Identification of Reaction Network Hypotheses for Complex Feedstocks from Spectroscopic Measurements with Minimal Human Intervention.

In this work, we detail an automated reaction network hypothesis generation protocol for processes involving complex feedstocks where information about the species and reactions involved is unknown. Our methodology is process agnostic and can be utilized in any reactive process with spectroscopic measurements that provide information on the evolution of the components in the mixture. We decompose the mixture spectra to obtain spectroscopic signatures of the individual components and use a 1-D convolutional neural network to automatically identify functional groups indicated by them. We employ atom-atom mapping to automatically recover reaction rules that are applied on candidate molecules identified from chemistry databases through fingerprint similarity. The method is tested on synthetic data and on spectroscopic measurements of lab-scale batch hydrothermal liquefaction (HTL) of biomass to determine the accuracy of prediction across datasets of varying complexities. Our methodology is able to identify reaction network hypotheses containing reaction networks close to the ground truth in the case of synthetic data, and we are also able to recover candidate molecules and reaction networks close to the ones reported in the previous literature studies for biomass pyrolysis.

Novel High-Throughput Strategy for the Aqueous Solubility Assessment of Peptides and Proteins Exhibiting a Propensity for Gelation: Application to the Discovery of Novel Antibacterial Teixobactin Analogues.

A novel high-throughput aqueous solubility assay was developed for peptides and proteins exhibiting a high gelling propensity (in this case, antibacterial teixobactin analogues). By integrating the assessment of gel formation, as indicated by an increase in the solution viscosity, into the peptide equilibrium solubility screening assay, we were able to estimate the "free-flowing solubility", which is defined as the concentration at which the peptide solution not only is fully dissolved but also is a liquid exhibiting ideal flowing characteristics. In this workflow, peptide solutions passing the turbidity assessment were further screened by viscosity measurements based on nanobead-assisted dynamic light scattering analysis in a 96-well plate. The method is able to effectively detect the initiation of peptide gelation and facilitate compound ranking based on their aqueous solubility. The application of such an approach helped confirm that the substitution of Ser3 in teixobactin led to desired physicochemical improvements and provided a focal point for further chemistry structure-activity relationship exploration.

Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS. SIGNIFICANCE STATEMENT: Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiates it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections.

Preparing for an Increased Need for Abortion Access in India during and after COVID-19: Challenges and Strategies.

Access to safe abortion is a reproductive rights and justice issue, and it is imperative that safe abortion access during and after the COVID-19 pandemic is a reality for all. India imposed a lockdown in March 2020 to contain the spread of the pandemic. Limited mobility, lack of clarity about abortion as an essential service and abortion as a service permitted through telemedicine, shut down of services providing long-acting and permanent methods of contraception, and changes to decision-making about birthing and parenting during a pandemic are factors that may impact the demand for abortion during and after the lockdown. Shortage of raw materials and limited inter- and intra- state transport of drugs may result in breakages in the supply of medication abortion. Given that 73 percent of abortions in India in 2015 occurred outside of health facilities, the pandemic may have several implications on the need for evidence-based information and quality abortion services, as well as if and how medication abortion is accessed in India, and what self-managed abortion looks like in the COVID-19 era. We discuss factors contributing to reduced access to abortion, changes in abortion need, and suggest strategies to respond to an increased demand for abortion in India.

Wellbuilt for wellbeing: Controlling relative humidity in the workplace matters for our health.

This study offers a new perspective on the role of relative humidity in strategies to improve the health and wellbeing of office workers. A lack of studies of sufficient participant size and diversity relating relative humidity (RH) to measured health outcomes has been a driving factor in relaxing thermal comfort standards for RH and removing a lower limit for dry air. We examined the association between RH and objectively measured stress responses, physical activity (PA), and sleep quality. A diverse group of office workers (n = 134) from four well-functioning federal buildings wore chest-mounted heart rate variability monitors for three consecutive days, while at the same time, RH and temperature (T) were measured in their workplaces. Those who spent the majority of their time at the office in conditions of 30%-60% RH experienced 25% less stress at the office than those who spent the majority of their time in drier conditions. Further, a correlational study of our stress response suggests optimal values for RH may exist within an even narrower range around 45%. Finally, we found an indirect effect of objectively measured poorer sleep quality, mediated by stress responses, for those outside this range.

Deep convolutional network for animal sound classification and source attribution using dual audio recordings.

