Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Immune checkpoint inhibitors in liver transplantation: Current practice, challenges, and opportunities.

Immune checkpoint inhibitors are becoming a mainstay of cancer treatment. While first studied and approved for patients with unresectable disease, due to their efficacy, they are becoming increasingly used in the perioperative period across many cancer types. In patients with HCC, immune checkpoint inhibitors have now become the standard of care in the advanced setting and have shown promising results in the adjuvant setting after liver resection. While these drugs continue to show promise, their role in the peritransplant setting still remains a question. In this review, we explore the current use of this class of medications in patients with HCC, as well as the immunologic role of the pathways that they inhibit. We also identify potential for future research opportunities to better understand the role of these medications.

Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Evaluation of 3D C-Arm Fluoroscopy versus Diagnostic CT for Deep Brain Stimulation Stereotactic Registration and Post-Operative Lead Localization.

INTRODUCTION: DBS efficacy depends on accuracy. CT-MRI fusion is established for both stereotactic registration and electrode placement verification. The desire to streamline DBS workflows, reduce operative time, and minimize patient transfers has increased interest in portable imaging modalities such as the Medtronic O-arm® and mobile CT. However, these remain expensive and bulky. 3D C-arm fluoroscopy (3DXT) units are a smaller and less costly alternative, albeit incompatible with traditional frame-based localization and without useful soft tissue resolution. We aimed to compare fusion of 3DXT and CT with pre-operative MRI to evaluate if 3DXT-MRI fusion alone is sufficient for accurate registration and reliable targeting verification. We further assess DBS targeting accuracy using a 3DXT workflow and compare radiation dosimetry between modalities. METHODS: Patients underwent robot-assisted DBS implantation using a workflow incorporating 3DXT which we describe. Two intra-operative 3DXT spins were performed for registration and accuracy verification followed by conventional CT post-operatively. Post-operative 3DXT and CT images were independently fused to the same pre-operative MRI sequence and co-ordinates generated for comparison. Registration accuracy was compared to 15 consecutive controls who underwent CT-based registration. Radial targeting accuracy was calculated and radiation dosimetry recorded. RESULTS: Data were obtained from 29 leads in 15 consecutive patients. 3DXT registration accuracy was significantly superior to CT with mean error 0.22 ± 0.03 mm (p < 0.0001). Mean Euclidean electrode tip position variation for CT to MRI versus 3DXT to MRI fusion was 0.62 ± 0.40 mm (range 0.0 mm-1.7 mm). In comparison, direct CT to 3DXT fusion showed electrode tip Euclidean variance of 0.23 ± 0.09 mm. Mean radial targeting accuracy assessed on 3DXT was 0.97 ± 0.54 mm versus 1.15 ± 0.55 mm on CT with differences insignificant (p = 0.30). Mean patient radiation doses were around 80% lower with 3DXT versus CT (p < 0.0001). DISCUSSION: Mobile 3D C-arm fluoroscopy can be safely incorporated into DBS workflows for both registration and lead verification. For registration, the limited field of view requires the use of frameless transient fiducials and is highly accurate. For lead position verification based on MRI co-registration, we estimate there is around a 0.4 mm discrepancy between lead position seen on 3DXT versus CT when corrected for brain shift. This is similar to that described in O-arm® or mobile CT series. For units where logistical or financial considerations preclude the acquisition of a cone beam CT or mobile CT scanner, our data support portable 3D C-arm fluoroscopy as an acceptable alternative with significantly lower radiation exposure.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Total neoadjuvant therapy versus standard neoadjuvant treatment strategies for the management of locally advanced rectal cancer: network meta-analysis of randomized clinical trials.

BACKGROUND: This study compared the advantages and disadvantages of total neoadjuvant therapy (TNT) strategies for patients with locally advanced rectal cancer, compared with the more traditional multimodal neoadjuvant management strategies of long-course chemoradiotherapy (LCRT) or short-course radiotherapy (SCRT). METHODS: A systematic review and network meta-analysis of exclusively RCTs was undertaken, comparing survival, recurrence, pathological, radiological, and oncological outcomes. The last date of the search was 14 December 2022. RESULTS: In total, 15 RCTs involving 4602 patients with locally advanced rectal cancer, conducted between 2004 and 2022, were included. TNT improved overall survival compared with LCRT (HR 0.73, 95 per cent credible interval 0.60 to 0.92) and SCRT (HR 0.67, 0.47 to 0.95). TNT also improved rates of distant metastasis compared with LCRT (HR 0.81, 0.69 to 0.97). Reduced overall recurrence was observed for TNT compared with LCRT (HR 0.87, 0.76 to 0.99). TNT showed an improved pCR compared with both LCRT (risk ratio (RR) 1.60, 1.36 to 1.90) and SCRT (RR 11.32, 5.00 to 30.73). TNT also showed an improvement in cCR compared with LCRT (RR 1.68, 1.08 to 2.64). There was no difference between treatments in disease-free survival, local recurrence, R0 resection, treatment toxicity or treatment compliance. CONCLUSION: This study provides further evidence that TNT has improved survival and recurrence benefits compared with current standards of care, and may increase the number of patients suitable for organ preservation, without negatively influencing treatment toxicity or compliance.

