A framework for the biophysical screening of antibody mutations targeting solvent-accessible hydrophobic and electrostatic patches for enhanced viscosity profiles.

The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of 24 mutants with modified viscosity profiles accompanied by experimental evaluation. Our experimental observations using a model anti-IL8 mAb and eight engineered mutant variants reveal that viscosity reduction is influenced by the location of hydrophobic interactions, while targeting positively charged patches significantly increases viscosity in comparison to wild-type anti-IL-8 mAb. We conclude that most predicted in silico physicochemical properties exhibit poor correlation with measured experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the need for comprehensive case-by-case evaluation of mAbs. This framework combining molecular design and triage via computational predictions with experimental evaluation aids the agile and rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.

Anti-seizure medication treatment and outcomes in acute ischemic stroke patients undergoing continuous EEG monitoring.

OBJECTIVES: To determine the association of anti-seizure medication (ASM) treatment with outcomes in acute ischemic stroke (AIS) patients undergoing continuous electroencephalography (cEEG). METHODS: Retrospective analysis of AIS patients admitted between 2012 and 2019. The following are the inclusion criteria: age ≥ 18 years and ≥ 16 h of cEEG within the first 7 days of admission. ASM treatment exposure was defined as > 48 h of treatment after the first 24 h of cEEG. The primary outcome measure was 90-day mortality, and the secondary outcome was 90-day functional recovery (Modified Ranking Scale 0-3). Propensity scores were used to adjust for baseline covariates and presence of epileptiform abnormalities (seizures, periodic and rhythmic patterns). RESULTS: One hundred thirteen patients met the inclusion criteria; 39 (34.5%) were exposed to ASM. ASM treatment was not associated with 90-day mortality (propensity adjusted HR 1.0 [0.31-3.27], p = 0.999) or functional outcomes (adjusted HR 0.99 [0.32-3.02], p = 0.989), compared to no treatment. CONCLUSIONS: In our study, ASM treatment in AIS patients with cEEG abnormalities was not significantly associated with a change in 90-day mortality and functional recovery. Larger comparative effectiveness studies are indicated to identify which acute ischemic stroke patients with cEEG abnormalities benefit most from ASM treatment.

Antiseizure Medication Treatment and Outcomes in Patients with Subarachnoid Hemorrhage Undergoing Continuous EEG Monitoring.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) with electroencephalographic epileptiform activity (seizures, periodic and rhythmic patterns, and sporadic discharges) are frequently treated with antiseizure medications (ASMs). However, the safety and effectiveness of ASM treatment for epileptiform activity has not been established. We used observational data to investigate the effectiveness of ASM treatment in patients with aSAH undergoing continuous electroencephalography (cEEG) to develop a causal hypothesis for testing in prospective trials. METHODS: This was a retrospective single-center cohort study of patients with aSAH admitted between 2011 and 2016. Patients underwent ≥ 24 h of cEEG within 4 days of admission. All patients received primary ASM prophylaxis until aneurysm treatment (typically within 24 h of admission). Treatment exposure was defined as reinitiation of ASMs after aneurysm treatment and cEEG initiation. We excluded patients with non-cEEG indications for ASMs (e.g., epilepsy, acute symptomatic seizures). Outcomes measures were 90-day mortality and good functional outcome (modified Rankin Scale scores 0-3). Propensity scores were used to adjust for baseline covariates and disease severity. RESULTS: Ninety-four patients were eligible (40 continued ASM treatment; 54 received prophylaxis only). ASM continuation was not significantly associated with higher 90-day mortality (propensity-adjusted hazard ratio [HR] = 2.01 [95% confidence interval (CI) 0.57-7.02]). ASM continuation was associated with lower likelihood for 90-day good functional outcome (propensity-adjusted HR = 0.39 [95% CI 0.18-0.81]). In a secondary analysis, low-intensity treatment (low-dose single ASM) was not significantly associated with mortality (propensity-adjusted HR = 0.60 [95% CI 0.10-3.59]), although it was associated with a lower likelihood of good outcome (propensity-adjusted HR = 0.37 [95% CI 0.15-0.91]), compared with prophylaxis. High-intensity treatment (high-dose single ASM, multiple ASMs, or anesthetics) was associated with higher mortality (propensity-adjusted HR = 6.80 [95% CI 1.67-27.65]) and lower likelihood for good outcomes (propensity-adjusted HR = 0.30 [95% CI 0.10-0.94]) compared with prophylaxis only. CONCLUSIONS: Our findings suggest the testable hypothesis that continuing ASMs in patients with aSAH with cEEG abnormalities does not improve functional outcomes. This hypothesis should be tested in prospective randomized studies.