This paper introduces an end-to-end feedforward convolutional neural network that is able to reliably classify the source and type of animal calls in a noisy environment using two streams of audio data after being trained on a dataset of modest size and imperfect labels. The data consists of audio recordings from captive marmoset monkeys housed in pairs, with several other cages nearby. The network in this paper can classify both the call type and which animal made it with a single pass through a single network using raw spectrogram images as input. The network vastly increases data analysis capacity for researchers interested in studying marmoset vocalizations, and allows data collection in the home cage, in group housed animals.

Developing a Three-Layered Synthetic Microsurgical Simulation Vessel.

BACKGROUND: Microsurgery is increasingly relevant, and is difficult to learn. Simulation is relied upon ever more in microvascular training. While living models provide the ultimate physiological feedback, we are ethically obliged to optimize non-living models to replace, refine, and reduce the use of animals in training. There is currently no three-layered synthetic vessel available for microsurgical training. METHODS: A three-layered synthetic vessel was designed with a simulation company. One anastomosis was performed by 14 microsurgical experts at one center. The realism of the vessel was assessed via user questionnaires and the construct validity using objective, validated task scores to assess the anastomosis performance and the final product. Videos were obtained, which were anonymized and marked remotely by a consultant plastic surgeon. RESULTS: The synthetic vessel intima and media displayed reasonable realism, while the adventitia was less realistic. Areas for improvement were identified. Both the task specific assessment score and the final product assessment appropriately identified experts. CONCLUSION: A three-layered synthetic model for microvascular training is a hygienic and useful intermediate-level alternative to commonly used synthetic and ex vivo alternatives.

Effects of office workstation type on physical activity and stress.

OBJECTIVE: Office environments have been causally linked to workplace-related illnesses and stress, yet little is known about how office workstation type is linked to objective metrics of physical activity and stress. We aimed to explore these associations among office workers in US federal office buildings. METHODS: We conducted a wearable, sensor-based, observational study of 231 workers in four office buildings. Outcome variables included workers' physiological stress response, physical activity and perceived stress. Relationships between office workstation type and these variables were assessed using structural equation modelling. RESULTS: Workers in open bench seating were more active at the office than those in private offices and cubicles (open bench seating vs private office=225.52 mG (31.83% higher on average) (95% CI 136.57 to 314.46); open bench seating vs cubicle=185.13 mG (20.16% higher on average) (95% CI 66.53 to 303.72)). Furthermore, workers in open bench seating experienced lower perceived stress at the office than those in cubicles (-0.27 (9.10% lower on average) (95% CI -0.54 to -0.02)). Finally, higher physical activity at the office was related to lower physiological stress (higher heart rate variability in the time domain) outside the office (-26.12 ms/mG (14.18% higher on average) (95% CI -40.48 to -4.16)). CONCLUSIONS: Office workstation type was related to enhanced physical activity and reduced physiological and perceived stress. This research highlights how office design, driven by office workstation type, could be a health-promoting factor.

Gynaecomastia correction: A review of our experience.

INTRODUCTION: Gynaecomastia is a common problem in the male population with a reported prevalence of up to 36%. Various treatment techniques have been described but none have gained universal acceptance. We reviewed all gynaecomastia patients operated on by one consultant over a 7-year period to assess the morbidity and complication rates associated with the procedure. MATERIALS AND METHODS: Clinical notes and outpatient records of all patients who underwent gynaecomastia correction at University Hospital North Staffordshire between 01/10/2001 to 01/10/2009 were retrospectively reviewed. A modified version of the Breast Evaluation Questionnaire was used to assess patients satisfaction with the procedure. RESULTS: Twenty-nine patients and a total of 53 breasts were operated on during the study period. Patients underwent either liposuction alone (6 breasts - 11.3%), excision alone (37 breasts - 69.8%) or both excision and liposuction (10 breasts - 18.9%). Twelve operated breasts (22.6%) experienced some form of complication. Minor complications included seroma (2 patients), superficial wound dehiscence (2 patients) and minor bleeding not requiring theatre (3 patients). Two patients developed haematomas requiring evacuation in theatre. No cases of wound infection, major wound dehiscence or revision surgery were encountered. Twenty-six patients (89.7%) returned the patient satisfaction questionnaire. Patients scored an average 4.12 with regards comfort of their chest in different settings, 3.98 with regards chest appearance in different settings, and 4.22 with regards satisfaction levels for themselves and their partner/family. Overall complication rate was 22.6%. Grade III patients experienced the highest complication rate (35.7%), followed by grade II (22.7%) and grade I (17.6%). Overall complication rates among the excision only group was the highest (29.8%) followed by the liposuction only group (16.7%) and the liposuction and excision group (10.0%). There were high satisfaction rates amongst both patients and surgeon. Eleven patients (37.9%) had their outcome classified as 'excellent' by the operating surgeon, 16 patients (55.2%) as 'good', 1 (3.4%) as 'satisfactory' and 1(3.4%) as 'poor'. CONCLUSION: Gynaecomastia is a complex condition which poses a significant challenge to the plastic surgeon. Despite the possible complications our case series demonstrates that outcomes of operative correction can be favourable and yield high levels of satisfaction from both patient and surgeon.

