SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.

Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections1. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to 'common cold' human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.

Advancements in nanomedicine: Precision delivery strategies for male pelvic malignancies - Spotlight on prostate and colorectal cancer.

BACKGROUND: Pelvic malignancies consistently pose significant global health challenges, adversely affecting the well-being of the male population. It is anticipated that clinicians will continue to confront these cancers in their practice. Nanomedicine offers promising strategies that revolutionize the treatment of male pelvic malignancies by providing precise delivery methods that aim to improve the efficacy of therapeutic outcomes while minimizing side effects. Nanoparticles are designed to encapsulate therapeutic agents and selectively target cancer cells. They can also be loaded with theragnostic agents, enabling multifunctional capabilities. OBJECTIVE: This review aims to summarize the latest nanomedicine research into clinical applications, focusing on nanotechnology-based treatment strategies for male pelvic malignancies, encompassing chemotherapy, radiotherapy, immunotherapy, and other cutting-edge therapies. The review is structured to assist physicians, particularly those with limited knowledge of biochemistry and bioengineering, in comprehending the functionalities and applications of nanomaterials. METHODS: Multiple databases, including PubMed, the National Library of Medicine, and Embase, were utilized to locate and review recently published articles on advancements in nano-drug delivery for prostate and colorectal cancers. CONCLUSION: Nanomedicine possesses considerable potential in improving therapeutic outcomes and reducing adverse effects for male pelvic malignancies. Through precision delivery methods, this emerging field presents innovative treatment modalities to address these challenging diseases. Nevertheless, the majority of current studies are in the preclinical phase, with a lack of sufficient evidence to fully understand the precise mechanisms of action, absence of comprehensive pharmacotoxicity profiles, and uncertainty surrounding long-term consequences.

A protocol for a prospective, multicentre observational study to determine if nonanaemic iron deficiency worsens postoperative outcome in patients undergoing elective surgery for resection of colorectal cancer: The NATO study.

BACKGROUND: Preoperative absolute and functional iron deficiency anaemia is associated with poor postoperative outcomes in patients undergoing surgery for colorectal cancer. It is biologically plausible that "early", or "nonanaemic" iron deficiency may also be associated with worse postoperative outcomes in similar cohorts, albeit at lesser severity than that seen for anaemia. The evidence supporting this assertion is of low quality. METHODS: We have designed a prospective, observational study to delineate associations between preoperative non-anaemic iron deficiency and postoperative outcomes after surgery for colorectal cancer. Patients without anaemia, undergoing elective surgery for colorectal cancer will be allocated to an iron replete or an iron deficient group based on preoperative transferrin saturation. The primary outcome is days alive and at home on postoperative day 90. Secondary outcomes include days alive and at home on postoperative day 30, length of hospital stay, readmission to acute care, postoperative complications, health-related quality of life scores, quality of postoperative recovery, and requirement for allogeneic blood transfusion. The planned sample size is 422 patients, which has 80% power to detect a two-day difference in the primary outcome. The study commenced in May 2019. CONCLUSION: The results of this study will provide patients and clinicians with high-quality evidence concerning associations between nonanaemic iron deficiency and patient-centred outcomes after surgery for colorectal cancer. The study will be conducted in multiple urban and rural centres across Australia and New Zealand. The results will be highly generalisable to contemporary surgical practice and should be rapidly translated.

Investigating the association factors of acute postpartum pain: a cohort study.

