Weaning from mechanical ventilation in the operating room: a systematic review.

BACKGROUND: Postoperative pulmonary complications (PPCs) are associated with postoperative mortality and prolonged hospital stay. Although intraoperative mechanical ventilation (MV) is a risk factor for PPCs, strategies addressing weaning from MV are understudied. In this systematic review, we evaluated weaning strategies and their effects on postoperative pulmonary outcomes. METHODS: Our protocol was registered on PROSPERO (CRD42022379145). Eligible studies included randomised controlled trials and observational studies of adults weaned from MV in the operating room. Primary outcomes included atelectasis and oxygenation; secondary outcomes included lung volume changes and PPCs. Risk of bias was assessed using the Cochrane Risk of Bias (RoB2) tool, and quality of evidence with the GRADE framework. RESULTS: Screening identified 14 randomised controlled trials including 1719 patients; seven studies were limited to the weaning phase and seven included interventions not restricted to the weaning phase. Strategies combining pressure support ventilation (PSV) with positive end-expiratory pressure (PEEP) and low fraction of inspired oxygen (FiO2) improved atelectasis, oxygenation, and lung volumes. Low FiO2 improved atelectasis and oxygenation but might not improve lung volumes. A fixed-PEEP strategy led to no improvement in oxygenation or atelectasis; however, individualised PEEP with low FiO2 improved oxygenation and might be associated with reduced PPCs. Half of included studies are of moderate or high risk of bias; the overall quality of evidence is low. CONCLUSIONS: There is limited research evaluating weaning from intraoperative MV. Based on low-quality evidence, PSV, individualised PEEP, and low FiO2 may be associated with reduced postoperative pulmonary outcomes. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42022379145).

Clinical Validation of Artificial Intelligence-Powered PD-L1 Tumor Proportion Score Interpretation for Immune Checkpoint Inhibitor Response Prediction in Non-Small Cell Lung Cancer.

PURPOSE: Evaluation of PD-L1 tumor proportion score (TPS) by pathologists has been very impactful but is limited by factors such as intraobserver/interobserver bias and intratumor heterogeneity. We developed an artificial intelligence (AI)-powered analyzer to assess TPS for the prediction of immune checkpoint inhibitor (ICI) response in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The AI analyzer was trained with 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 whole-slide images (WSIs) stained by 22C3 pharmDx immunohistochemistry. The clinical performance of the analyzer was validated in an external cohort of 430 WSIs from patients with NSCLC. Three pathologists performed annotations of this external cohort, and their consensus TPS was compared with AI-based TPS. RESULTS: In comparing PD-L1 TPS assessed by AI analyzer and by pathologists, a significant positive correlation was observed (Spearman coefficient = 0.925; P < .001). The concordance of TPS between AI analyzer and pathologists according to TPS ≥50%, 1%-49%, and <1% was 85.7%, 89.3%, and 52.4%, respectively. In median progression-free survival (PFS), AI-based TPS predicted prognosis in the TPS 1%-49% or TPS <1% group better than the pathologist's reading, with the TPS ≥50% group as a reference (hazard ratio [HR], 1.49 [95% CI, 1.19 to 1.86] v HR, 1.36 [95% CI, 1.08 to 1.71] for TPS 1%-49% group, and HR, 2.38 [95% CI, 1.69 to 3.35] v HR, 1.62 [95% CI, 1.23 to 2.13] for TPS <1% group). CONCLUSION: PD-L1 TPS assessed by AI analyzer correlates with that of pathologists, with clinical performance also being comparable when referenced to PFS. The AI model can accurately predict tumor response and PFS of ICI in advanced NSCLC via assessment of PD-L1 TPS.

Perioperative Methadone for Spine Surgery: A Scoping Review.

Complex spine surgery is associated with significant acute postoperative pain. Methadone possesses pharmacological properties that make it an attractive analgesic modality for major surgeries. This scoping review aimed to summarize the evidence for the perioperative use of methadone in adults undergoing complex spine surgery. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). A search was performed using MEDLINE, CINAHL, Cochrane Library, Scopus, Embase, and Joanna Briggs between January 1946 and April 2023. The initial search identified 317 citations, of which 12 met the criteria for inclusion in the review. There was significant heterogeneity in the doses, routes of administration, and timing of perioperative methadone administration in the included studies. On the basis of the available literature, methadone has been associated with reduced postoperative pain scores and reduced postoperative opioid consumption. Though safety concerns have been raised by observational studies, these have not been confirmed by prospective randomized studies. Further research is required to explore optimal methadone dosing regimens, the potential synergistic relationships between methadone and other pharmacological adjuncts, as well as the potential long-term antinociceptive benefits of perioperative methadone administration.

