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Lung cancer is the number one cause of cancer-related deaths. The malignancy is characterized by dismal prognosis and poor clinical outcome mostly due to advanced-stage at diagnosis, thereby inflicting a heavy burden on public health worldwide. Recent breakthroughs in immunotherapy have greatly benefited a subset of lung cancer patients, and more importantly, they are undauntedly bringing forth a paradigm shift in the drugs approved for cancer treatment, by introducing \"tumor-type agnostic therapies\". Yet, and to fulfill immunotherapy's potential of personalized cancer treatment, demarcating the immune and genomic landscape of cancers at their earliest possible stages will be crucial to identify ideal targets for early treatment and to predict how a particular patient will fare with immunotherapy. Recent genomic surveys of premalignant lung cancer have shed light on early alterations in the evolution of lung cancer. More recently, the advent of immunogenomic technologies has provided prodigious opportunities to study the multidimensional landscape of lung tumors as well as their microenvironment at the molecular, genomic, and cellular resolution. In this review, we will summarize the current state of immune-based therapies for cancer, with a focus on lung malignancy, and highlight learning outcomes from clinical and preclinical studies investigating the naïve immune biology of lung cancer. The review also collates immunogenomic-based evidence from seminal reports which collectively warrant future investigations of premalignancy, the tumor-adjacent normal-appearing lung tissue, pulmonary inflammatory conditions such as chronic obstructive pulmonary disease, as well as systemic microbiome imbalance. Such future directions enable novel insights into the evolution of lung cancers and, thus, can provide a low-hanging fruit of targets for early immune-based treatment of this fatal malignancy.

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration. This study shows that glial reactivity is linked to synaptic dysfunction in aging and Alzheimer’s disease, with tau pathology mediating these effects–highlighting the potential of synaptic biomarkers track disease progression.

The need for consultation-liaison psychiatry on COVID-19 wards has substantially increased since the start of the pandemic. In this cross-sectional study, we aimed to summarize the characteristics of patients admitted to the post-COVID-19 ward of the American University of Beirut Medical Center who received a psychiatric consultation. We collected relevant sociodemographic and medical data, information about past psychiatric history, psychiatry consultation details, hospital course, and disposition outcome. We also conducted chi-square and binary logistic regression analyses to assess the association between the different variables and disposition outcome. A total of 52 patients (mean age 57.33 years; equal gender distribution) were seen by the psychiatry consult-liaison team. Most had medical comorbidities and 21.2% required intubation. The most prevalent psychiatric diagnoses were delirium (30.8%), major depressive episode (15.4%), and other anxiety disorder (15.4%). Pharmacological management was implemented in 90.4% of cases and mainly included second-generation antipsychotics (36.5%). Non-pharmacological interventions consisted of those related to delirium and therapy for anxiety. Only intubation was significantly associated with disposition outcome (p = 0.004). This study highlights the various psychiatric themes emerging during the acute and post-acute periods of hospitalization for COVID-19. Hospitalized individuals recovering from the infection should be diligently screened and referred to the psychiatry consultation-liaison team to ensure the implementation of appropriate interventions.

Background Delirium is a very common occurrence in hospital settings and is frequently missed by the primary care team. It remains, however, poorly studied in the Middle East despite abundant global reports. In this study, we aimed to estimate the prevalence of missed delirium diagnosis in a tertiary care center in Lebanon and investigate potential predictors of this missed diagnosis. This was a retrospective study of adult patients admitted to the American University of Beirut Medical Center between March 2019 and December 2019 and assessed by the consultation-liaison psychiatry (CLP) team. The primary endpoint was the rate of missed delirium diagnosis among CLP consultations. Relevant statistical tests were performed to assess the association between the missed diagnosis of delirium and characteristics of patients. Results Five hundred fifty-three patients were included with a mean age of 69.19 ± 14.79 years. 86.13% of the patients received a delirium diagnosis by the CLP team that had been missed prior to the CLP referral. A missed delirium diagnosis was more likely to be found in patients with a history of depression (OR = 24, p  < 0.01) and a longer hospital stay [in days] (OR = 1.04, p  = 0.04). Conclusion The alarmingly high prevalence of missed delirium diagnosis is the first evidence of its kind in the Middle East. This urges the implementation of educational interventions to increase the detection of delirium among healthcare providers and ultimately improve patient outcomes.

