A hematopoietic cell-driven mechanism involving SLAMF6 receptor, SAP adaptors and SHP-1 phosphatase regulates NK cell education.

Activation of natural killer (NK) cells by hematopoietic target cells is controlled by the SLAM family of receptors and by the associated SAP family of adaptors. Here we found that SLAM receptors also enhanced NK cell activation by nonhematopoietic target cells, which lack ligands for SLAM receptors. This function was mediated by SLAMF6, a homotypic SLAM receptor found on NK cells and other hematopoietic cells, and was regulated by SAP adaptors, which uncoupled SLAM receptors from phosphatase SHP-1 and diminished the effect of SLAMF6 on NK cell responsiveness toward nonhematopoietic cells. Thus, in addition to their role in NK cell activation by hematopoietic cells, the SLAM-SAP pathways influence responsiveness toward nonhematopoietic targets by a process akin to NK cell 'education'.

Inadvertent laparoscopic lavage of perforated colon cancer: a systematic review.

BACKGROUND: Although laparoscopic lavage for perforated diverticulitis with peritonitis has been grabbing the headlines, it is known that the clinical presentation of peritonitis can also be caused by an underlying perforated carcinoma. The aim of this study was to determine the incidence of patients undergoing inadvertent laparoscopic lavage of perforated colon cancer as well as the delay in cancer diagnosis. METHODS: The PubMed database was systematically searched to include all studies meeting inclusion criteria. Studies were screened through titles and abstracts with potentially eligible studies undergoing full-text screening. The primary endpoints of this meta-analysis were the rates of perforated colon cancer patients having undergone inadvertent laparoscopic lavage as well as the delay in cancer diagnosis. This was expressed in pooled rate % and 95% confidence intervals. RESULTS: Eleven studies (three randomized, two prospective, six retrospective) totaling 642 patients met inclusion criteria. Eight studies reported how patients were screened for cancer and the number of patients who completed follow-up. The pooled cancer rate was 3.4% (0.9%, 5.8%) with low heterogeneity (Isquare2 = 34.02%) in eight studies. Cancer rates were 8.2% (0%, 3%) (Isquare2 = 58.2%) and 1.7% (0%, 4.5%) (Isquare2 = 0%) in prospective and retrospective studies, respectively. Randomized trials reported a cancer rate of 7.2% (3.1%, 11.2%) with low among-study heterogeneity (Isquare2 = 0%) and a median delay to diagnosis of 2 (1.5-5) months. CONCLUSIONS: This systematic review found that 7% of patients undergoing laparoscopic lavage for peritonitis had perforated colon cancer with a delay to diagnosis of up to 5 months.

SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin.

Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18, 19, 20) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα-CD47 blockade therapy.

Association of hypoglossal nerve stimulator response with machine learning identified negative effort dependence patterns.

BACKGROUND: Hypoglossal nerve stimulator (HGNS) is a therapeutic option for moderate to severe obstructive sleep apnea (OSA). Improved patient selection criteria are needed to target those most likely to benefit. We hypothesized that the pattern of negative effort dependence (NED) on inspiratory flow limited waveforms recorded during sleep, which has been correlated with the site of upper airway collapse, would contribute to the prediction of HGNS outcome. We developed a machine learning (ML) algorithm to identify NED patterns in pre-treatment sleep studies. We hypothesized that the predominant NED pattern would differ between HGNS responders and non-responders. METHODS: An ML algorithm to identify NED patterns on the inspiratory portion of the nasal pressure waveform was derived from 5 development set polysomnograms. The algorithm was applied to pre-treatment sleep studies of subjects who underwent HGNS implantation to determine the percentage of each NED pattern. HGNS response was defined by STAR trial criteria for success (apnea-hypopnea index (AHI) reduced by > 50% and < 20/h) as well as by a change in AHI and oxygenation metrics. The predominant NED pattern in HGNS responders and non-responders was determined. Other variables including demographics and oxygenation metrics were also assessed between responders and non-responders. RESULTS: Of 45 subjects, 4 were excluded due to technically inadequate polysomnograms. In the remaining 41 subjects, ML accurately distinguished three NED patterns (minimal, non-discontinuous, and discontinuous). The percentage of NED minimal breaths was significantly greater in responders compared with non-responders (p = 0.01) when the response was defined based on STAR trial criteria, change in AHI, and oxygenation metrics. CONCLUSION: ML can accurately identify NED patterns in pre-treatment sleep studies. There was a statistically significant difference in the predominant NED pattern between HGNS responders and non-responders with a greater NED minimal pattern in responders. Prospective studies incorporating NED patterns into predictive modeling of factors determining HGNS outcomes are needed.