Seizure Prophylaxis After Spontaneous Intracerebral Hemorrhage.

Importance: Limited evidence is available concerning optimal seizure prophylaxis after spontaneous intracerebral hemorrhage (sICH). Objective: To evaluate which of 4 seizure prophylaxis strategies provides the greatest net benefit for patients with sICH. Design, Setting, and Participants: This decision analysis used models to simulate the following 4 common scenarios: (1) a 60-year-old man with low risk of early (≤7 days after stroke) (10%) and late (3.6% or 9.8%) seizures and average risk of short- (9%) and long-term (30%) adverse drug reaction (ADR); (2) an 80-year-old woman with low risk of early (10%) and late (3.6% or 9.8%) seizures and high short- (24%) and long-term (80%) ADR risks; (3) a 55-year-old man with high risk of early (19%) and late (34.8% or 46.2%) seizures and low short- (9%) and long-term (30%) ADR risks; and (4) a 45-year-old woman with high risk of early (19%) and late (34.8% or 46.2%) seizures and high short- (18%) and long-term (60%) ADR risks. Interventions: The following 4 antiseizure drug strategies were included: (1) conservative, consisting of short-term (7-day) secondary early-seizure prophylaxis with long-term therapy after late seizure; (2) moderate, consisting of long-term secondary early-seizure prophylaxis or late-seizure therapy; (3) aggressive, consisting of long-term primary prophylaxis; and (4) risk guided, consisting of short-term secondary early-seizure prophylaxis among low-risk patients (2HELPS2B score, 0), short-term primary prophylaxis among patients at higher risk (2HELPS2B score, ≥1), and long-term secondary therapy for late seizure. Main Outcomes and Measures: Quality-adjusted life-years (QALYs). Results: For scenario 1, the risk-guided strategy (8.13 QALYs) was preferred over the conservative (8.08 QALYs), moderate (8.07 QALYs), and aggressive (7.88 QALYs) strategies. For scenario 2, the conservative strategy (2.18 QALYs) was preferred over the risk-guided (2.17 QALYs), moderate (2.09 QALYs), and aggressive (1.15 QALYs) strategies. For scenario 3, the aggressive strategy (9.21 QALYs) was preferred over the risk-guided (8.98 QALYs), moderate (8.93 QALYs), and conservative (8.77 QALYs) strategies. For scenario 4, the risk-guided strategy (11.53 QALYs) was preferred over the conservative (11.23 QALYs), moderate (10.93 QALYs), and aggressive (8.08 QALYs) strategies. Sensitivity analyses suggested that short-term strategies (conservative and risk guided) are preferred under most scenarios, and the risk-guided strategy performs comparably to or better than alternative strategies in most settings. Conclusions and Relevance: This decision analytical model suggests that short-term (7-day) prophylaxis dominates longer-term therapy after sICH. Use of the 2HELPS2B score to guide clinical decisions for initiation of short-term primary vs secondary early-seizure prophylaxis should be considered for all patients after sICH.

Anticonvulsant Primary and Secondary Prophylaxis for Acute Ischemic Stroke Patients: A Decision Analysis.