Coding, Decoding and Retrieving a Message Using DNA: An Experience from a Brazilian Center Research on DNA Data Storage.

DNA data storage based on synthetic oligonucleotides is a major attraction due to the possibility of storage over long periods. Nowadays, the quantity of data generated has been growing exponentially, and the storage capacity needs to keep pace with the growth caused by new technologies and globalization. Since DNA can hold a large amount of information with a high density and remains stable for hundreds of years, this technology offers a solution for current long-term data centers by reducing energy consumption and physical storage space. Currently, research institutes, technology companies, and universities are making significant efforts to meet the growing need for data storage. DNA data storage is a promising field, especially with the advancement of sequencing techniques and equipment, which now make it possible to read genomes (i.e., to retrieve the information) and process this data easily. To overcome the challenges associated with developing new technologies for DNA data storage, a message encoding and decoding exercise was conducted at a Brazilian research center. The exercise performed consisted of synthesizing oligonucleotides by the phosphoramidite route. An encoded message, using a coding scheme that adheres to DNA sequence constraints, was synthesized. After synthesis, the oligonucleotide was sequenced and decoded, and the information was fully recovered.

Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.

We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

Inflamed immune phenotype predicts favorable clinical outcomes of immune checkpoint inhibitor therapy across multiple cancer types.

BACKGROUND: The inflamed immune phenotype (IIP), defined by enrichment of tumor-infiltrating lymphocytes (TILs) within intratumoral areas, is a promising tumor-agnostic biomarker of response to immune checkpoint inhibitor (ICI) therapy. However, it is challenging to define the IIP in an objective and reproducible manner during manual histopathologic examination. Here, we investigate artificial intelligence (AI)-based immune phenotypes capable of predicting ICI clinical outcomes in multiple solid tumor types. METHODS: Lunit SCOPE IO is a deep learning model which determines the immune phenotype of the tumor microenvironment based on TIL analysis. We evaluated the correlation between the IIP and ICI treatment outcomes in terms of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in a cohort of 1,806 ICI-treated patients representing over 27 solid tumor types retrospectively collected from multiple institutions. RESULTS: We observed an overall IIP prevalence of 35.2% and significantly more favorable ORRs (26.3% vs 15.8%), PFS (median 5.3 vs 3.1 months, HR 0.68, 95% CI 0.61 to 0.76), and OS (median 25.3 vs 13.6 months, HR 0.66, 95% CI 0.57 to 0.75) after ICI therapy in IIP compared with non-IIP patients, respectively (p<0.001 for all comparisons). On subgroup analysis, the IIP was generally prognostic of favorable PFS across major patient subgroups, with the exception of the microsatellite unstable/mismatch repair deficient subgroup. CONCLUSION: The AI-based IIP may represent a practical, affordable, clinically actionable, and tumor-agnostic biomarker prognostic of ICI therapy response across diverse tumor types.

Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases.

BACKGROUND: Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations. METHODS: AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment. RESULTS: Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p < 0.001), ER (from 93.0 to 96.5%, p = 0.096), and PR (from 84.6 to 91.5%, p = 0.006). This improvement was especially evident in cases of HER2 2+ and 1+, where the concordance significantly increased from 46.2 to 68.4% and from 26.5 to 70.7%, respectively. Consequently, a refinement in the classification of breast cancer molecular subtypes (from 58.2 to 78.6%, p < 0.001) was achieved with AI assistance. CONCLUSIONS: This study underscores the significant role of AI analyzers in improving pathologists' concordance in the classification of breast cancer molecular subtypes.

Expiratory Muscle Activity Counteracts Positive End-Expiratory Pressure and Is Associated with Fentanyl Dose in Patients with Acute Respiratory Distress Syndrome.