Neuroendocrine neoplasms of the gallbladder: early detection and surgery is key to improved outcome.

PURPOSE: Neuroendocrine neoplasms (NENs) of the gallbladder are very rare. As a result, the classification of pathologic specimens from gallbladder NENs, currently classified as gallbladder neuroendocrine tumors (GB-NETs) and carcinomas (GB-NECs), is inconsistent and makes nomenclature, classification, and management difficult. Our study aims to evaluate the epidemiological trend, tumor biology, and outcomes of GB-NET and GB-NEC over the last 5 decades. METHODS: This is a retrospective analysis of the SEER database from 1973 to 2016. The epidemiological trend was analyzed using the age-adjusted Joinpoint regression analysis. Survival was assessed with Kaplan-Meier analysis and Cox regression was used to assess predictors of poor survival. RESULTS: A total of 482 patients with GB-NEN were identified. Mean age at diagnosis was 65.2 ± 14.3 years. Females outnumbered males (65.6% vs. 34.4%). The Joinpoint nationwide trend analysis showed a 7% increase per year from 1973 to 2016. The mean survival time after diagnosis of GB-NEN was 37.11 ± 55.3 months. The most common pattern of nodal distribution was N0 (50.2%) followed by N1 (30.9%) and N2 (19.2%). Advanced tumor spread (into the liver, regional, and distant metastasis) was seen in 60.3% of patients. Patients who underwent surgery had a significant survival advantage (111.0 ± 8.3 vs. 8.3 ± 1.2 months, p < 0.01). Cox regression analysis showed advanced age (p < 0.01), tumor stage (P < 0.01), tumor extension (p < 0.01), and histopathologic grade (p < 0.01) were associated with higher mortality. CONCLUSION: Gallbladder NENs are a rare histopathological variant of gallbladder cancer that is showing a rising incidence in the USA. In addition to tumor staging, surgical resection significantly impacts patient survival, when patients are able to undergo surgery irrespective of tumor staging. Advanced age, tumor extension, and histopathological grade of the tumor were associated with higher mortality.

A Ferrofluid with Surface Modified Nanoparticles for Magnetic Hyperthermia and High ROS Production.

A ferrofluid with 1,2-Benzenediol-coated iron oxide nanoparticles was synthesized and physicochemically analyzed. This colloidal system was prepared following the typical co-precipitation method, and superparamagnetic nanoparticles of 13.5 nm average diameter, 34 emu/g of magnetic saturation, and 285 K of blocking temperature were obtained. Additionally, the zeta potential showed a suitable colloidal stability for cancer therapy assays and the magneto-calorimetric trails determined a high power absorption density. In addition, the oxidative capability of the ferrofluid was corroborated by performing the Fenton reaction with methylene blue (MB) dissolved in water, where the ferrofluid was suitable for producing reactive oxygen species (ROS), and surprisingly a strong degradation of MB was also observed when it was combined with H2O2. The intracellular ROS production was qualitatively corroborated using the HT-29 human cell line, by detecting the fluorescent rise induced in 2,7-dichlorofluorescein diacetate. In other experiments, cell metabolic activity was measured, and no toxicity was observed, even with concentrations of up to 4 mg/mL of magnetic nanoparticles (MNPs). When the cells were treated with magnetic hyperthermia, 80% of cells were dead at 43 °C using 3 mg/mL of MNPs and applying a magnetic field of 530 kHz with 20 kA/m amplitude.

The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells.