BACKGROUND: Labor pain intensity is known to predict persistent postpartum pain, whereas acute postpartum pain may interfere with maternal postpartum physical, mental, and emotional well-being. Nevertheless, there is little research studying the association between labor pain intensity and acute postpartum pain. This study investigated the associations between labor pain intensity and psychological factors with acute postpartum pain. METHODS: We included women with American Society of Anesthesiologists (ASA) physical status II, having ≥ 36 gestational weeks and a singleton pregnancy. We investigated the association between labor pain intensity (primary exposure) and high acute postpartum pain at 0 to 24 h after delivery (Numeric Rating Scale (NRS) ≥ 3 of 10; primary outcome). Pre-delivery questionnaires including Angle Labor Pain Questionnaire (A-LPQ), Pain Catastrophizing Scale (PCS), Fear Avoidance Components Scale (FACS) and State Trait Anxiety Inventory (STAI) were administered. Demographic, pain, obstetric and neonatal characteristics were also collected accordingly. RESULTS: Of the 880 women studied, 121 (13.8%) had high acute postpartum pain at 0 to 24 h after delivery. A-LPQ total, PCS, FACS and STAI scores were not significantly associated with acute postpartum pain. Greater A-LPQ subscale on birthing pain (adjusted odds ratio (aOR) 1.03, 95% CI 1.01-1.05, p = 0.0008), increased blood loss during delivery (for every 10ml change; aOR 1.01, 95% CI 1.00-1.03, p = 0.0148), presence of shoulder dystocia (aOR 10.06, 95% CI 2.28-44.36, p = 0.0023), and use of pethidine for labor analgesia (aOR 1.74, 95% CI 1.07-2.84, p = 0.0271) were independently associated with high acute postpartum pain. "Sometimes" having nausea during menstruation before current pregnancy (aOR 0.34, 95% CI 0.16-0.72, p = 0.0045) was found to be independently associated with reduced risk of high acute postpartum pain. CONCLUSIONS: Pre-delivery pain factor together with obstetric complications (shoulder dystocia, blood loss during delivery) were independently associated with high acute postpartum pain. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov registry (NCT03167905) on 30/05/2017.

A Bayesian model of the jumping-to-conclusions bias and its relationship to psychopathology.

The mechanisms by which delusion and anxiety affect the tendency to make hasty decisions (Jumping-to-Conclusions bias) remain unclear. This paper proposes a Bayesian computational model that explores the assignment of evidence weights as a potential explanation of the Jumping-to-Conclusions bias using the Beads Task. We also investigate the Beads Task as a repeated measure by varying the key aspects of the paradigm. The Bayesian model estimations from two online studies showed that higher delusional ideation promoted reduced belief updating but the impact of general and social anxiety on evidence weighting was inconsistent. The altered evidence weighting as a result of a psychopathological trait appeared insufficient in contributing to the Jumping-to-Conclusions bias. Variations in Beads Task aspects significantly affected subjective certainty at the point of decisions but not the number of draws to decisions. Repetitions of the Beads Task are feasible if one assesses the Jumping-to-Conclusions bias using number of draws to decisions.

Association of obstructive sleep apnea with thyroid cancer incidence: a systematic review and meta-analysis.

PURPOSE: Obstructive sleep apnea (OSA) is a postulated carcinogen based on epidemiological associations with all-cancer incidence and non-thyroid biological models. However, associations with thyroid carcinoma are unclear. METHODS: We included observational/randomized studies of associations of OSA with thyroid carcinoma incidence/mortality in adults, from four databases. Random-effects meta-analyses and the population attributable fraction (PAF; from published global OSA prevalence estimates) were computed. RESULTS: We included four observational studies (N = 2,839,325), all with moderate/low risk of bias. OSA diagnosis was associated with twofold incidence of thyroid carcinoma (pooled HR 2.32, 95% CI 1.35-3.98, I2 = 95%), after multi-adjustment for demographics, BMI, smoking, alcohol, and comorbidities. Subgroup analysis of studies with at least 5 years of follow-up showed a stronger association of OSA with thyroid cancer incidence (pooled HR 3.27, 95% CI 2.80-3.82, I2 = 0%). Up to 14.5% (95% CI 4.29-27.6%) of incident thyroid carcinomas globally may be associated with OSA. Thyroid carcinoma mortality data was unavailable. CONCLUSIONS: OSA is associated with higher thyroid carcinoma incidence, though this does not prove causation. Biological/clinical studies should investigate OSA severity in relation to thyroid carcinoma progression and mortality, stratified by tumor histology.