Background and Purpose: We examined the impact of 3 anticonvulsant prophylaxis strategies on quality-adjusted life-years (QALYs) among patients with an incident acute ischemic stroke. Methods: We created a decision tree to evaluate 3 strategies: (1) long-term primary prophylaxis; (2) short-term secondary prophylaxis after an early seizure with lifetime prophylaxis if persistent or late seizures (LSs) developed; and (3) long-term secondary prophylaxis if either early, late, or persistent seizures developed. The outcome was quality-adjusted life expectancy (QALY). We created 4 base cases to simulate common clinical scenarios: (1) female patient aged 40 years with a 2% or 11% lifetime risk of an LS and a 33% lifetime risk of an adverse drug reaction (ADR); (2) male patient aged 65 years with a 6% or 29% LS risk and 60% ADR risk; (3) male patient aged 50 years with an 18% or 65% LS risk and 33% ADR risk; and (4) female patient aged 80 years with a 29% or 83% LS risk and 80% ADR risk. In sensitivity analyses, we altered the parameters and assumptions. Results: Across all 4 base cases, primary prophylaxis yielded the fewest QALYs when compared with secondary prophylaxis. For example, under scenario 1, strategies 2 and 3 resulted in 7.17 QALYs each, but strategy 1 yielded only 6.91 QALYs. Under scenario 4, strategies 2 and 3 yielded 2.85 QALYs compared with 1.40 QALYs for strategy 1. Under scenarios in which patients had higher ADR risks, strategy 2 led to the most QALYs. Conclusions: Short-term therapy with continued anticonvulsant prophylaxis only after postischemic stroke seizures arise dominates lifetime primary prophylaxis in all scenarios examined. Our findings reinforce the necessity of close follow-up and discontinuation of anticonvulsant seizure prophylaxis started during acute ischemic stroke hospitalization.

Telemedicine Can Support Measurable and High-Quality Epilepsy Care During the COVID-19 Pandemic.

Routine outpatient epilepsy care has shifted from in-person to telemedicine visits in response to safety concerns posed by the coronavirus disease 2019 (COVID-19) pandemic. But whether telemedicine can support and maintain standardized documentation of high-quality epilepsy care remains unknown. In response, the authors conducted a quality improvement study at a level 4 epilepsy center between January 20, 2019, and May 31, 2020. Weekly average completion proportion of standardized documentation used by a team of neurologists for adult patients for the diagnosis of epilepsy, seizure classification, and frequency were analyzed. By December 15, 2019, a 94% average weekly completion proportion of standardized epilepsy care documentation was achieved that was maintained through May 31, 2020. Moreover, during the period of predominately telemedicine encounters in response to the pandemic, the completion proportion was 90%. This study indicates that high completion of standardized documentation of seizure-related information can be sustained during telemedicine appointments for routine outpatient epilepsy care at a level 4 epilepsy center.

Complete Genome Sequence of Bacillus velezensis LABIM40, an Effective Antagonist of Fungal Plant Pathogens.

Bacillus velezensis strain LABIM40 holds high potential for biological control of plant pathogens. Its complete genome contains one chromosome of 3,972,310 bp with 3,777 DNA coding sequences and displays 33 gene clusters potentially involved in the suppression of fungal pathogens.

Outcomes of patients with altered level of consciousness and abnormal electroencephalogram: A retrospective cohort study.