The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity. SAP enhanced NK cell responsiveness by a dual molecular mechanism. It coupled SLAM family receptors to the kinase Fyn, which triggered the exchange factor Vav-1 and augmented NK cell activation. SAP also prevented the inhibitory function of SLAM family receptors. This effect was Fyn independent and correlated with uncoupling of SLAM family receptors from the lipid phosphatase SHIP-1. Both mechanisms cooperated to enable conjugate formation with target cells and to stimulate cytotoxicity and cytokine secretion by NK cells. These data showed that SAP secures NK cell activation by a dichotomous molecular mechanism, which is required for conjugate formation. These findings may have implications for the role of SAP in other immune cell types.

Optimization of Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea With Ultrasound Assessment of Tongue Movement.

BACKGROUND: Hypoglossal nerve stimulation (HGNS) is an Food and Drug Administration-approved therapy for obstructive sleep apnea. Initial programming of HGNS is based on the observation of anterior tongue movement, which may not reflect opening at the retroglossal airway. We developed an ultrasonographic technique to assess the base of tongue movement with HGNS to be used to optimize the initial voltage settings. STUDY QUESTION: This study aimed to investigate the use of ultrasound to assess tongue movement with HGNS and related this measure to the apnea hypopnea index (AHI) on subsequent home sleep apnea testing or in-laboratory polysomnography with therapy. STUDY DESIGN: Seventeen subjects (n = 17) implanted with HGNS were enrolled at least 1 month postimplantation. Ultrasonographic measures were then used to optimize HGNS voltage to produce observable base of tongue protrusion without producing discomfort. Responders were defined as a reduction in AHI > 50% and an AHI of <20 events/h. RESULTS: There were 17 subjects, 11 men and 6 women, with age = 64.6 ± 9.8 years, body mass index = 27.9 ± 2.7 kg/m2, and pretreatment AHI = 36.5 ± 14.4/h, T-90% = 10.7 ± 14.8%. The mean hyoid bone excursion (HBE) in responders = 1.0 ± 0.13 cm versus 0.82 ± 0.12 cm in nonresponders (P = 0.017). HBE was correlated with AHI during HGNS treatment (coef. -0.54, P = 0.03). Best subsets regression analysis using treatment-based AHI as the dependent variable and age, body mass index, baseline AHI, HBE, and HGNS voltage as independent variables showed that HBE (coef. -44.6, P = 0.044) was the only independent predictor of response. Receiver operator curve analysis showed that HBE > 0.85 cm had a sensitivity of 83.3% and specificity of 80.0% with a positive likelihood ratio of 4.17 to predict responder status. CONCLUSION: We demonstrated that ultrasound assessment of HBE during HGNS programming is a useful tool to optimize therapy.

Postoperative venous thromboembolism and mortality in patients with pancreatic surgery.

BACKGROUND AND OBJECTIVES: Pancreatic cancer is strongly associated with thrombosis. We investigated early postoperative venous thromboembolism (PVTE) mortality among patients with pancreatic surgery and compared outcomes in adenocarcinoma pancreatic cancer (ACPC) to non-adenocarcinoma pancreatic neoplasm (NACPN). METHODS: We analyzed a prospectively collected database of patients who underwent pancreatic cancer or neoplasm-related surgery. As NACPN is underrepresented in other studies, we selected NACPN patients and a random sample of ACPC patients. PVTE was defined as VTE occurring within 3 months of surgical intervention. Statistical analysis was performed using Cox proportional hazards regression. RESULTS: A total of 441 pancreatic surgery patients were included, with 331 ACPC and 110 NACPN. Median follow-up was 449 days during which 90 (20.4%) patients developed VTE. PVTE occurred in 53 (12.0%) patients, including 41 (12.4%) ACPC patients and 12 (10.9%) NACPN patients. Those with PVTE had 60% higher mortality rate. A multivariable analysis found that PVTE is an independent predictor of increased mortality (HR Adj, 1.6; 95% CI, 1.1-2.2; P < .01). The mortality impact was not consistent between ACPC (HR, 3.2; 95% CI, 1.3-7.9) and NACPN groups (HR, 1.3; 95% CI, 0.9-1.8). CONCLUSIONS: Postoperative venous thromboembolism is an independent predictor of increased mortality in pancreatic surgery, specifically in adenocarcinoma pancreatic cancer surgery.