Brain fog and vessel clogs.

We present a unique case of a 36-year-old female presenting with features suggestive of bilateral combined vascular occlusion, hearing loss, and encephalopathy. Multimodal imaging was done for both eyes fundus evaluation including wide-field color fundus photography, optical coherence tomography, and fundus fluorescein angiography. After extensive ocular and systemic investigations, she was diagnosed to have Susac syndrome (SS). She was referred to a neurologist and otologist for systemic evaluation and underwent laser photocoagulation in both eyes, followed by pars plana vitrectomy in her left eye. Combined bilateral retinal vascular occlusion in association with SS is very rare.

Comparative analysis of outcomes of two (popular) techniques of haptic exteriorization in scleral fixation intra-ocular lens surgery - A retrospective study.

PURPOSE: To compare the visual outcomes and complication rates between the extra-ocular needle-guided haptic insertion technique (XNIT) and the conventional handshake (HS) technique of scleral fixation intra-ocular lens (SFIOL). METHODS: In this retrospective study, we retrieved data of those patients who had undergone SFIOL surgery from January 2018 to May 2022 at our institute for aphakia following either a complicated cataract surgery or an ocular trauma and had a minimum follow-up of 3 months. RESULTS: Of the 156 eyes, the HS technique was done in 80 eyes and the remaining 76 eyes with XNIT. At 3 months follow-up visit, there was no significant difference in the median best corrected visual acuity (BCVA) ( P = 0.988) and uncorrected visual acuity (UCVA) ( P = 0.765) between the two techniques. There was no statistically significant difference between pre-operative median BCVA and post-operative UCVA in XNIT ( P = 0.961) and the HS technique ( P = 0.831) at 3 months follow-up visit. The complication rates between the two techniques were minimal and comparable. The most common post-operative complication was corneal edema. The incidence of cystoid macular edema was slightly more in the XNIT group but not statistically significant ( P = 0.05). Two patients in the HS group developed retinal detachment, which settled after repeat surgery. CONCLUSION: The newer XNIT technique was found to be as safe and effective as compared to the conventional HS technique.

Protocol to identify biomarkers in patients with post-COVID condition using multi-omics and machine learning analysis of human plasma.

Here, we present a workflow for analyzing multi-omics data of plasma samples in patients with post-COVID condition (PCC). Applicable to various diseases, we outline steps for data preprocessing and integrating diverse assay datasets. Then, we detail statistical analysis to unveil plasma profile changes and identify biomarker-clinical variable associations. The last two steps discuss machine learning techniques for unsupervised clustering of patients based on their inherent molecular similarities and feature selection to identify predictive biomarkers. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

Adaptive Tensor-Based Feature Extraction for Pupil Segmentation in Cataract Surgery.

Cataract surgery remains the only definitive treatment for visually significant cataracts, which are a major cause of preventable blindness worldwide. Successful performance of cataract surgery relies on stable dilation of the pupil. Automated pupil segmentation from surgical videos can assist surgeons in detecting risk factors for pupillary instability prior to the development of surgical complications. However, surgical illumination variations, surgical instrument obstruction, and lens material hydration during cataract surgery can limit pupil segmentation accuracy. To address these problems, we propose a novel method named adaptive wavelet tensor feature extraction (AWTFE). AWTFE is designed to enhance the accuracy of deep learning-powered pupil recognition systems. First, we represent the correlations among spatial information, color channels, and wavelet subbands by constructing a third-order tensor. We then utilize higher-order singular value decomposition to eliminate redundant information adaptively and estimate pupil feature information. We evaluated the proposed method by conducting experiments with state-of-the-art deep learning segmentation models on our BigCat dataset consisting of 5,700 annotated intraoperative images from 190 cataract surgeries and a public CaDIS dataset. The experimental results reveal that the AWTFE method effectively identifies features relevant to the pupil region and improved the overall performance of segmentation models by up to 2.26% (BigCat) and 3.31% (CaDIS). Incorporation of the AWTFE method led to statistically significant improvements in segmentation performance (P < 1.29 × 10-10 for each model) and yielded the highest-performing model overall (Dice coefficients of 94.74% and 96.71% for the BigCat and CaDIS datasets, respectively). In performance comparisons, the AWTFE consistently outperformed other feature extraction methods in enhancing model performance. In addition, the proposed AWTFE method significantly improved pupil recognition performance by up to 2.87% in particularly challenging phases of cataract surgery.