INTRODUCTION: Nonconvulsive seizures (NCS) are frequent in hospitalized patients and may further aggravate injury in the already damaged brain, potentially worsening outcomes in encephalopathic patients. Therefore, both early seizure recognition and treatment have been advocated to prevent further neurological damage. OBJECTIVE: Evaluate the main EEG patterns seen in patients with impaired consciousness and address the effect of treatment with antiepileptic drugs (AEDs), continuous intravenous anesthetic drugs (IVADs), or the combination of both, on outcomes. METHODS: This was a single center retrospective cohort study conducted in a private, tertiary care hospital. Consecutive adult patients with altered consciousness submitted to a routine EEG between January 2008 and February 2011 were included in this study. Based on EEG pattern, patients were assigned to one of three groups: Group Interictal Patterns (IP; EEG showing only interictal epileptiform discharges or triphasic waves), Group Rhythmic and Periodic Patterns (RPP; at least one EEG with rhythmic or periodic patterns), and Group Ictal (Ictal; at least one EEG showing ictal pattern). Groups were compared in terms of administered antiepileptic treatment and frequency of unfavorable outcomes (modified Rankin scale ≥3 and in-hospital mortality). RESULTS: Two hundred and six patients (475 EEGs) were included in this analysis. Interictal pattern was observed in 35.4% (73/206) of patients, RPP in 53.4% (110/206) and ictal in 11.2% (23/206) of patients. Treatment with AEDs, IVADs or a combination of both was administered in half of the patients. While all Ictal group patients received treatment (AEDs or IVADs), only 24/73 (32.9%) IP group patients and 55/108 (50.9%) RPP group patients were treated (p<0.001). Hospital length of stay (LOS) and frequency of unfavorable outcomes did not differ among the groups. In-hospital mortality was higher in IVADs treated RPP patients compared to AEDs treated RPP patients [11/19 (57.9%) vs. 11/36 (30.6%) patients, respectively, p = 0.049]. Hospital LOS, in-hospital mortality and frequency of unfavorable outcomes did not differ between Ictal patients treated exclusively with AEDs or IVADs. CONCLUSION: In patients with acute altered consciousness and abnormal routine EEG, antiepileptic treatment did not improve outcomes regardless of the presence of periodic, rhythmic or ictal EEG patterns.

Performance of noninvasive ventilation in acute respiratory failure in critically ill patients: a prospective, observational, cohort study.

BACKGROUND: Noninvasive ventilation (NIV) is used in critically ill patients with acute respiratory failure (ARF) to avoid endotracheal intubation. However, the impact of NIV use on ARF patient's outcomes is still unclear. Our objectives were to evaluate the rate of NIV failure in hypoxemic patients with an arterial carbon dioxide partial pressure (PaCO2) < 45 mmHg or ≥ 45 mmHg at ICU admission, the predictors of NIV failure, ICU and hospital length of stay and 28-day mortality. METHODS: Prospective single center cohort study. All consecutive patients admitted to a mixed ICU during a three-month period who received NIV, except for palliative care purposes, were included in this study. Demographic data, APACHE II score, cause of ARF, number of patients that received NIV, incidence of NIV failure, length of ICU, hospital stay and mortality rate were compared between NIV failure and success groups. RESULTS: Eighty-five from 462 patients (18.4 %) received NIV and 26/85 (30.6 %) required invasive mechanical ventilation. NIV failure patients were comparatively younger (67 ± 21 vs. 77 ± 14 years; p = 0.031), had lower arterial bicarbonate (p = 0.005), lower PaCO2 levels (p = 0.032), higher arterial lactate levels (p = 0.046) and APACHE II score (p = 0.034) compared to NIV success patients. NIV failure occurred in 25.0 % of patients with PaCO2 ≥ 45 mmHg and in 33.3 % of patients with PaCO2 < 45 mmHg (p = 0.435). NIV failure was associated with an increased risk of in-hospital death (OR 4.64, 95 % CI 1.52 to 14.18; p = 0.007) and length [median (IQR)] of ICU [12 days (8-31) vs. 2 days (1-4); p < 0.001] and hospital [30 (19-42) vs. 15 (9-33) days; p = 0.010] stay. Predictors of NIV failure included age (OR 0.96, 95 % CI 0.93 to 0.99; p = 0.007) and APACHE II score (OR 1.13, 95 % CI 1.02 to 1.25; p = 0.018). CONCLUSION: NIV failure was associated with an increased risk of in-hospital death, ICU and hospital stay and was not affected by baseline PaCO2 levels. Patients that failed were comparatively younger and had higher APACHE II score, suggesting the need for a careful selection of patients that might benefit from NIV. A well-designed study on the impact of a short monitored NIV trial on outcomes is needed.