Rationale: Hypoxemia during mechanical ventilation might be worsened by expiratory muscle activity, which reduces end-expiratory lung volume through lung collapse. A proposed mechanism of benefit of neuromuscular blockade in acute respiratory distress syndrome (ARDS) is the abolition of expiratory efforts. This may contribute to the restoration of lung volumes. The prevalence of this phenomenon, however, is unknown. Objectives: To investigate the incidence and amount of end-expiratory lung impedance (EELI) increase after the administration of neuromuscular blocking agents (NMBAs), clinical factors associated with this phenomenon, its impact on regional lung ventilation, and any association with changes in pleural pressure. Methods: We included mechanically ventilated patients with ARDS monitored with electrical impedance tomography (EIT) who received NMBAs in one of two centers. We measured changes in EELI, a surrogate for end-expiratory lung volume, before and after NMBA administration. In an additional 10 patients, we investigated the characteristic signatures of expiratory muscle activity depicted by EIT and esophageal catheters simultaneously. Clinical factors associated with EELI changes were assessed. Measurements and Main Results: We included 46 patients, half of whom showed an increase in EELI of >10% of the corresponding Vt (46.2%; IQR, 23.9-60.9%). The degree of EELI increase correlated positively with fentanyl dosage and negatively with changes in end-expiratory pleural pressures. This suggests that expiratory muscle activity might exert strong counter-effects against positive end-expiratory pressure that are possibly aggravated by fentanyl. Conclusions: Administration of NMBAs during EIT monitoring revealed activity of expiratory muscles in half of patients with ARDS. The resultant increase in EELI had a dose-response relationship with fentanyl dosage. This suggests a potential side effect of fentanyl during protective ventilation.

Experts' recommendations in laser use for the treatment of urolithiasis: a comprehensive guide by the European Section of Uro-Technology (ESUT) and Training-Research in Urological Surgery and Technology (T.R.U.S.T.)-Group.

PURPOSE: To identify laser lithotripsy settings used by experts for specific clinical scenarios and to identify preventive measures to reduce complications. METHODS: After literature research to identify relevant questions, a survey was conducted and sent to laser experts. Participants were asked for preferred laser settings during specific clinical lithotripsy scenarios. Different settings were compared for the reported laser types, and common settings and preventive measures were identified. RESULTS: Twenty-six laser experts fully returned the survey. Holmium-yttrium-aluminum-garnet (Ho:YAG) was the primary laser used (88%), followed by thulium fiber laser (TFL) (42%) and pulsed thulium-yttrium-aluminum-garnet (Tm:YAG) (23%). For most scenarios, we could not identify relevant differences among laser settings. However, the laser power was significantly different for middle-ureteral (p = 0.027), pelvic (p = 0.047), and lower pole stone (p = 0.018) lithotripsy. Fragmentation or a combined fragmentation with dusting was more common for Ho:YAG and pulsed Tm:YAG lasers, whereas dusting or a combination of dusting and fragmentation was more common for TFL lasers. Experts prefer long pulse modes for Ho:YAG lasers to short pulse modes for TFL lasers. Thermal injury due to temperature development during lithotripsy is seriously considered by experts, with preventive measures applied routinely. CONCLUSIONS: Laser settings do not vary significantly between commonly used lasers for lithotripsy. Lithotripsy techniques and settings mainly depend on the generated laser pulse's and generator settings' physical characteristics. Preventive measures such as maximum power limits, intermittent laser activation, and ureteral access sheaths are commonly used by experts to decrease thermal injury-caused complications.

In vitro anticancer and antifungal properties of the essential oil from the leaves of Lippia origanoides kunth.

The essential oil from Lippia origanoides (EOLO) is employed in traditional medicine as it has both antimicrobial and anti-inflammatory properties. The current investigation first evaluated the EOLO's cytotoxic activity in tumour (SiHa and HT-29) and non-tumour (human lymphocyte) cells by MTT. The effect on ROS production was further evaluated in cancer cells by fluorimetry. The oil's mutagenic and antifungal activities were also evaluated using, respectively, the in vitro micronucleus test and the broth microdilution method. The EOLO displayed significant cytotoxicity in both cancer cell lines, with IC50 values of 20.2 µg/mL and 24.3 µg/mL for HT-29 and for SiHa cell lines, respectively. EOLO increased ROS production, was unable to raise the micronucleus frequencies and significantly reduced the cytokinesis block proliferation indices, revealing its anti-proliferative action. The results demonstrate that EOLO is devoid of mutagenic activity but possesses significant activity against tumour and non-tumour human cells, reinforcing its biological potential.

Deep learning model improves tumor-infiltrating lymphocyte evaluation and therapeutic response prediction in breast cancer.