Rate and impact of venous thromboembolism in patients with ST-segment elevation myocardial infarction: Analysis of the Nationwide Inpatient Sample database 2003-2013.

Venous thromboembolism (VTE) and coronary artery disease are major health issues that cause substantial morbidity and mortality. New data have emerged suggesting that these two conditions could have a close relationship. Thus, we sought to determine the trends in annual rate of VTE occurrence in patients with ST-segment elevation myocardial infarction (STEMI) and measure its impact on in-hospital mortality, bleeding complications, and cost and length of hospitalization. We queried the 2003-2013 Nationwide Inpatient Sample databases to identify adults with primary diagnosis of STEMI. VTE events were then allocated. Inpatient outcomes of patients with VTE were compared to those without VTE. Out of 2,495,757 hospitalizations for STEMI, VTE was diagnosed in 25,149 (1%) hospitalizations. Patients who experienced VTE were older (mean age: 67.5 vs 64.8, p < 0.01) and had a higher proportion of black patients (10.1% vs 7.7%, p < 0.001) and females (40.1% vs 35%, p < 0.001) compared to patients without VTE. There was an increasing trend in the rate of VTE during the study period (2003: 0.8% vs 2013: 1.0%, p < 0.001). Patients with VTE had a prolonged hospitalization (median: 9 vs 3 days, p < 0.001), increased cost, higher risk of gastrointestinal bleeding (OR: 2.13, p < 0.001), intracranial hemorrhage (OR: 2.14, p < 0.001), blood transfusions (OR: 1.94, p < 0.001), and mortality (OR: 1.39, p < 0.001). The rate of VTE occurrence in patients with STEMI in our study was 10 per 1000 admissions. VTE was associated with more bleeding complications, longer hospital stays, higher costs, and mortality. These findings suggest that a more aggressive approach for VTE prophylaxis may be warranted in this population.

Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity.

The family of protein tyrosine phosphatases (PTPs) includes 107 genes in humans that are diverse in their structures and expression profiles. The majority are present in immune cells and play various roles in either inhibiting or promoting the duration and amplitude of signaling cascades. Several PTPs, including TC-PTP (PTPN2) and SHP-1 (PTPN6), have been recognized as being crucial for maintaining proper immune response and self-tolerance, and have gained recognition as true immune system checkpoint modulators. This chapter details the most recent literature on PTPs and immunity by examining their known functions in regulating signaling from either established checkpoint inhibitors or by their intrinsic properties, as modulators of the immune response. Notably, we review PTP regulatory properties in macrophages, antigen-presenting dendritic cells, and T cells. Overall, we present the PTP gene family as a remarkable source of novel checkpoint inhibitors wherein lies a great number of new targets for immunotherapies.

A new and updated resource for codon usage tables.

BACKGROUND: Due to the degeneracy of the genetic code, most amino acids can be encoded by multiple synonymous codons. Synonymous codons naturally occur with different frequencies in different organisms. The choice of codons may affect protein expression, structure, and function. Recombinant gene technologies commonly take advantage of the former effect by implementing a technique termed codon optimization, in which codons are replaced with synonymous ones in order to increase protein expression. This technique relies on the accurate knowledge of codon usage frequencies. Accurately quantifying codon usage bias for different organisms is useful not only for codon optimization, but also for evolutionary and translation studies: phylogenetic relations of organisms, and host-pathogen co-evolution relationships, may be explored through their codon usage similarities. Furthermore, codon usage has been shown to affect protein structure and function through interfering with translation kinetics, and cotranslational protein folding. RESULTS: Despite the obvious need for accurate codon usage tables, currently available resources are either limited in scope, encompassing only organisms from specific domains of life, or greatly outdated. Taking advantage of the exponential growth of GenBank and the creation of NCBI's RefSeq database, we have developed a new database, the High-performance Integrated Virtual Environment-Codon Usage Tables (HIVE-CUTs), to present and analyse codon usage tables for every organism with publicly available sequencing data. Compared to existing databases, this new database is more comprehensive, addresses concerns that limited the accuracy of earlier databases, and provides several new functionalities, such as the ability to view and compare codon usage between individual organisms and across taxonomical clades, through graphical representation or through commonly used indices. In addition, it is being routinely updated to keep up with the continuous flow of new data in GenBank and RefSeq. CONCLUSION: Given the impact of codon usage bias on recombinant gene technologies, this database will facilitate effective development and review of recombinant drug products and will be instrumental in a wide area of biological research. The database is available at hive.biochemistry.gwu.edu/review/codon .