Clinical and economic impact of procalcitonin to shorten antimicrobial therapy in septic patients with proven bacterial infection in an intensive care setting.

Biomarkers such as procalcitonin (PCT) have been studied to guide duration of antibiotic therapy. We aimed to assess whether a decrease in PCT levels could be used to reduce the duration of antibiotic therapy in intensive care unit (ICU) patients with a proven infection without risking a worse outcome. We assessed 265 patients with suspected sepsis, severe sepsis, or septic shock in our ICU. Of those, we randomized 81 patients with a proven bacterial infection into 2 groups: an intervention group in which the duration of the antibiotic therapy was guided by a PCT protocol and a control group in which there was no PCT guidance. In the per-protocol analysis, the median antibiotic duration was 9 days in the PCT group (n = 20) versus 13 days in the non-PCT group (n = 31), P = 0.008. This study demonstrates that PCT can be a useful tool for limiting antimicrobial therapy in ICU patients with documented bacterial infection.

Clustering behavior in microbial communities from acute endodontic infections.

INTRODUCTION: Acute endodontic infections harbor heterogeneous microbial communities in both the root canal (RC) system and apical tissues. Data comparing the microbial structure and diversity in endodontic infections in related ecosystems, such as RC with necrotic pulp and acute apical abscess (AAA), are scarce in the literature. The aim of this study was to examine the presence of selected endodontic pathogens in paired samples from necrotic RC and AAA using polymerase chain reaction (PCR) followed by the construction of cluster profiles. METHODS: Paired samples of RC and AAA exudates were collected from 20 subjects and analyzed by PCR for the presence of selected strict and facultative anaerobic strains. The frequency of species was compared between the RC and the AAA samples. A stringent neighboring clustering algorithm was applied to investigate the existence of similar high-order groups of samples. A dendrogram was constructed to show the arrangement of the sample groups produced by the hierarchical clustering. RESULTS: All samples harbored bacterial DNA. Porphyromonas endodontalis, Prevotella nigrescens, Filifactor alocis, and Tannerela forsythia were frequently detected in both RC and AAA samples. The selected anaerobic species were distributed in diverse small bacteria consortia. The samples of RC and AAA that presented at least one of the targeted microorganisms were grouped in small clusters. CONCLUSIONS: Anaerobic species were frequently detected in acute endodontic infections and heterogeneous microbial communities with low clustering behavior were observed in paired samples of RC and AAA.

Influência da amamentação natural e artificial sobre a ocorrência de hábitos de succção não nutritivos / Breastfeeding and bottle feeding influence on non nutritive sucking habits

O objetivo deste trabalho foi investigar a influência do tempo de aleitamento natural e artificial sobre a ocorrência de hábitos de sucção não nutritivos. Para tanto, foi aplicado um questionário aos pais de 155 crianças, com idades entre três e oito anos. Pesquisou-se o período em que foram amamentadas, bem como a presença ou não de hábitos de sucção e a duração dos mesmos. Concluiu-se que a amamentação natural por um período adequado pôde prevenir a instalação destes hábitos de sucção não nutritivos, sendo a chupeta o hábito mais freqüente.

The purpose of this study was to evaluate the influence of breast-feeding and bottle-feeding period on occurring of nonnutritive sucking habits. It was applied a questionnaire to 155 parents. The children were three to eight years age. It was investigate the breast and bottle feeding period as well the presence or not of nonnutritive sucking habits and its duration. It was conc1ude that the breast-feeding for an appropriate period could prevent the development of nonnutritive sucking habits, being the pacifier the most frequent habito.