Quantifying physical degradation alongside recording and stimulation performance of 980 intracortical microelectrodes chronically implanted in three humans for 956-2246 days.

Motivation: The clinical success of brain-machine interfaces depends on overcoming both biological and material challenges to ensure a long-term stable connection for neural recording and stimulation. Therefore, there is a need to quantify any damage that microelectrodes sustain when they are chronically implanted in the human cortex. Methods: Using scanning electron microscopy (SEM), we imaged 980 microelectrodes from Neuroport arrays chronically implanted in the cortex of three people with tetraplegia for 956-2246 days. We analyzed eleven multi-electrode arrays in total: eight arrays with platinum (Pt) electrode tips and three with sputtered iridium oxide tips (SIROF); one Pt array was left in sterile packaging, serving as a control. The arrays were implanted/explanted across three different clinical sites surgeries (Caltech/UCLA, Caltech/USC and APL/Johns Hopkins) in the anterior intraparietal area, Brodmann's area 5, motor cortex, and somatosensory cortex.Human experts rated the electron micrographs of electrodes with respect to five damage metrics: the loss of metal at the electrode tip, the amount of separation between the silicon shank and tip metal, tissue adherence or bio-material to the electrode, damage to the shank insulation and silicone shaft. These metrics were compared to functional outcomes (recording quality, noise, impedance and stimulation ability). Results: Despite higher levels of physical degradation, SIROF electrodes were twice as likely to record neural activity than Pt electrodes (measured by SNR), at the time of explant. Additionally, 1 kHz impedance (measured in vivo prior to explant) significantly correlated with all physical damage metrics, recording, and stimulation performance for SIROF electrodes (but not Pt), suggesting a reliable measurement of in vivo degradation. We observed a new degradation type, primarily occurring on stimulated electrodes ("pockmarked" vs "cracked") electrodes; however, tip metalization damage was not significantly higher due to stimulation or amount of charge. Physical damage was centralized to specific regions of an array often with differences between outer and inner electrodes. This is consistent with degradation due to contact with the biologic milieu, influenced by variations in initial manufactured state. From our data, we hypothesize that erosion of the silicon shank often precedes damage to the tip metal, accelerating damage to the electrode / tissue interface. Conclusions: These findings link quantitative measurements, such as impedance, to the physical condition of the microelectrodes and their capacity to record and stimulate. These data could lead to improved manufacturing or novel electrode designs to improve long-term performance of BMIs making them are vitally important as multi-year clinical trials of BMIs are becoming more common.

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.

Tractography of sensorimotor pathways in dyskinetic cerebral palsy: Association with motor function.

OBJECTIVES: Neuroimaging studies of dyskinetic cerebral palsy (CP) are scarce and the neuropathological underpinnings are not fully understood. We delineated the corticospinal tract (CST) and cortico-striatal-thalamocortical (CSTC) pathways with probabilistic tractography to assess their (1) integrity and (2) association with motor functioning in people with dyskinetic CP. METHODS: Diffusion weighted magnetic resonance images were obtained for 33 individuals with dyskinetic CP and 33 controls. Fractional anisotropy (FA) and mean diffusivity (MD) for the CST and the CSTC pathways were compared between groups. Correlation analyses were performed between tensor metric values and motor function scores of participants with dyskinetic CP as assessed by the Gross Motor Function Classification System (GMFCS), the Bimanual Fine Motor Function (BFMF), and the Manual Ability Classification System (MACS). RESULTS: White matter integrity in both the CST and the CSTC pathways was reduced in people with dyskinetic CP. The GMFCS, MACS and, less commonly, the BFMF were associated with FA and, particularly, MD in most portions of these pathways. INTERPRETATION: The present study advances our understanding of the involvement of white matter microstructure in sensorimotor pathways and its relationship with motor impairment in people with dyskinetic CP. Our results are consistent with well-described relationships between upper limb function and white matter integrity in the CST and CSTC pathways in other forms of CP. This knowledge may ultimately help prognosis and therapeutic programmes.

Phylogeny, morphology, and behavior of the new ciliate species Stentor stipatus.