3D-Reconstructed Retinal Pigment Epithelial Cells Provide Insights into the Anatomy of the Outer Retina.

The retinal pigment epithelium (RPE) is located between the neuroretina and the choroid, and plays a critical role in vision. RPE cells internalise outer segments (OS) from overlying photoreceptors in the daily photoreceptor renewal. Changes to RPE structure are linked with age and retinopathy, which has been described in the past by conventional 2D electron microscopy. We used serial block face scanning electron microscopy (SBF-SEM) to reconstruct RPE cells from the central mouse retina. Three-dimensional-reconstructed OS revealed the RPE to support large numbers of photoreceptors (90-216 per RPE cell). Larger bi-nucleate RPE maintained more photoreceptors, although their cytoplasmic volume was comparable to smaller mono-nucleate RPE supporting fewer photoreceptors. Scrutiny of RPE microvilli and interdigitating OS revealed the angle and surface area of contact between RPE and photoreceptors. Bi-nucleate RPE contained more mitochondria compared to mono-nucleate RPE. Furthermore, bi-nucleate cells contained larger sub-RPE spaces, supporting a likely association with disease. Use of perfusion-fixed tissues ensured the highest possible standard of preservation, providing novel insights into the 3D RPE architecture and changes linked with retinopathy. This study serves as a benchmark for comparing retinal tissues from donor eyes with age-related macular degeneration (AMD) and other retinopathies.

Dengue Virus and Zika Virus Serological Cross-reactivity and Their Impact on Pathogenesis in Mice.

Preexisting immunity to Zika virus (ZIKV) or dengue virus (DENV) may alter the course of their infection, and here we use robust mouse models to examine pathological outcomes following passive immunization, sequential cross-infection, or vaccination with inactivated virus. DENV infection was enhanced (through antibody-dependent enhancement [ADE]) or was suppressed by both DENV and ZIKV immunity. Notably, inactivated ZIKV vaccination enhanced dengue disease severity, although it was highly protective against ZIKV infection. On the other hand, ADE was not observed upon ZIKV infection in mice that were passively immunized or preinfected with DENV. Surprisingly, however, we found that vaccination with inactivated DENV enhanced ZIKV infection, mainly in the mesenteric lymph node, indicating the potential for DENV immunity to cause ADE in vivo. Collectively, our data call for greater attention to detail in the design of ZIKV or DENV vaccines.

Impact of Local Infiltration Analgesia on the Quality of Recovery After Anterior Total Hip Arthroplasty: A Randomized, Triple-Blind, Placebo-Controlled Trial.

BACKGROUND: Local infiltration analgesia (LIA) is commonly used in anterior total hip arthroplasty (THA) surgery; however, evidence for its efficacy is lacking. We hypothesized that LIA with 0.2% ropivacaine when compared with injection of placebo (0.9% saline) would improve patient quality of recovery on postoperative day (POD) 1, as measured by the Quality of Recovery-15 (QoR-15) score. METHODS: Patients scheduled to have a primary unilateral anterior THA with a single surgeon in a tertiary level metropolitan hospital were randomized to receive LIA with either 2.5 mL/kg of 0.2% ropivacaine or 0.9% saline as placebo. Patients and clinical and study personnel were blinded to group allocation. Perioperative care was standardized and this included spinal anesthesia and oral multimodal analgesia. The primary outcome was a multidimensional (pain, physical comfort, physical independence, emotions, and psychological support) patient-reported quality of recovery scale, QoR-15, measured on POD 1. RESULTS: One hundred sixty patients were randomized; 6 patients were withdrawn after randomization and 2 patients had incomplete outcome data. The intention-to-treat analysis included 152 patients. The median (interquartile range [IQR]) QoR-15 score on POD 1 of the ropivacaine group was 119.5 (102-124), compared with the placebo group which had a median (IQR) of 115 (98-126). The median difference of 2 (95% confidence interval [CI], -4 to 7; P = .56) was not statistically or clinically significant. An as-per-protocol sensitivity analysis of 146 patients who received spinal anesthesia without general anesthesia, and the allocated intervention, also showed no evidence of a significant difference between groups. Secondary outcomes (worst pain numerical rating scale at rest and with movement on POD 1, opioid consumption on PODs 1 and 2, mobilization on POD 1, Brief Pain Inventory severity and interference on POD 90, and length of stay) were similar in both groups. CONCLUSIONS: LIA with 0.2% ropivacaine when compared with 0.9% saline as placebo did not improve quality of recovery 1 day after anterior THA.

