Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop ...EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.
Abstract
B
arrett's esophagus (
BE
), a common condition, is the only known precursor to esophageal adenocarcinoma (
EAC
). There is uncertainty about the best way to manage
BE
as most people with
BE
...never develop
EAC
and most patients diagnosed with
EAC
have no preceding diagnosis of
BE
. Moreover, there have been recent advances in knowledge and practice about the management of
BE
and early
EAC
. To aid clinical decision making in this rapidly moving field,
C
ancer
C
ouncil
A
ustralia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of
BE
and early
EAC
; prevalence, incidence, natural history, and risk factors for
BE
; and methods for managing
BE
and early
EAC
. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.
Cancers are immunologically heterogeneous. A range of immunotherapies target abnormal tumor immunity via different mechanisms of actions (MOAs), particularly various tumor-infiltrate leukocytes ...(TILs). We modeled loss of function (LOF) in four common anti-PD-1 antibody-responsive syngeneic tumors, MC38, Hepa1-6, CT-26 and EMT-6, by systematical depleting a series of TIL lineages to explore the mechanisms of tumor immunity and treatment. CD8
-T-cells, CD4
-T-cells, T
, NK cells and macrophages were individually depleted through either direct administration of anti-marker antibodies/reagents or using DTR (diphtheria toxin receptor) knock-in mice, for some syngeneic tumors, where specific subsets were depleted following diphtheria toxin (DT) administration. These LOF experiments revealed distinctive intrinsic tumor immunity and thus different MOAs in their responses to anti-PD-1 antibody among different syngeneic tumors. Specifically, the intrinsic tumor immunity and the associated anti-PD-1 MOA were predominately driven by CD8
cytotoxic TILs (CTL) in all syngeneic tumors, excluding Hepa1-6 where CD4
T
TILs played a key role. TIL-T
also played a critical role in supporting tumor growth in all four syngeneic models as well as M
-macrophages. Pathway analysis using pharmacodynamic readouts of immuno-genomics and proteomics on MC38 and Hepa1-6 also revealed defined, but distinctive, immune pathways of activation and suppression between the two, closely associated with the efficacy and consistent with TIL-pharmacodynamic readouts. Understanding tumor immune-pathogenesis and treatment MOAs in the different syngeneic animal models, not only assists the selection of the right model for evaluating new immunotherapy of a given MOA, but also can potentially help to understand the potential disease mechanisms and strategize optimal immune-therapies in patients.
Depression associated with traumatic brain injury (TBI) is believed to be clinically distinct from primary major depressive disorder (MDD) and may be less responsive to conventional treatments. Brain ...connectivity differences between the dorsal attention network (DAN), default mode network (DMN), and subgenual cingulate have been implicated in TBI and MDD. To characterize these distinctions, we applied precision functional mapping of brain network connectivity to resting-state functional magnetic resonance imaging data from five published patient cohorts, four discovery cohorts (
= 93), and one replication cohort (
= 180). We identified a distinct brain connectivity profile in TBI-associated depression that was independent of TBI, MDD, posttraumatic stress disorder (PTSD), depression severity, and cohort. TBI-associated depression was independently associated with decreased DAN-subgenual cingulate connectivity, increased DAN-DMN connectivity, and the combined effect of both. This effect was stronger when using precision functional mapping relative to group-level network maps. Our results support the possibility of a physiologically distinct "TBI affective syndrome," which may benefit from individualized neuromodulation approaches to target its distinct neural circuitry.
Post-stroke depression and anxiety, collectively known as post-stroke adverse mental outcome (PSAMO) are common sequelae of stroke. About 30% of stroke survivors develop depression and about 20% ...develop anxiety. Stroke survivors with PSAMO have poorer health outcomes with higher mortality and greater functional disability. In this study, we aimed to develop a machine learning (ML) model to predict the risk of PSAMO. We retrospectively studied 1780 patients with stroke who were divided into PSAMO vs. no PSAMO groups based on results of validated depression and anxiety questionnaires. The features collected included demographic and sociological data, quality of life scores, stroke-related information, medical and medication history, and comorbidities. Recursive feature elimination was used to select features to input in parallel to eight ML algorithms to train and test the model. Bayesian optimization was used for hyperparameter tuning. Shapley additive explanations (SHAP), an explainable AI (XAI) method, was applied to interpret the model. The best performing ML algorithm was gradient-boosted tree, which attained 74.7% binary classification accuracy. Feature importance calculated by SHAP produced a list of ranked important features that contributed to the prediction, which were consistent with findings of prior clinical studies. Some of these factors were modifiable, and potentially amenable to intervention at early stages of stroke to reduce the incidence of PSAMO.