The study of evolution at the cellular level traditionally has focused on the evolution of metabolic pathways, endomembrane systems, and genomes, but there has been increasing interest in evolution of more complex cellular structures and behaviors, particularly in the eukaryotes. Ciliates have major advantages for such studies due to their easily visible surface patterning and their dramatic and complex behaviors that can be easily analyzed. Among the ciliates, the genus Stentor epitomizes the features that are useful for studying evolution: they are widespread in freshwater environments, easy to visualize because of their large size, and capable of complex behaviors such as learning, decision-making, and phototaxis. Here, we introduce the discovery of a new species within this genus: Stentor stipatus, so named for their distinctive dark brown aggregates. We present morphological, phylogenetic, ecological, and behavioral characterizations of these cells. The S. stipatus clade has a bootstrap value of 93 and is phylogenetically distinct from S. amethystinus, the closest related species which shares a sequence similarity of 98.9%. S. stipatus is capable of phototaxis and can also habituate more quickly than S. coeruleus, the Stentor species in which most habituation studies have previously been conducted. These findings expand our understanding of Stentor species diversity, natural history, and demonstrate common principles of complex behavior that are present in single-celled organisms.

Plant, insect, and fungi fossils under the center of Greenland's ice sheet are evidence of ice-free times.

The persistence and size of the Greenland Ice Sheet (GrIS) through the Pleistocene is uncertain. This is important because reconstructing changes in the GrIS determines its contribution to sea level rise during prior warm climate periods and informs future projections. To understand better the history of Greenland's ice, we analyzed glacial till collected in 1993 from below 3 km of ice at Summit, Greenland. The till contains plant fragments, wood, insect parts, fungi, and cosmogenic nuclides showing that the bed of the GrIS at Summit is a long-lived, stable land surface preserving a record of deposition, exposure, and interglacial ecosystems. Knowing that central Greenland was tundra-covered during the Pleistocene informs the understanding of Arctic biosphere response to deglaciation.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Seattle proportional risk model in GISSI-HF: Estimated benefit of ICD in patients with EF less than 50.

BACKGROUND: The Seattle Proportional Risk Model (SPRM) estimates the proportion of sudden cardiac death (SCD) in heart failure (HF) patients, identifying those most likely to benefit from implantable cardioverter-defibrillator (ICD) therapy (those with ≥50% estimated proportion of SCD). The GISSI-HF trial tested fish oil and rosuvastatin in HF patients. We used the SPRM to evaluate its accuracy in this cohort in predicting potential ICD benefit in patients with EF ≤50% and an SPRM-predicted proportion of SCD either ≥50% or <50%. METHODS: The SPRM was estimated in patients with EF ≤50% and in a logistic regression model comparing SCD with non-SCD. RESULTS: We evaluated 6,750 patients with EF ≤50%. There were 1,892 all-cause deaths, including 610 SCDs. Fifty percent of EF ≤35% patients and 43% with EF 36% to 50% had an SPRM of ≥50%. The SPRM (OR: 1.92, P < 0.0001) accurately predicted the risk of SCD vs non-SCD with an estimated proportion of SCD of 44% vs the observed proportion of 41% at 1 year. By traditional criteria for ICD implantation (EF ≤35%, NYHA class II or III), 64.5% of GISSI-HF patients would be eligible, with an estimated ICD benefit of 0.81. By SPRM >50%, 47.8% may be eligible, including 30.2% with EF >35%. GISSI-HF participants with EF ≤35% with SPRM ≥50% had an estimated ICD HR of 0.64, comparable to patients with EF 36% to 50% with SPRM ≥50% (HR: 0.65). CONCLUSIONS: The SPRM discriminated SCD vs non-SCD in GISSI-HF, both in patients with EF ≤35% and with EF 36% to 50%. The comparable estimated ICD benefit in patients with EF ≤35% and EF 36% to 50% supports the use of a proportional risk model for shared decision making with patients being considered for primary prevention ICD therapy.

CRIMP: a CRISPR/Cas9 insertional mutagenesis protocol and toolkit.

Site-directed insertion is a powerful approach for generating mutant alleles, but low efficiency and the need for customisation for each target has limited its application. To overcome this, we developed a highly efficient targeted insertional mutagenesis system, CRIMP, and an associated plasmid toolkit, CRIMPkit, that disrupts native gene expression by inducing complete transcriptional termination, generating null mutant alleles without inducing genetic compensation. The protocol results in a high frequency of integration events and can generate very early targeted insertions, during the first cell division, producing embryos with expression in one or both halves of the body plan. Fluorescent readout of integration events facilitates selection of successfully mutagenized fish and, subsequently, visual identification of heterozygous and mutant animals. Together, these advances greatly improve the efficacy of generating and studying mutant lines. The CRIMPkit contains 24 ready-to-use plasmid vectors to allow easy and complete mutagenesis of any gene in any reading frame without requiring custom sequences, modification, or subcloning.