Background Recent studies have shown that patients with attention‐deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). Increased genetic risk for ADHD, measured with ADHD polygenic risk scores (ADHD‐PRS), was associated with a more severe AD presentation, including worse cognitive function and higher tau pathology. Neuropsychiatric symptoms (NPSs) are common in AD and are hypothesized to occur with disease progression. It is unclear whether ADHD predispose individuals to the development of NPSs. Method We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to investigate the associations between ADHD‐PRS and the development of NPSs in cognitively impaired (CI, including MCI and AD) subjects who had brain amyloidosis at baseline. NPSs were assessed with the NPI or NPI‐Q and divided into four syndromes: hyperactive (agitation, disinhibition, irritability, and aberrant motor behavior), psychosis (delusions, hallucinations, and night‐time behavior disturbances), apathy (apathy and appetite and eating abnormalities), and affective (depression and anxiety). Additionally, we tested the specificity of our findings by analyzing the association between the genetic risk for depression, bipolar disorder (BD), schizophrenia, and autism spectrum disorder (ASD) with the development of NPSs. Data were represented with Kaplan‐Meier survival curves, and analyses were performed with Cox proportional hazards regression models controlled by age, sex, and ancestry. Result We evaluated data from 852 participants (636 MCI [74.1%], 350 women [40.8%], mean [SD] age of 73.4 [7.3] years). ADHD‐PRS was associated with a higher risk of developing hyperactive (HR 1.41; 95% CI 1.04‐1.89) and apathy (HR 1.34; 95% CI 1.01‐1.77) symptoms, but not psychosis (HR 1.04; 95% CI 0.78‐1.41) or affective (HR 0.97; 95% CI 0.72‐1.32) symptoms. There was no association between the genetic risk for depression, BP, schizophrenia, or ASD with any neuropsychiatric syndrome. Conclusion Findings indicate that a higher genetic risk for ADHD may be a risk factor for the development of hyperactive and apathy symptoms in CI individuals. These effects were specific for ADHD and were not observed for other prevalent psychiatric disorders. Clinically, our results contribute to the literature that highlights the need for tailored assessments for CI individuals with ADHD histories.

Cerebrospinal fluid (CSF) total tau (t-tau) is considered a biomarker of neuronal degeneration alongside brain atrophy and fluid neurofilament light chain protein (NfL) in biomarker models of Alzheimer’s disease (AD). However, previous studies show that CSF t-tau correlates strongly with synaptic dysfunction/degeneration biomarkers like neurogranin (Ng) and synaptosomal-associated protein 25 (SNAP25). Here, we compare the association between CSF t-tau and synaptic degeneration and axonal/neuronal degeneration biomarkers in cognitively unimpaired and impaired groups from two independent cohorts. We observe a stronger correlation between CSF t-tau and synaptic biomarkers than neurodegeneration biomarkers in both groups. Synaptic biomarkers explain a greater proportion of variance in CSF t-tau levels compared to neurodegeneration biomarkers. Notably, CSF t-tau levels are elevated in individuals with abnormalities only in synaptic biomarkers, but not in individuals with abnormalities only in neurodegeneration biomarkers. Our findings suggest that CSF t-tau is a closer proxy for synaptic degeneration than for axonal/neuronal degeneration. CSF total tau (t-tau), often used as a marker of neuronal damage, is more strongly linked to synaptic degeneration. Here, the authors show that t-tau better reflects synaptic dysfunction than axonal or neuronal loss in Alzheimer’s disease.

Background Previous studies demonstrated an association between tau pathology and the development of neuropsychiatric symptoms (NPS) in individuals with Alzheimer’s disease (AD). However, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and each NPS domain in the AD continuum. We hypothesized that tau plays a comparatively greater effect on the emergence of hyperactive and psychotic symptoms compared to other NPS domains. Method We assessed 385 individuals (216 cognitively unimpaired (CU), 128 MCI, and 41 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as a reference region. All individuals with dementia had a positive Aß‐PET. Voxel‐wise and Tobit censored regression tested the association between NPS domains and biomarkers accounting for age, sex, cognitive status, and study site. We used censored regression models to account for skewed data alongside a leave‐one‐out (loo) approach to identify which NPS domains most contributed to results. Result CI individuals had significantly higher NPI‐Q scores and Tau PET SUVR than CU (Figure 1A, 1B). NPI‐Q score was significantly associated with tau‐PET predominantly in fronto‐parietal regions. Removing irritability from the models strengthened this association (Figures 2A‐C). Regression loo models revealed that motor disturbances contributed most to the association between NPS and tau‐PET across all Braak stages. Notably, irritability had a negative effect on the association in all Braak stages, suggesting that tau does not play a role in the development of irritability and is highly associated with motor disturbances (Figure 3). Conclusion Our study suggests that tau contributes to the development of motor disturbances but has no effect on the development of irritability across the AD continuum. These findings provide additional rationale for the development of new therapeutics aiming to mitigate motor disturbances and irritability in AD patients.