Tumor-infiltrating lymphocytes (TILs) have been recognized as key players in the tumor microenvironment of breast cancer, but substantial interobserver variability among pathologists has impeded its utility as a biomarker. We developed a deep learning (DL)-based TIL analyzer to evaluate stromal TILs (sTILs) in breast cancer. Three pathologists evaluated 402 whole slide images of breast cancer and interpreted the sTIL scores. A standalone performance of the DL model was evaluated in the 210 cases (52.2%) exhibiting sTIL score differences of less than 10 percentage points, yielding a concordance correlation coefficient of 0.755 (95% confidence interval [CI], 0.693-0.805) in comparison to the pathologists' scores. For the 226 slides (56.2%) showing a 10 percentage points or greater variance between pathologists and the DL model, revisions were made. The number of discordant cases was reduced to 116 (28.9%) with the DL assistance (p < 0.001). The DL assistance also increased the concordance correlation coefficient of the sTIL score among every two pathologists. In triple-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who underwent the neoadjuvant chemotherapy, the DL-assisted revision notably accentuated higher sTIL scores in responders (26.8 ± 19.6 vs. 19.0 ± 16.4, p = 0.003). Furthermore, the DL-assistant revision disclosed the correlation of sTIL-high tumors (sTIL ≥ 50) with the chemotherapeutic response (odd ratio 1.28 [95% confidence interval, 1.01-1.63], p = 0.039). Through enhancing inter-pathologist concordance in sTIL interpretation and predicting neoadjuvant chemotherapy response, here we report the utility of the DL-based tool as a reference for sTIL scoring in breast cancer assessment.

Structural Monitoring of a Large-Span Arch Bridge Using Customized Sensors.

Due to the increasing importance of the continuous monitoring of Civil Structures, this research aims to take advantage of new solutions of measurement systems and sensors in the Structural Health Monitoring of bridges, using the reinforced concrete arch Arrábida Bridge as a case study. With the support of customized sensors, this work starts by performing preliminary ambient vibration tests on Arrábida Bridge, aiming at the identification of the natural frequencies and respective vibration modes of the deck. Then, the measurement campaigns carried over time are described, which involved different types of customized sensors, namely, accelerometers, temperature sensors and displacement sensors. Based on the signals collected by these devices, some preliminary analyses were performed. The results show that the temperature measured at the deck sections presents different amplitudes and phase shifts when compared to the temperature measured at the arch sections. Moreover, using the temperature measurements, it is possible to estimate with good accuracy the displacements in the expansion joints of the bridge. It was also observed that the displacements in these joints, although being conditioned by the temperature effects, are also marked by a dynamic component arising from the traffic loads over the deck. The observation of this phenomenon is an innovative aspect found in this investigation, which can be used in the future to characterize the traffic loads on the structure.

Exposure to Dichlorvos pesticide alters the morphology of and lipid metabolism in the ventral prostate of rats.

Organophosphate pesticides are widely used in agriculture, leading to soil, water, and food contamination. Among these compounds is Dichlorvos [O,O-dimethyl O-(2,2-dichlorovinyl)phosphate, DDVP], which is listed as a highly toxic compound by the Environmental Protection Agency and World Health Organization. Exposure to DDVP can result in nervous, respiratory, hepatic, and reproductive abnormalities, in addition to endocrine disrupting, mutagenic, and carcinogenic effects. Little is known about the impacts of DDVP on the reprogramming of lipid metabolism, which is also associated with the development and progression of cancer, since the tumor cells need to recruit, capture, and use fatty acids to compose their building membranes. This study aimed to evaluate the influence of the pesticide DDVP on lipid metabolism in the prostate, after chemical induction by the carcinogen N-methyl-N-nitrosourea (MNU). For this, 32 Fischer rats aged 90 days were randomly divided into four experimental groups: Control, DDVP, MNU, and MNU + DDVP. The MNU and MNU + DDVP groups underwent chemical induction with MNU (15 mg/kg) and the DDVP and MNU + DDVP groups received a diet supplemented with DDVP (10 mg/kg). Histopathological analyses of the rat ventral prostate showed 100% incidence of epithelial hyperplasia in the MNU and MNU + DDVP groups. This finding was accompanied by an increase of the epithelial compartment in the MNU + DDVP group. Immunolocalization of important proteins linked to lipid metabolism has been established. In the MNU + DDVP group, Western blotting analyses pointed out an increased expression of the protein LIMP II (Lysosomal Integral Membrane Protein-II), which is correlated with the capture and distribution of lipids in tumor cells. Together, these results indicate that the association of a low dose of DDVP with MNU was able to promote alterations in the morphology and lipid metabolism of the rat ventral prostate, which may be related to tumor progression in this organ.

Three generation families: Analysis of de novo variants in autism.