Early onset metastatic colorectal cancer in Australia.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.

Iron burden and endocrine complications in transfusion-dependent thalassemia patients In Sarawak, Malaysia: a retrospective study.

INTRODUCTION: Thalassaemia is one of the major health problems in Malaysia. With safe blood transfusion regime, the lifespan of patients with transfusion-dependent thalassaemia (TDT) has improved but at the cost of a higher risk of developing endocrine disorders. It is crucial for us to monitor the iron overload to prevent end organ damage. This study aims to evaluate the iron burden and prevalence of endocrinopathies in patients with TDT in Sarawak. MATERIALS AND METHODS: This retrospective cohort study was conducted between January 2020 to June 2020 in six government hospitals in Sarawak. A total of 89 patients with TDT, aged 10 years and above, were recruited. RESULTS: Out of the 89 patients, there were 54 males (60.7%) and 35 females (39.3%) with a median age of 21 years (range 10.0-65.0). Sixty-seven (75.3%) patients had betathalassaemia major and 15 (16.9%) patients had haemoglobin E beta-thalassaemia (HbE beta-thalassaemia), remaining seven patients had other genotypes. Thirty-one (34.8%) patients had mean serum ferritin 2500ng/ml and above, and 44 (66.6%) had liver iron concentration (LIC) ≥7mg/g. The prevalence of endocrine disorders in our cohort was 69.7%. The most common endocrinopathies were short stature (n=46, 51.7%), followed by hypogonadism (n=24, 26.9%), delayed puberty (n=23, 25.8%), hypothyroidism (n=10, 11.2%), diabetes mellitus (n=9, 10.1%), impaired glucose tolerance (n=6, 6.7%) and hypoparathyroidism (n=3, 3.3%). Endocrinopathies were significantly associated with age (p=0.01), age at initiating regular blood transfusion (p<0.01) and duration of regular blood transfusion (p<0.01). CONCLUSION: Our data shows that the development of endocrinopathies in TDT can be time dependent. Early detection of endocrine-related complications and prompt treatment with iron chelation therapy are important to improve morbidity and mortality. A multidisciplinary approach with good patient-doctor collaboration is the key to improving patient care in our settings.

A Case of Persistent Junctional Reciprocating Tachycardia Coincident With Cor Triatriatum Sinister.

Persistent junctional reciprocating tachycardia is a rare form of refractory atrioventricular reentrant tachycardia that accounts for <1% of supraventricular tachycardia in pediatrics. The accessory pathways are generally isolated with few reported underlying structural heart defects. We present a case of a five-month-old male with refractory tachyarrhythmia found to have cor triatriatum sinister, which to our knowledge, is the first reported case of these two rare anomalies coexisting.

Antitumor Activity of a Novel LAIR1 Antagonist in Combination with Anti-PD1 to Treat Collagen-Rich Solid Tumors.

We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding to LAIR1 and blocking collagen engagement. Furthermore, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T-cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.

Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease.

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast (TNNI2) and TnI-slow (TNNI1), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca2+] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca2+], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.

Prevalence of occupational heat stress across the seasons and its management amongst healthcare professionals in the UK.

Occupational heat stress (OHS) is an issue in healthcare facilities (HCFs) in the United Kingdom (UK). The aims of this study were to evaluate perceived levels of OHS during two seasons and its perceived consequences on healthcare professionals (HCPs) and to assess the efficacy of heat stress management (HSM) policies. An anonymous online survey was distributed to HCPs working in HCFs in the UK. The survey returned 1014 responses (87% women). Descriptive statistics and content analysis of survey data identified that OHS in HCFs is frequently experienced throughout the year and concerned most HCPs. Over 90% perceived OHS impairs their performance and 20% reported heat-related absenteeism. Awareness of HSM policies was poor and 73% deemed them not adequate. To help reduce the financial loss and impact on staff performance, health and well-being and patient safety, it is recommended that revisions and widespread dissemination of HSM policies are made.

Management of newborns and healthcare workers exposed to isoniazid-resistant congenital tuberculosis in the neonatal intensive care unit.