Background Amyloid (Aβ) pathology potentiates the association between GFAP, a biomarker for reactive astrogliosis, and neurodegeneration, while it remains unclear whether GFAP is associated with neurodegeneration without Aβ abnormalities. Preclinical studies suggest vascular pathology may activate glial cells, triggering deleterious effects. Here, we tested the hypothesis that, similar to Aβ pathology, vascular pathology may also potentiate the effects of plasma GFAP on neurodegeneration and cognitive decline in Aβ‐negative individuals. Method We assessed 324 cognitively impaired (CDR < 0) Aβ‐negative (Centiloid < 24) participants from a memory clinic cohort (BICWALZS), with available CDR global, MMSE, plasma GFAP, clinical assessment of peripheral vascular risk factors [PVPs: hypertension (HTN), diabetes (DBT), and dyslipidemia (DLP)], FLAIR and T1‐based volumetrics. Participants were divided into two groups according to their WMH status: Fazekas 1 (Fz1; n = 203) and Fazekas 2‐3 (Fz2‐3; n = 121). Group differences were analyzed using ANCOVA. Associations were assessed using linear regressions, and the contribution of PVPs to the effects of biomarkers was accessed through multicollinearity analysis accounting for age, sex, and years of education. Result Individuals in the Fz2‐3 group showed more hippocampal atrophy (Figure 1A, 1B; p = 0.0115), plasma NfL levels (1C; p = 0.0020), no changes in plasma GFAP levels (Figure 1D) and lower MMSE score (Figure 1E). In the Fz2‐3 group, hippocampal atrophy (Table 1; β: ‐0.179, p = 0.0440) and cognitive decline (Table 1; β: ‐0.194, p = 0.0390) was associated with plasma GFAP. No abnormalities or associations between biomarkers were found in the Fz1 group. Among the PVPs evaluated, HTN and DBT presented a stronger effect in the association of plasma GFAP in hippocampal atrophy (R2: 0.2089; p = 0.0001) and cognitive decline (R2: 0.1707; p < 0.0001), respectively (Figure 3). Conclusion Our study found that plasma GFAP is strongly linked to neurodegeneration and MMSE decline in Aβ‐negative individuals with high vascular burden. HTN and DBT, prevalent in the elderly, were the main contributors. This highlights vascular pathology as a key driver of neuroinflammation‐related neurodegeneration, underscoring the importance of managing these conditions to prevent brain atrophy.

Background Previous studies demonstrated an association between tau pathology and the development of neuropsychiatric symptoms (NPS) in individuals with Alzheimer's disease (AD). However, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and each NPS domain in the AD continuum. We hypothesized that tau plays a comparatively greater effect on the emergence of hyperactive and psychotic symptoms compared to other NPS domains. Method We assessed 385 individuals (216 cognitively unimpaired (CU), 128 MCI, and 41 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as a reference region. All individuals with dementia had a positive Aß‐PET. Voxel‐wise and Tobit censored regression tested the association between NPS domains and biomarkers accounting for age, sex, cognitive status, and study site. We used censored regression models to account for skewed data alongside a leave‐one‐out (loo) approach to identify which NPS domains most contributed to results. Result CI individuals had significantly higher NPI‐Q scores and Tau PET SUVR than CU (Figure 1A, 1B). NPI‐Q score was significantly associated with tau‐PET predominantly in fronto‐parietal regions. Removing irritability from the models strengthened this association (Figures 2A‐C). Regression loo models revealed that motor disturbances contributed most to the association between NPS and tau‐PET across all Braak stages. Notably, irritability had a negative effect on the association in all Braak stages, suggesting that tau does not play a role in the development of irritability and is highly associated with motor disturbances (Figure 3). Conclusion Our study suggests that tau contributes to the development of motor disturbances but has no effect on the development of irritability across the AD continuum. These findings provide additional rationale for the development of new therapeutics aiming to mitigate motor disturbances and irritability in AD patients.

Background Recent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains. Method We assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score ≥1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site. Result CI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D) Conclusion Our study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.