Associations of baseline obstructive sleep apnea and sleep macroarchitecture with cognitive function after 8 years in middle-aged and older men from a community-based cohort study.

Previous prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea-hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for baseline demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea-hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9-8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better Trail-Making Test A performance (B = -0.04, 95% confidence interval [CI] -0.06, -0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should consider arousal events and non-routine hypoxaemia measures, which may show associations with cognitive decline.

Association of alcohol and bone mineral density dependent on type of alcohol consumed.

INTRODUCTION: Osteoporosis prevalence will increase in coming decades, with significant financial and economic implications. Whilst alcohol excess has significant detrimental impacts on bone mineral density (BMD), knowledge of low-volume consumption is inconsistent. Type of alcohol may mediate impact on BMD and warrants further investigation. MATERIALS AND METHODS: Participants were drawn from the Florey Adelaide Male Aging Study, a cohort of community dwelling men from Adelaide, Australia (n = 1195). The final cohort (n = 693) provided information regarding alcohol consumption and undertook BMD scan at wave one (2002-2005) and wave two (2007-2010). Cross-sectional and longitudinal multivariable regression was performed for whole-body and spine BMD. To assess change in exposure over time, change in BMD was compared to change in covariates between waves. RESULTS: Cross-sectionally, whole-body BMD was positively associated with obesity (p < 0.001), exercise (p = 0.009), prior smoking (p = 0.001), oestrogen concentration (p = 0.001), rheumatoid arthritis (p = 0.013) and grip strength (p < 0.001). No association was identified with volume of differing types of alcohol consumed. Spinal BMD was inversely associated with low-strength beer consumption (p = 0.003). The volume of alcohol consumed at Wave 1 did not predict change in whole-body or spinal BMD; however, increases in full-strength beer consumption between waves were associated with reduced spinal BMD (p = 0.031). CONCLUSION: When consumed at quantities in the usual social range, alcohol was not associated with whole-body BMD. However, low-strength beer consumption was inversely related to spinal BMD.

Comparing neoadjuvant therapy followed by local excision to total mesorectal excision in the treatment of early stage rectal cancer: a systematic review and meta-analysis of randomised clinical trials.

INTRODUCTION: Total mesorectal excision (TME) is the standard-of-care in early, clinical stage (cT2-3 N0 M0) rectal cancer. Local excision (LE) may be an alternative after adequate response to neoadjuvant therapy (NAT), with either long-course chemoradiotherapy (nCRT) or short-course radiotherapy (SCRT), as a means of preserving the rectum and potentially obviating the morbidity of TME. METHODS: A systematic review was performed according to PRISMA guidelines for studies that randomly assigned patients with cT2-3 N0 M0 rectal cancer to either NAT + LE or TME that reported radiologic, oncologic, surgical, and morbidity outcomes. RESULTS: A total of 4 RCTs comprise 462 patients (232 patients receiving NAT + LE; nCRT n = 205; SCRT n = 27) and 230 undergoing TME, respectively. NAT compliance was 98.86%. The rate of early completion TME in the NAT + LE group was 22.3%, while the proportion of patients achieving durable organ preservation was 75.4% at mean follow-up of 5.6 years. There was no difference in disease-free survival (DFS) (HR [hazard ratio] 1.19; 95% CI 0.95, 1.49; p = 0.13) or overall survival (OS) (HR 0.94; 95% CI 0.72, 1.23; p = 0.63]) according to the assigned treatment arm. The local recurrence rate (LRR) (HR 1.22; 95% CI 0.5-3.02; p = 0.66) and distant metastases (HR 0.92; 95% CI 0.45, 1.90; p = 0.82) were also comparable between the groups. There was a significant reduction in major (OR 0.45; 95% CI 0.21, 0.95; p = 0.04) and minor morbidity (OR 0.45; 95% CI 0.24, 0.85; p = 0.01) for patients undergoing NAT + LE. Overall stoma formation was decreased in the NAT + LE group (OR 0.03; 95% CI 0.0, 0.23; p ≤ 0.00001). CONCLUSION: NAT + LE reduces adverse effects of TME, without any compromise in oncological outcomes, and the potential for an organ preserving strategy should be discussed with patients with T2-3N0 rectal cancers prior to treatment.