Plasma taurine level is linked to symptom burden and clinical outcomes in post-COVID condition.

BACKGROUND: A subset of individuals (10-20%) experience post-COVID condition (PCC) subsequent to initial SARS-CoV-2 infection, which lacks effective treatment. PCC carries a substantial global burden associated with negative economic and health impacts. This study aims to evaluate the association between plasma taurine levels with self-reported symptoms and adverse clinical outcomes in patients with PCC. METHODS AND FINDINGS: We analyzed the plasma proteome and metabolome of 117 individuals during their acute COVID-19 hospitalization and at the convalescence phase six-month post infection. Findings were compared with 28 age and sex-matched healthy controls. Plasma taurine levels were negatively associated with PCC symptoms and correlated with markers of inflammation, tryptophan metabolism, and gut dysbiosis. Stratifying patients based on the trajectories of plasma taurine levels during six-month follow-up revealed a significant association with adverse clinical events. Increase in taurine levels during the transition to convalescence were associated with a reduction in adverse events independent of comorbidities and acute COVID-19 severity. In a multivariate analysis, increased plasma taurine level between acute and convalescence phase was associated with marked protection from adverse clinical events with a hazard ratio of 0.13 (95% CI: 0.05-0.35; p<0.001). CONCLUSIONS: Taurine emerges as a promising predictive biomarker and potential therapeutic target in PCC. Taurine supplementation has already demonstrated clinical benefits in various diseases and warrants exploration in large-scale clinical trials for alleviating PCC.

Transfer learning predicts species-specific drug interactions in emerging pathogens.

Machine learning (ML) algorithms are necessary to efficiently identify potent drug combinations within a large candidate space to combat drug resistance. However, existing ML approaches cannot be applied to emerging and under-studied pathogens with limited training data. To address this, we developed a transfer learning and crowdsourcing framework (TACTIC) to train ML models on data from multiple bacteria. TACTIC was built using 2,965 drug interactions from 12 bacterial strains and outperformed traditional ML models in predicting drug interaction outcomes for species that lack training data. Top TACTIC model features revealed genetic and metabolic factors that influence cross-species and species-specific drug interaction outcomes. Upon analyzing ~600,000 predicted drug interactions across 9 metabolic environments and 18 bacterial strains, we identified a small set of drug interactions that are selectively synergistic against Gram-negative (e.g., A. baumannii) and non-tuberculous mycobacteria (NTM) pathogens. We experimentally validated synergistic drug combinations containing clarithromycin, ampicillin, and mecillinam against M. abscessus, an emerging pathogen with growing levels of antibiotic resistance. Lastly, we leveraged TACTIC to propose selectively synergistic drug combinations to treat bacterial eye infections (endophthalmitis).

Management of rhegmatogenous retinal detachment with coexisting macular hole: a comparison of vitrectomy with and without internal limiting membrane peeling.

PURPOSE: To compare the outcomes of vitrectomy with or without internal limiting membrane peeling for rhegmatogenous retinal detachment and coexisting macular hole. METHODS: Thirty-one consecutive patients (31 eyes) with macula-off retinal detachment, peripheral breaks and a coexisting macular hole were prospectively enrolled over a 3-year period. All patients underwent vitrectomy with encirclage and gas or silicone oil tamponade. The 17 patients who underwent internal limiting membrane peeling for macular hole constituted Group A and the remaining 14 patients constituted Group B. The main outcome measures were change in best-corrected visual acuity, retinal reattachment, macular hole closure, and type of macular hole closure. RESULTS: The two groups were comparable in preoperative demographics and clinical parameters. The retinal reattachment rate was 100% in both the groups. Macular hole closed in 14 of 17 eyes (82.4%) in Group A and 13 of 14 eyes (92.9%) in Group B (P = 0.607). A flat-open configuration of macular hole closure was observed in 8 of 14 eyes (57%) in Group A and 3 of 13 eyes (27.5%) in Group B (P = 0.188). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved to 1.0 ± 0.3 (20/200; range, 0.8-1.7) in Group A and 0.6 ± 0.2 (20/80; range, 0.3-1.1) in Group B (P < 0.0001). Ten patients achieved best-corrected visual acuity of ≥ 20/80 in Group B and none in Group A (P < 0.0001). CONCLUSION: The anatomical and visual outcomes of vitrectomy without internal limiting membrane peeling in macular hole in retinal detachment were similar to or better than the outcomes obtained with internal limiting membrane peeling.