SOA-based model for value-added ITS services delivery.

Integration is currently a key factor in intelligent transportation systems (ITS), especially because of the ever increasing service demands originating from the ITS industry and ITS users. The current ITS landscape is made up of multiple technologies that are tightly coupled, and its interoperability is extremely low, which limits ITS services generation. Given this fact, novel information technologies (IT) based on the service-oriented architecture (SOA) paradigm have begun to introduce new ways to address this problem. The SOA paradigm allows the construction of loosely coupled distributed systems that can help to integrate the heterogeneous systems that are part of ITS. In this paper, we focus on developing an SOA-based model for integrating information technologies (IT) into ITS to achieve ITS service delivery. To develop our model, the ITS technologies and services involved were identified, catalogued, and decoupled. In doing so, we applied our SOA-based model to integrate all of the ITS technologies and services, ranging from the lowest-level technical components, such as roadside unit as a service (RSUAAS), to the most abstract ITS services that will be offered to ITS users (value-added services). To validate our model, a functionality case study that included all of the components of our model was designed.

AVDOS-VR: Affective Video Database with Physiological Signals and Continuous Ratings Collected Remotely in VR.

Investigating emotions relies on pre-validated stimuli to evaluate induced responses through subjective self-ratings and physiological changes. The creation of precise affect models necessitates extensive datasets. While datasets related to pictures, words, and sounds are abundant, those associated with videos are comparatively scarce. To overcome this challenge, we present the first virtual reality (VR) database with continuous self-ratings and physiological measures, including facial EMG. Videos were rated online using a head-mounted VR device (HMD) with attached emteqPRO mask and a cinema VR environment in remote home and laboratory settings with minimal setup requirements. This led to an affective video database with continuous valence and arousal self-rating measures and physiological responses (PPG, facial-EMG (7x), IMU). The AVDOS-VR database includes data from 37 participants who watched 30 randomly ordered videos (10 positive, neutral, and negative). Each 30-second video was assessed with two-minute relaxation between categories. Validation results suggest that remote data collection is ecologically valid, providing an effective strategy for future affective study designs. All data can be accessed via: www.gnacek.com/affective-video-database-online-study .

Surgical Urgency, Patient Comorbidities, and Socioeconomic Factors in Surgical Site Infections in Pediatric Surgery.

BACKGROUND: The rise of value-based purchasing has led to decreased compensation for hospital-acquired conditions, including surgical site infections (SSI). This study aims to assess the risk factors for SSI in children and teenagers undergoing gastrointestinal surgery across US hospitals. METHODS: The 2018-2020 Nationwide Readmissions Database was queried for patients undergoing gastrointestinal surgery under the age of 18. The primary outcome was SSI during index admission or readmission within a year. Comparison groups were elective, trauma, and emergent surgery based on anatomic location and urgency. Univariable comparison used chi-squared tests for relevant variables. Confounders were addressed through multivariable logistic regression with significant variables from univariable analysis. RESULTS: 113 108 total patients met the study criteria. The SSI rate during admission or readmission was 2.9% (n = 3254). Infections during admission and readmission were 1.4% (n = 1560) and 1.5% (n = 1694), respectively. The most common site was organ space (48.6%, n = 1657). Increased infection risk was associated with trauma (OR 1.80 [1.51-2.16] P < .001), emergency surgery (OR 1.31 [1.17-1.47] P < .001), large bowel surgery (OR 2.78 [2.26-3.43] P < .001), and those with three or more comorbidities (OR 2.03 [1.69-2.45] P < .001). Investor-owned hospitals (OR .65 [.56-.76] P < .001) and highest quartile income (OR .80 [.73-.88] P < .001) were associated with decreased infection risk. CONCLUSIONS: Pediatric patients undergoing gastrointestinal surgery face an elevated risk of SSI, especially in trauma and emergency surgeries, particularly with multiple comorbidities. Meanwhile, a reduced risk is observed in high-income and investor-owned hospital settings. Hospitals and surgeons caring for high risk patients should advocate for risk adjustment in value-based payment systems.