Does implementation of an enhanced recovery after surgery program for hip replacement improve quality of recovery in an Australian private hospital: a quality improvement study.

BACKGROUND: Enhanced recovery after surgery programs may improve recovery and reduce duration of hospital stay after joint replacement surgery. However, uptake is incomplete, and the relative importance of program components is unknown. This before-and-after quality improvement study was designed to determine whether adding 'non-surgical' components, to pre-existing 'surgical' components, in an Australian private healthcare setting, would improve patient recovery after total hip replacement. METHODS: We prospectively collected data regarding care processes and health outcomes of 115 consecutive patients undergoing hip replacement with a single surgeon in a private hospital in Melbourne, Australia. Based on this data, a multidisciplinary team (surgeon, anesthetists, nurse unit managers, physiotherapists, perioperative physician) chose and implemented 12 'non-surgical' program components. Identical data were collected from a further 115 consecutive patients. The primary outcome measure was Quality of Recovery-15 score at 6 weeks postoperatively; the linear regression model was adjusted for baseline group differences. RESULTS: The majority of health outcomes, including the primary outcome measure, were similar in pre- and post-implementation groups (quality of recovery score, pain rating and disability score, at time-points up to six weeks postoperatively). The proportion of patients with zero oral morphine equivalent consumption at six weeks increased from 57 to 80% (RR 1.34, 95% CI 1.13, 1.58). Mean (SD) length of hospital stay decreased from 5.94 (5.21) to 5.02 (2.46) days but was not statistically significant once adjusted for baseline group differences. Four of ten measurable program components were successfully implemented. Antiemetic prophylaxis increased by 53% (risk ratio [RR] 95% confidence interval [CI] 1.16, 2.02). Tranexamic acid use increased by 41% (RR 95% CI 1.18, 1.68). Postoperative physiotherapy treatment on the day of surgery increased by 87% (RR 95% CI 1.36, 2.59). Postoperative patient mobilisation ≥ three metres on the day of surgery increased by 151% (RR 95% CI 1.27, 4.97). CONCLUSIONS: Implementation of a full enhanced recovery after surgery program, and optimal choice of program components, remains a challenge. Improved implementation of non-surgical components of a program may further reduce duration of acute hospital stay, while maintaining quality of recovery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12615001170516 ), 2.11.2015 (retrospective).

New species of Cloacina von Linstow, 1898 (Nematoda: Strongyloidea) parasitic in the stomachs of wallaroos, Osphranter spp. (Marsupialia: Macropodidae) from northern Australia.