BACKGROUND: Management of newborns and healthcare workers (HCWs) exposed to congenital tuberculosis (TB) in the neonatal intensive care unit (NICU) has been reported rarely. AIM: To outline a contact investigation process for individuals exposed to congenital TB in the NICU and investigate nosocomial transmission. Additionally, to assess the efficacy and safety of window prophylaxis in exposed newborns. METHODS: A baby, born at a gestational age of 28 + 1 weeks, was diagnosed with isoniazid-resistant congenital TB on the 39th day of admission to the level IV NICU. Newborns and HCWs exposed cumulatively for ≥8 h underwent contact investigation and follow-up for a year. FINDINGS: Eighty-two newborns underwent contact investigation. All newborns displayed normal chest X-rays, and 42 hospitalized newborns tested negative for acid-fast bacilli stain and Xpert® MTB/RIF assay in their endotracheal sputum or gastric juices. Eighty received window prophylaxis: six of 75 on rifampin experienced mild adverse events, and none of the five on levofloxacin. After 12 weeks, five (6.1%) had a positive tuberculin skin test, all of whom had already received the Bacillus Calmette-Guérin vaccine and tested negative on TB interferon-gamma releasing assay. Of 119 exposed HCWs, three (2.5%) were diagnosed with latent TB infection and completed a four-month rifampin therapy. There was no active TB disease among exposed newborns and HCWs during a one-year follow-up. CONCLUSION: Timely diagnosis of congenital TB is crucial for minimizing transmission among exposed neonates and HCWs in the NICU setting. In cases of isoniazid-resistant index patients, even premature newborns may consider the use of rifampin or levofloxacin for window prophylaxis.

Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP.

Skeletal muscle wasting results from numerous pathological conditions affecting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role of E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss-of-function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 resulted in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fiber integrity. We further implicated a disruption in atrogin-1-mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We revealed that BiP was not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorated pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicate atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy and highlight atrogin-1's essential role in maintaining muscle homeostasis.

ILT2 and ILT4 Drive Myeloid Suppression via Both Overlapping and Distinct Mechanisms.

Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment.

The iBelong Scale: Construction and validation of a measure of racial-ethnic-cultural belonging.

The purpose of this study was to develop a measure of racial-ethnic-cultural (REC) belonging for Black, Indigenous, and other people of color (BIPOC). The iBelong Scale was designed to assess the multidimensional components of REC belonging across diverse BIPOC groups. The scale was constructed based on a grounded conceptual framework of REC belonging, and the initial pool of items received feedback from community members and content experts. Validation of the iBelong Scale comprised data from 808 BIPOC participants collected across three interrelated studies for the purposes of initial validation, construct validity, and test-retest reliability. In Study 1, an exploratory factor analysis yielded a 25-item scale with five factors: (a) Home, (b) Connection, (c) Authenticity, (d) REC Thriving, and (e) Self-Definition. Results from Study 2's confirmatory factor analysis indicated that the five-factor model was an acceptable fit of the data and the best fit among competing models. Measurement invariance was assessed, and results indicated that the iBelong Scale measures REC belonging similarly across differing BIPOC groups. The iBelong Scale was related to a range of measures in theoretically expected ways, including positive associations with general belonging, racial/ethnic identity, and general well-being, and negative associations with loneliness and REC nonbelonging. Findings from Study 3 indicated the test-retest reliability of the iBelong Scale over a 2-week period. Limitations of the studies and implications for research and practice are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Thyroglossal Duct Cyst Infection Caused by Neisseria gonorrhoeae: An Unusual Complication of Pharyngeal Gonorrhea.

ABSTRACT: Neisseria gonorrhoeae is a human obligate pathogen whose clinical expression of disease ranges from localized genital infection to involvement of extragenital sites such as the conjunctiva and throat. We describe the second case of a thyroglossal duct abscess due to N. gonorrhoeae, an uncommon complication of pharyngeal gonococcal infection. The fortuitous occurrence in the same individual of these 2 conditions that both exhibit an occult clinical presentation likely accounts for rarity of this infection. We discuss the pertinent gonococcal and host factors that underlie the clinical manifestations of this infection. A particular focus is the fundamental role that the binding of the gonococcal opacity-associated protein to the ubiquitous human carcinoembryonic cell adhesion molecule plays in the pathogenesis of pharyngeal gonorrhea.