Excessive alcohol intake, e.g., binge drinking, is a serious and mounting public health problem in the United States and throughout the world. Hence the need for novel insights into the underlying ...neurobiology that may help improve prevention and therapeutic strategies. Therefore, our group employed a darkness-induced alcohol intake protocol to define the reward deficiency domains of alcohol and other substance use disorders in terms of reward pathways' reduced dopamine signaling and its restoration via specifically-designed therapeutic compounds. It has been determined that KCNK13 and RASGRF2 genes, respectively, code for potassium two pore domain channel subfamily K member 13 and Ras-specific guanine nucleotide-releasing factor 2, and both genes have important dopamine-related functions pertaining to alcohol binge drinking. We present a hypothesis that identification of KCNK13 and RASGRF2 genes' risk polymorphism, coupled with genetic addiction risk score (GARS)-guided precision pro-dopamine regulation, will mitigate binge alcohol drinking. Accordingly, we review published reports on the benefits of this unique approach and provide data on favorable outcomes for both binge-drinking animals and drunk drivers, including reductions in alcohol intake and prevention of relapse to drinking behavior. Since driving under the influence of alcohol often leads to incarceration rather than rehabilitation, there is converging evidence to support the utilization of GARS with or without KCNK13 and RASGRF2 risk polymorphism in the legal arena, whereby the argument that "determinism" overrides the "free will" account may be a plausible defense strategy. Obviously, this type of research is tantamount to helping resolve a major problem related to polydrug abuse.
A 73-year-old man presented to his primary physician with an ulcerative growth on his scalp vertex. Biopsy of the lesion confirmed the growth to be a moderately differentiated squamous cell ...carcinoma, but the patient declined medical intervention. The lesion increased in size over six months, measuring 12 cm in diameter and 3 cm thickness with erosion of the skull of the vertex. CT and MRI scans showed a large fungating mass with erosion of the skull of vertex without intra-cranial extension, meningeal enhancement, or distant metastatic disease. The patient declined surgical intervention. The patient received radiotherapy using volumetric-modulated arc therapy (VMAT) to a total dose of 60 Gy over six weeks. No evidence of clinical invasive disease apart from a 15 cm * 12 cm skin defect detected three months after completion of radiotherapy. At three years of follow-up, the patient is clinically disease-free. This case report provides evidence that high-dose radiotherapy is a potential effective definitive treatment for locally advanced (T4) squamous cell carcinoma for patients who are unwilling to undergo surgery.
Aim
The main treatment for meibomian gland dysfunction (MGD), a major cause of dry eye, is eyelid warming. Lack of compliance is the main reason for treatment failure. This has led to the development ...of eyelid-warming devices that are safe, effective and convenient. To obtain robust evidence demonstrating their efficacy, the authors conducted a 3-arm randomized clinical study.
Methods
The authors conducted a 3-month assessor-blinded, randomized, controlled trial of patients from the Singapore National Eye Centre experiencing at least one of eight dry eye symptoms ‘often’ or ‘all the time’. Patients who wore contact lenses, had an active infection or known diagnosis of thyroid dysfunction and rheumatoid arthritis were excluded from the study. MGD participants were randomly assigned to warm towel (
n
= 25), EyeGiene
®
(Eyedetec Medical Inc., Danville, CA, USA) (
n
= 25) and Blephasteam
®
(Spectrum Thea Pharmaceuticals LTD, Macclesfield, UK) (
n
= 25) treatments. The primary efficacy and safety outcomes included the proportions of participants with improved symptoms and changes in best corrected visual acuity (BCVA), respectively. Other outcomes included tear break up time (TBUT), Schirmer test, corneal fluorescein dye staining and number of visibly occluded meibomian gland (MG) orifices.
Results
The study population was 53.5 ± 11.1 years old and predominantly Chinese. For severity of symptom after 3 months of treatment, 78.3% Blephasteam
®
participants reported improvement compared to 45.5% warm towel participants (
p
= 0.023). The corresponding proportions for improvement in the frequency of symptoms were 82.6% and 50.0%, respectively (
p
= 0.020). The proportions of improvement of symptoms in EyeGiene
®
patients were not significantly different from warm towel intervention. At 1 month of treatment, the crude odds ratio of improvement of severity of irritation for Blephasteam
®
compared to control was 3.0 (95% CI 0.88–10.18). However, the odds ratio adjusted by age was 5.67 (1.30–24.66). The lid-warming treatments did not significantly change the TBUT, Schirmer test results or number of visibly occluded MGs in the study period. All treatment modalities did not worsen BCVA after 3 months.
Conclusion
Blephasteam
®
is more effective than warm towel for MGD treatment, with warm towel and EyeGiene
®
being comparable effective. Older age might predict for treatment efficacy. All studied therapies were safe for visual acuity (VA) for 3 months of treatment.
Alcohol and other substance use disorders share comorbidity with other RDS disorders, i.e., a reduction in dopamine signaling within the reward pathway. RDS is a term that connects addictive, ...obsessive, compulsive, and impulsive behavioral disorders. An estimated 2 million individuals in the United States have opioid use disorder related to prescription opioids. It is estimated that the overall cost of the illegal and legally prescribed opioid crisis exceeds one trillion dollars. Opioid Replacement Therapy is the most common treatment for addictions and other RDS disorders. Even after repeated relapses, patients are repeatedly prescribed the same opioid replacement treatments. A recent JAMA report indicates that non-opioid treatments fare better than chronic opioid treatments. Research demonstrates that over 50 percent of all suicides are related to alcohol or other drug use. In addition to effective fellowship programs and spirituality acceptance, nutrigenomic therapies (e.g., KB220Z) optimize gene expression, rebalance neurotransmitters, and restore neurotransmitter functional connectivity. KB220Z was shown to increase functional connectivity across specific brain regions involved in dopaminergic function. KB220/Z significantly reduces RDS behavioral disorders and relapse in human DUI offenders. Taking a Genetic Addiction Risk Severity (GARS) test combined with a the KB220Z semi-customized nutrigenomic supplement effectively restores dopamine homeostasis (WC 199).
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