Three new species of the parasitic nematode genus Cloacina von Linstow, 1898 (Strongyloidea: Cloacininae) are described from the stomachs of wallaroos, Osphranter spp. (Marsupialia: Macropodidae), from northern Australia. Cloacina spearei n. sp. is described from O. robustus woodwardi (Thomas) and O. antilopinus (Gould) and is distinguished from congeners by the shape of the cephalic papillae, the shallow buccal capsule, the presence of an oesophageal denticle and the convoluted but non-recurrent vagina in the female. Cloacina longibursata n. sp. also from O. robustus woodwardi and O. antilopinus is distinguished from congeners by the elongate dorsal lobe of the bursa, with the origin of the lateral branchlets posterior to the principal bifurcation, in the features of the spicule tip, the lack of bosses lining the oesophagus and the absence of an oesophageal denticle. Cloacina crassicaudata n. sp., from the same two host species was formerly identified as C. cornuta (Davey & Wood, 1938). Differences in the cephalic cuticle (inflation lacking in the new species), the shape of the cephalic papillae, the dorsal oesophageal tooth and the spicule tips, as well as differences in the sequences of the internal transcribed spacers of the nuclear ribosomal DNA, indicate that this is an independent species. The geographical distribution of this species is disjunct with populations in both the Northern Territory and Queensland. Possible reasons for the disjunct distribution are discussed.

Time of day and glycaemic response in pregnant women: A gap in current guidelines?

BACKGROUND & AIMS: Advice to monitor and distribute carbohydrate intake is a key recommendation for treatment of gestational diabetes, but fails to consider circadian regulation of glucose homeostasis. In the non-pregnant state, glucose responses to a meal at night-time are significantly higher than during the day and are associated with an increased risk of developing type 2 diabetes. However, the impact of night time eating on postprandial glucose in pregnancy is uncertain. Using a systematic approach we explored postprandial glucose responses to dietary intake at night compared to during the day in pregnant women. METHODS: Searches were conducted in four databases (Ovid MEDLINE, Ovid Embase, CINAHL plus and Scopus), in September 2022 (updated, June 2023). Eligible studies reported on postprandial glucose at a minimum of two times a day, after identical meals or an oral glucose tolerance test, in pregnant women with or without gestational diabetes. Publication bias was assessed using the ROBINS-I tool. RESULTS: Four eligible studies were retrieved. Two studies reported within group comparison of two timepoints, and observed reduced glucose tolerance in the afternoon compared to the morning in pregnant women, irrespective of diabetes status. The other two studies meeting inclusion criteria did not report time of day comparisons. CONCLUSION: It is unclear as to whether the higher (and extended) postprandial glucose levels observed at night in non-pregnant populations are observed in pregnancy. Clinical studies are needed to explore the impact of circadian rhythmicity on glucose metabolism during pregnancy, and the implications of current dietary advice on when and what to eat for management of gestational diabetes.

Risk of Suicide and Psychiatric Disorders Among Isotretinoin Users: A Meta-Analysis.

Importance: Isotretinoin is hypothesized to contribute to the development of psychiatric disorders, but the epidemiological association and risk factors associated with psychiatric disorders among isotretinoin users remain unclear. Objective: To clarify the absolute and relative risk and risk factors associated with suicide and psychiatric disorders among isotretinoin users. Data Sources: PubMed, Embase, Web of Science, and Scopus were searched from inception until January 24, 2023. Study Selection: Randomized trials and observational studies were selected if they reported the absolute risk, relative risk, and risk factors for suicide and psychiatric disorders among isotretinoin users. Data Extraction and Synthesis: Relevant data were extracted and risk of bias was evaluated at the study level using the Newcastle-Ottawa Scale. Data were pooled using inverse variance-weighted meta-analyses. Heterogeneity was measured using the I2 statistic, and meta-regression analyses were performed. Main Outcomes and Measures: Absolute risk (percentage), relative risks (risk ratios [RR]), and risk factors (RR) of suicide and psychiatric disorders among isotretinoin users. Results: A total of 25 studies including 1 625 891 participants were included in the review and 24 in the meta-analysis. Among the included studies, participants' average age ranged from 16 to 38 years, and distribution by sex ranged from 0% to 100% male. The 1-year pooled absolute risk from between 2 and 8 studies of completed suicide, suicide attempt, suicide ideation, and self-harm were each less than 0.5%, while that of depression was 3.83% (95% CI, 2.45-5.93; I2 = 77%) in 11 studies. Isotretinoin users were less likely than nonusers to attempt suicide at 2 years (RR, 0.92; 95% CI, 0.84-1.00; I2 = 0%), 3 years (RR, 0.86; 95% CI, 0.77-0.95; I2 = 0%), and 4 years (RR, 0.85; 95% CI, 0.72-1.00; I2 = 23%) following treatment. Isotretinoin was not associated with the risk of all psychiatric disorders (RR, 1.08; 95% CI, 0.99-1.19; I2 = 0%). Study-level meta-regression found that studies with participants of older age reported lower 1-year absolute risk of depression, while those with a higher percentage of male participants reported a higher 1-year absolute risk of completed suicide. Conclusions and Relevance: The findings suggest that at a population level, isotretinoin users do not have increased risk of suicide or psychiatric conditions but may instead have a lower risk of suicide attempts at 2 to 4 years following treatment. While these findings are reassuring, clinicians should continue to practice holistic psychodermatologic care and monitor patients for signs of mental distress during isotretinoin treatment.