Venous Thromboembolism in Children and Teenagers Admitted for Trauma: A 5-Year Nationwide Perspective.

Venous thromboembolism (VTE) in pediatric trauma patients is under-investigated. The purpose of this study was to perform an evaluation of the risk factors for VTE after pediatric trauma, including readmissions across the United States. The Nationwide Readmissions Database for 2016-2020 was queried for all patients under the age of 18 years admitted for trauma. 276 670 patients were identified; 2063 (.8%) were diagnosed with VTE. Among those with VTE, 300 (15%) were identified during a readmission. Higher rates of VTE were seen in ages 15-17 years (n = 1,294, 1.3%, P < .001), penetrating injuries (n = 478, .9%, P < .001), and assault (n = 271, 2.7%, P < .001). The strongest risk factor for VTE was prolonged mechanical ventilation (OR 5.5 [4.9-6.3] P < .001). Our study found that a significant portion of post-traumatic VTE in children and teenagers occur during readmissions. A deeper understanding of the risk factors outlined here can guide enhanced clinical protocols, ensuring early detection and prevention of this complication.

Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP.

In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.

Multiplex detection and identification of viral, bacterial, and protozoan pathogens in human blood and plasma using an expanded high-density resequencing microarray platform.

Introduction: Nucleic acid tests for blood donor screening have improved the safety of the blood supply; however, increasing numbers of emerging pathogen tests are burdensome. Multiplex testing platforms are a potential solution. Methods: The Blood Borne Pathogen Resequencing Microarray Expanded (BBP-RMAv.2) can perform multiplex detection and identification of 80 viruses, bacteria and parasites. This study evaluated pathogen detection in human blood or plasma. Samples spiked with selected pathogens, each with one of 6 viruses, 2 bacteria and 5 protozoans were tested on this platform. The nucleic acids were extracted, amplified using multiplexed sets of primers, and hybridized to a microarray. The reported sequences were aligned to a database to identify the pathogen. To directly compare the microarray to an emerging molecular approach, the amplified nucleic acids were also submitted to nanopore next generation sequencing (NGS). Results: The BBP-RMAv.2 detected viral pathogens at a concentration as low as 100 copies/ml and a range of concentrations from 1,000 to 100,000 copies/ml for all the spiked pathogens. Coded specimens were identified correctly demonstrating the effectiveness of the platform. The nanopore sequencing correctly identified most samples and the results of the two platforms were compared. Discussion: These results indicated that the BBP-RMAv.2 could be employed for multiplex detection with potential for use in blood safety or disease diagnosis. The NGS was nearly as effective at identifying pathogens in blood and performed better than BBP-RMAv.2 at identifying pathogen-negative samples.

Trends in Opioid Use Disorder Outpatient Treatment and Telehealth Utilization Before and During the COVID-19 Pandemic.

OBJECTIVE: The authors examined trends in opioid use disorder treatment and in-person and telehealth modalities before and after COVID-19 pandemic onset among patients who had received treatment prepandemic. METHODS: The sample included 13,113 adults with commercial insurance or Medicare Advantage and receiving opioid use disorder treatment between March 2018 and February 2019. Trends in opioid use disorder outpatient treatment, treatment with medications for opioid use disorder (MOUD), and in-person and telehealth modalities were examined 1 year before pandemic onset and 2 years after (March 2019-February 2022). RESULTS: From March 2019 to February 2022, the proportion of patients with opioid use disorder outpatient and MOUD visits declined by 2.8 and 0.3 percentage points, respectively. Prepandemic, 98.6% of outpatient visits were in person; after pandemic onset, at least 34.9% of patients received outpatient care via telehealth. CONCLUSIONS: Disruptions in opioid use disorder outpatient and MOUD treatments were marginal during the pandemic, possibly because of increased telehealth utilization.