De novo variants (DNVs) analysis has proven to be a powerful approach to gene discovery in Autism Spectrum Disorder (ASD), which has not yet been shown in a Brazilian ASD cohort. The relevance of inherited rare variants has also been suggested, particularly in oligogenic models. We hypothesized that three-generation analyses of DNVs could provide new insights into the relevance of de novo and inherited variants across generations. To accomplish this goal, we performed whole-exome sequencing of 33 septet families composed of probands, parents, and grandparents (n = 231 individuals) and compared DNV rates (DNVr) between generations and those from two control cohorts. The DNVr in the probands (DNVr = 1.16) was marginally higher than in parents (DNVr = 0.60; p = 0.054), and in controls (DNVr = 0.68; p = 0.035, congenital heart disorder and DNVr = 0.70; p = 0.047, unaffected ASD siblings from Simons Simplex Collection). Moreover, most of the DNVs were found to have paternal origin in both generations (84.6%). Finally, we observed that 40% (6/15) of the DNVs in parents transmitted for probands are in ASD or ASD candidate genes, representing recently emerged risk variants to ASD in their families and suggest ZNF536, MSL2 and HDAC9 as ASD candidate genes. We did not observe an enrichment of risk variants nor sex bias of transmitted variants in the three generations, that can be due to sample size. These results further reinforce the relevance of de novo variants in ASD.

Organizing Pneumonia and Ulcerative Colitis: A Relationship To Remember.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterised by relapsing and remitting mucosal inflammation of the colon. Despite primarily affecting the gastrointestinal tract, UC has various extraintestinal manifestations that often affect other organs and systems. Although pulmonary involvement is uncommon, organising pneumonia (OP), which affects the lung parenchyma, is one of the potential extraintestinal manifestations of UC. We report a case of OP in a 35-year-old male with a longstanding history of UC, well-medicated with sulfasalazine (SSZ). He presented to the emergency department (ED) with complaints of fatigue, coughing, myalgia, thoracalgia and dyspnoea. A chest X-ray showed parenchymal infiltrates and computed tomography revealed bilateral consolidation. Under a preliminary diagnosis of atypical pneumonia, he was treated with an empirical broad-spectrum antimicrobial agent, which did not lead to any clinical, laboratory or imaging improvement. Furthermore, the diagnostic work-up excluded any malignancy or infectious cause. A probable diagnostic hypothesis was OP as an extraintestinal manifestation of UC or as an adverse effect of SSZ therapy. Hence, SSZ was discontinued, and he was successfully treated with corticosteroids, exhibiting significant improvements and recovering completely during the follow-up period. Despite lung involvement in UC being rare, we present this case to emphasise the importance of a thorough differential diagnosis when treating acute respiratory illness in patients with UC, including extraintestinal manifestations of UC, especially OP, even during a period of remission. We also emphasise the importance of early initiation of corticosteroid therapy to prevent major complications and promote recovery.

Potential Role of Fourier Transform Infrared Spectroscopy as a Screening Approach for Breast Cancer.

Breast cancer is a heterogeneous disease, and its spread involves a succession of clinical and pathological stages. Screening is predominantly based on mammography, which has critical limitations related to the effectiveness and production of false-positive or false-negative results, generating discomfort and low adherence. In this context, infrared with attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy emerges as a non-destructive sample tool, which is non-invasive, label-free, has a low operating-cost, and requires only a small amount of sample, including liquid plasma samples. We sought to evaluate the clinical applicability of ATR FT-IR in breast cancer screening. ATR FT-IR spectroscopy through its highest potential spectral biomarker could distinguish, by liquid plasma biopsy, breast cancer patients and healthy controls, obtaining a sensitivity of 97%, specificity of 93%, a receiver operating characteristic ROC curve of 97%, and a prediction accuracy of 94%. The main variance between the groups was mainly in the band 1511 cm-1 of the control group, 1502 and 1515 cm-1 of the cancer group, which are the peaks of the bands referring to proteins and amide II. ATR FT-IR spectroscopy has demonstrated to be a promising tool for breast cancer screening, given its time efficiency, cost of approach, and its high ability to distinguish between the liquid plasma samples of breast cancer patients and healthy controls.

Mixed-integer quadratic programming approach for noninvasive estimation of respiratory effort profile during pressure support ventilation.