A rapid method to assess the in vivo multi-functionality of adoptively transferred engineered TCR T cells.

Introduction: The clinical efficacy of chimeric antigen and T cell receptor (TCR) T cell immunotherapies is attributed to their ability to proliferate and persist in vivo. Since the interaction of the engineered T cells with the targeted tumour or its environment might suppress their function, their functionality should be characterized not only before but also after adoptive transfer. Materials and methods: We sought to achieve this by adapting a recently developed Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid whole blood T cell assay to stimulate engineered TCR T cells in small volumes of whole blood (<1 ml) without in vitro cellular purification. As a proof-of-concept, we used this method to longitudinally study two patients with primary Hepatitis B Virus (HBV)-related hepatocellular carcinoma who received multiple dose-escalating infusions of transiently functional mRNA-engineered HBV-TCR T cells. Results: We demonstrated that a simple pulsing of whole blood with a peptide corresponding to the epitope recognized by the specific HBV-TCR elicited Th1 cytokine secretion in both patients only after HBV-TCR T cell treatment and not before. The amount of cytokines secreted also showed an infusion-dose-dependent association. Discussions: These findings support the utility of the whole blood cytokine release assay in monitoring the in vivo function and quantity of engineered T cell products following adoptive transfer.

The Association of Obstructive Sleep Apnea with Urological Cancer Incidence and Mortality-A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: While obstructive sleep apnea (OSA) and urological cancer are both strongly associated with hypoxia, controversy exists regarding their association with each other. This study aims to summarize and synthesize evidence to clarify the association between OSA and urological cancer incidence and mortality. METHODS: According to a prespecified protocol, PubMed, Embase, Cochrane Library, and Scopus were searched from inception to November 16, 2023, for observational and randomized studies reporting the association of OSA with urological cancer incidence or mortality. We pooled maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted model. Two reviewers independently assessed the quality of evidence using the Newcastle-Ottawa Scale and the Grading of Recommendations, Assessment, Development and Evaluation framework. KEY FINDINGS AND LIMITATIONS: From 1814 records, we included 12 studies comprising 9 290 818 participants in total, of which nine studies were analyzed quantitatively. OSA patients had an increased risk of kidney (HR: 1.75, 95% confidence interval [CI]: 1.21-2.53) and bladder (HR: 1.76, 95% CI: 1.05-2.96) cancer. However, OSA was not associated with prostate cancer incidence (HR: 1.29, 95% CI: 0.82-2.04). We systematically reviewed evidence surrounding OSA and testicular cancer incidence and urological cancer mortality. CONCLUSIONS AND CLINICAL IMPLICATIONS: OSA may be associated with a higher risk of kidney and bladder cancer, but not prostate cancer. Future work may help clarify the possibility of a dose-response relationship between OSA and urological cancer, and the effect of OSA treatment on urological cancer incidence or progression. PATIENT SUMMARY: This research highlights a potential longitudinal association between OSA and kidney and bladder cancer, but not prostate cancer.

Fratricide-resistant CD7-CAR T cells in T-ALL.

