Z)-11- and (E)-11-hexadecenyl acetate (Z11- and E11-16:OAc). Z11-16:OAc is a pheromone gland constituent of E-strain O. nubilalis females in Europe but has not previously been shown to have behavioral activity to males. Here, we demonstrate that Z11-16:OAc evokes high levels of upwind flight and source location in E-strain males when substituted for Z11-14:OAc (minor component) in the E-strain blend. Since Z11-16:OAc is found in the gland and has behavioral activity when Z11-14:OAc is missing, then it should be classified as a cryptic, redundant minor pheromone component in E-strain O. nubilalis. The opposite geometric isomer, E11-16:OAc, also functions in Z-strain O. nubilalis, substituting behaviorally for the E11-14:OAc minor component, but has not been found in Z-strain female glands. Single-sensillum recordings showed that sensory neurons of E- and Z-strain male antennae expressing OnubOR3 and OnubOR6 produced responses to these hexadecenyl acetates similar to those evoked by the natural (tetradecenyl acetate) pheromone components. We postulate that the wide responsiveness of these two ORs to the 16-carbon acetates could be a preadaptation for O. nubilalis to use these compounds as minor components in lieu of the respective 14-carbon acetates. Alternatively, the responsiveness of OnubOR3 to E11-16:OAc and OnubOR6 to Z11-16:OAc could represent a vestigial state of these receptors, with the 16-carbon acetates having previously acted as functional minor components in an ancestral blend.