Information about respiratory mechanics such as resistance, elastance, and muscular pressure is important to mitigate ventilator-induced lung injury. Particularly during pressure support ventilation, the available options to quantify breathing effort and calculate respiratory system mechanics are often invasive or complex. We herein propose a robust and flexible estimation of respiratory effort better than current methods. We developed a method for non-invasively estimating breathing effort using only flow and pressure signals. Mixed-integer quadratic programming (MIQP) was employed, and the binary variables were the switching moments of the respiratory effort waveform. Mathematical constraints, based on ventilation physiology, were set for some variables to restrict feasible solutions. Simulated and patient data were used to verify our method, and the results were compared to an established estimation methodology. Our algorithm successfully estimated the respiratory effort, resistance, and elastance of the respiratory system, resulting in more robust performance and faster solver times than a previously proposed algorithm that used quadratic programming (QP) techniques. In a numerical simulation benchmark, the worst-case errors for resistance and elastance were 25% and 23% for QP versus <0.1% and <0.1% for MIQP, whose solver times were 4.7 s and 0.5 s, respectively. This approach can estimate several breathing effort profiles and identify the respiratory system's mechanical properties in invasively ventilated critically ill patients.

Genomic architecture of autism from comprehensive whole-genome sequence annotation.

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Artificial Intelligence-Powered Whole-Slide Image Analyzer Reveals a Distinctive Distribution of Tumor-Infiltrating Lymphocytes in Neuroendocrine Neoplasms.

Despite the importance of tumor-infiltrating lymphocytes (TIL) and PD-L1 expression to the immune checkpoint inhibitor (ICI) response, a comprehensive assessment of these biomarkers has not yet been conducted in neuroendocrine neoplasm (NEN). We collected 218 NENs from multiple organs, including 190 low/intermediate-grade NENs and 28 high-grade NENs. TIL distribution was derived from Lunit SCOPE IO, an artificial intelligence (AI)-powered hematoxylin and eosin (H&E) analyzer, as developed from 17,849 whole slide images. The proportion of intra-tumoral TIL-high cases was significantly higher in high-grade NEN (75.0% vs. 46.3%, p = 0.008). The proportion of PD-L1 combined positive score (CPS) ≥ 1 case was higher in high-grade NEN (85.7% vs. 33.2%, p < 0.001). The PD-L1 CPS ≥ 1 group showed higher intra-tumoral, stromal, and combined TIL densities, compared to the CPS < 1 group (7.13 vs. 2.95, p < 0.001; 200.9 vs. 120.5, p < 0.001; 86.7 vs. 56.1, p = 0.004). A significant correlation was observed between TIL density and PD-L1 CPS (r = 0.37, p < 0.001 for intra-tumoral TIL; r = 0.24, p = 0.002 for stromal TIL and combined TIL). AI-powered TIL analysis reveals that intra-tumoral TIL density is significantly higher in high-grade NEN, and PD-L1 CPS has a positive correlation with TIL densities, thus showing its value as predictive biomarkers for ICI response in NEN.

A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17-11).

PURPOSE: Although programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are promising agents for recurrent or metastatic nasopharyngeal carcinoma (NPC), PD-1/PD-L1 inhibitor monotherapy has shown modest efficacy. This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with NPC who failed prior platinum-based chemotherapy. PATIENTS AND METHODS: This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. To identify potential biomarkers, whole-exome sequencing, whole-transcriptome sequencing, and immune phenotype analysis based on Lunit SCOPE IO, an artificial intelligence-powered spatial tumor-infiltrating lymphocyte analyzer, were performed. RESULTS: Thirty-six patients were enrolled between June 2018 and June 2019. The ORR was 36.1% and disease control rate was 97.2%. With median follow-up of 22.0 months, median PFS was 13.8 months [95% confidence interval (CI), 8.6-16.8 months]. Median OS was not reached, and OS rate at 6 months was 97.0% (95% CI, 80.4%-99.6%). The grade ≥3 treatment-related adverse events were hypertension (2.8%) and anemia (2.8%). In multivariate analysis of mutation of chromatin modifier gene, tumor mutational burden (≥ 2.1 mut/Mb), and somatic copy-number alteration (SCNA) level, the group with high SCNA (> 3 points; HR, 7.0; 95% CI, 1.3-37.9; P = 0.02) had independently associated with poor PFS. Immune phenotype analysis showed that tumors with high proportion of immune-excluded immune phenotype was significantly correlated with poor PFS (HR, 4.4; 95% CI, 1.2-16.2; P = 0.018). CONCLUSIONS: Nivolumab plus gemcitabine showed promising efficacy with favorable toxicity profiles in patients with advanced NPC in whom platinum-based combination chemotherapy failed.