Stimulus representations in visual cortex shaped by spatial attention and microsaccades.

Microsaccades (MSs) are commonly associated with spatially directed attention, but how they affect visual processing is still not clear. We studied MSs in a task in which the animal was randomly cued to attend to a target stimulus and ignore distractors, and it was rewarded for detecting a color change in the target. We found that the enhancement of firing rates normally found with attention to a cued stimulus was delayed until the first MS directed towards that stimulus. Once that MS occurred, attention to the target was engaged and there were persistent effects of attention on firing rates for the remainder of the trial. These effects were found in the superficial and deep layers of V4 as well as the lateral pulvinar and IT cortex. Although the tuning curves of V4 cells do not change depending on the locus of spatial attention, we found pronounced effects of MS direction on stimulus representations that persisted for the length of the trial in V4. In intervals following a MS towards the target in the RF, stimulus decoding from population activity was substantially better than in intervals following a MS away from the target. Likewise, turning curves of cells were substantially sharper following a MS towards the target in the RF. This sharpening appeared to result from both a "refreshing" of the initial transient sensory response to stimulus onset, and a magnification of the effects of attention in this condition. MSs to the target also enhanced the neuronal response to the behaviorally relevant target color change and led to faster reaction times. These results thus reveal a major link between spatial attention, object processing and its coordination with eye movements.

Human Fecal Bile Acid Analysis after Investigational Microbiota-Based Live Biotherapeutic Delivery for Recurrent Clostridioides difficile Infection.

Microbiome-based therapeutics are increasingly evaluated as a strategy to reduce recurrent Clostridioides difficile infection (rCDI), with proposed mechanisms including restoration of the microbiota and microbiota-mediated functions, such as bile acid (BA) metabolism. This study reports a quantitative and sensitive assay for targeted metabolomic assessment, and the application of the assay to profile BA composition in a Phase 2 trial of the investigational microbiota-based live biotherapeutic RBX2660 for reduction of rCDI. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 35 BAs from 113 participant stool samples from 27 RBX2660-treated rCDI participants in the double-blinded, placebo-controlled clinical trial. The results demonstrate a high-confidence assay as represented by sensitivity, linearity, accuracy, and precision. Furthermore, the assay enabled the observation of primary BAs as the dominant BA species at baseline in stool samples from clinical trial participants, consistent with the expected loss of commensals after broad-spectrum antibiotic treatment. After RBX2660 administration, there was a significant drop in primary BAs concurrent with increased secondary BAs that sustained through 24 months post-RBX2660. Taken together, we describe a robust assay that demonstrates altered BA metabolism in rCDI patients treated with RBX2660 administration.

Characterization of synthetic antigen binding fragments targeting Toc75 for the isolation of TOC in A. thaliana and P. sativum.

Roughly 95% of the proteins that make up the chloroplast must be imported from the cytoplasm. The machinery responsible for the translocation of these cargo proteins is called the translocon at the outer membrane of chloroplast (TOC). The TOC core consists of three proteins, Toc34, Toc75, and Toc159; no high-resolution structure has been solved of fully assembled TOC from plants. Efforts toward determining the structure of the TOC have been hindered almost entirely by difficulties in producing sufficient yields for structural studies. In this study, we introduce an innovative method that utilizes synthetic antigen binding fragments (sABs) to isolate TOC directly from wild-type plant biomass including A. thaliana and P. sativum. Binding between the sABs and the POTRA domains was characterized by size-exclusion chromatography coupled with small-angle X-ray scattering (SEC-SAXS), X-ray crystallography, and isothermal titration calorimetry. We also demonstrate the isolation of the TOC from P. sativum, laying the framework for large-scale isolation and purification of TOC for functional and structural studies.