T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7- T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.

The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.

Neuroimaging data repositories and AI-driven healthcare-Global aspirations vs. ethical considerations in machine learning models of neurological disease.

Neuroimaging data repositories are data-rich resources comprising brain imaging with clinical and biomarker data. The potential for such repositories to transform healthcare is tremendous, especially in their capacity to support machine learning (ML) and artificial intelligence (AI) tools. Current discussions about the generalizability of such tools in healthcare provoke concerns of risk of bias-ML models underperform in women and ethnic and racial minorities. The use of ML may exacerbate existing healthcare disparities or cause post-deployment harms. Do neuroimaging data repositories and their capacity to support ML/AI-driven clinical discoveries, have both the potential to accelerate innovative medicine and harden the gaps of social inequities in neuroscience-related healthcare? In this paper, we examined the ethical concerns of ML-driven modeling of global community neuroscience needs arising from the use of data amassed within neuroimaging data repositories. We explored this in two parts; firstly, in a theoretical experiment, we argued for a South East Asian-based repository to redress global imbalances. Within this context, we then considered the ethical framework toward the inclusion vs. exclusion of the migrant worker population, a group subject to healthcare inequities. Secondly, we created a model simulating the impact of global variations in the presentation of anosmia risks in COVID-19 toward altering brain structural findings; we then performed a mini AI ethics experiment. In this experiment, we interrogated an actual pilot dataset (n = 17; 8 non-anosmic (47%) vs. 9 anosmic (53%) using an ML clustering model. To create the COVID-19 simulation model, we bootstrapped to resample and amplify the dataset. This resulted in three hypothetical datasets: (i) matched (n = 68; 47% anosmic), (ii) predominant non-anosmic (n = 66; 73% disproportionate), and (iii) predominant anosmic (n = 66; 76% disproportionate). We found that the differing proportions of the same cohorts represented in each hypothetical dataset altered not only the relative importance of key features distinguishing between them but even the presence or absence of such features. The main objective of our mini experiment was to understand if ML/AI methodologies could be utilized toward modelling disproportionate datasets, in a manner we term "AI ethics." Further work is required to expand the approach proposed here into a reproducible strategy.

Unleashing novel horizons in advanced prostate cancer treatment: investigating the potential of prostate specific membrane antigen-targeted nanomedicine-based combination therapy.

Prostate cancer (PCa) is a prevalent malignancy with increasing incidence in middle-aged and older men. Despite various treatment options, advanced metastatic PCa remains challenging with poor prognosis and limited effective therapies. Nanomedicine, with its targeted drug delivery capabilities, has emerged as a promising approach to enhance treatment efficacy and reduce adverse effects. Prostate-specific membrane antigen (PSMA) stands as one of the most distinctive and highly selective biomarkers for PCa, exhibiting robust expression in PCa cells. In this review, we explore the applications of PSMA-targeted nanomedicines in advanced PCa management. Our primary objective is to bridge the gap between cutting-edge nanomedicine research and clinical practice, making it accessible to the medical community. We discuss mainstream treatment strategies for advanced PCa, including chemotherapy, radiotherapy, and immunotherapy, in the context of PSMA-targeted nanomedicines. Additionally, we elucidate novel treatment concepts such as photodynamic and photothermal therapies, along with nano-theragnostics. We present the content in a clear and accessible manner, appealing to general physicians, including those with limited backgrounds in biochemistry and bioengineering. The review emphasizes the potential benefits of PSMA-targeted nanomedicines in enhancing treatment efficiency and improving patient outcomes. While the use of PSMA-targeted nano-drug delivery has demonstrated promising results, further investigation is required to comprehend the precise mechanisms of action, pharmacotoxicity, and long-term outcomes. By meticulous optimization of the combination of nanomedicines and PSMA ligands, a novel horizon of PSMA-targeted nanomedicine-based combination therapy could bring renewed hope for patients with advanced PCa.