Articular Surface Involvement With Retrograde Headless Screw Fixation of the Proximal Phalanx.

PURPOSE: Intramedullary (IM) screw fixation of proximal phalanx (P1) fractures is a treatment option increasing in popularity. This study aimed to quantify the articular surface loss after retrograde screw insertion and to determine the range of motion (ROM) of the proximal interphalangeal (PIP) joint while the defect in the P1 head is engaged with the base of the middle phalanx (P2). METHODS: Twelve fresh frozen cadaver hand specimens were analyzed for prefixation ROM of the PIP joint. A retrograde screw was placed using a percutaneous technique under fluoroscopic guidance. Following screw insertion, specimens were dissected to determine size of the extensor mechanism defect, evaluate the lateral bands with passive ROM of the PIP joint, and determine the angle at which the dorsal aspect of P2 ceases to engage with the defect and the amount of articular surface loss. The percentage of articular surface loss was calculated using a digital image software program. RESULTS: The angle at which P2 ceased to engage with the articular surface defect was an average of 36.8° of PIP joint flexion. In full PIP joint flexion, the average extensor mechanism defect was 8.8%. The average total articular surface loss was 4.4% across all digits. CONCLUSION: Percutaneous retrograde P1 intramedullary screw fixation results in minimal damage to the extensor mechanism and articular surface. The arc during which the defect in the head of P1 engages the base of the P2 is almost entirely outside the functional ROM of the PIP joint. CLINICAL RELEVANCE: Quantifying the amount of articular surface loss through the P1 head and extensor apparatus damage in IM screw fixation can inform surgeons of the consequences of this technique. This study supports the use of a retrograde intramedullary screw as a safe option for fixation of P1 fractures.

Anterior Thalamic Inputs Are Required for Subiculum Spatial Coding, with Associated Consequences for Hippocampal Spatial Memory.

Just as hippocampal lesions are principally responsible for "temporal lobe" amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, "diencephalic" amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology.SIGNIFICANCE STATEMENT At present, we know little about interactions between temporal lobe and diencephalic memory systems. Here, we focused on the subiculum, as the sole hippocampal formation region directly interconnected with the anterior thalamic nuclei. We combined reversible and permanent lesions of the anterior thalamic nuclei, electrophysiological recordings of the subiculum, and behavioral analyses. Our results were striking and clear: following permanent thalamic lesions, the diverse spatial signals normally found in the subiculum (including place cells, grid cells, and head-direction cells) all disappeared. Anterior thalamic lesions had no discernible impact on hippocampal CA1 place fields. Thus, spatial firing activity within the subiculum requires anterior thalamic function, as does successful spatial memory performance. Our findings provide a key missing part of the much bigger puzzle concerning why anterior thalamic damage is so catastrophic for spatial memory in rodents and episodic memory in humans.

Gait-Phase Modulates Alpha and Beta Oscillations in the Pedunculopontine Nucleus.

The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of the midbrain and pons, playing an important role in modulating posture and locomotion. Deep brain stimulation of the PPN has been proposed as an emerging treatment for patients with Parkinson's disease (PD) or multiple system atrophy (MSA) who have gait-related atypical parkinsonian syndromes. In this study, we investigated PPN activities during gait to better understand its functional role in locomotion. Specifically, we investigated whether PPN activity is rhythmically modulated by gait cycles during locomotion. PPN local field potential (LFP) activities were recorded from PD or MSA patients with gait difficulties during stepping in place or free walking. Simultaneous measurements from force plates or accelerometers were used to determine the phase within each gait cycle at each time point. Our results showed that activities in the alpha and beta frequency bands in the PPN LFPs were rhythmically modulated by the gait phase within gait cycles, with a higher modulation index when the stepping rhythm was more regular. Meanwhile, the PPN-cortical coherence was most prominent in the alpha band. Both gait phase-related modulation in the alpha/beta power and the PPN-cortical coherence in the alpha frequency band were spatially specific to the PPN and did not extend to surrounding regions. These results suggest that alternating PPN modulation may support gait control. Whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control remains to be tested.SIGNIFICANCE STATEMENT The therapeutic efficacy of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) and the extent to which it can improve quality of life are still inconclusive. Understanding how PPN activity is modulated by stepping or walking may offer insight into how to improve the efficacy of PPN DBS in ameliorating gait difficulties. Our study shows that PPN alpha and beta activity was modulated by the gait phase, and that this was most pronounced when the stepping rhythm was regular. It remains to be tested whether enhancing alternating PPN modulation by stimulating in an alternating fashion could positively affect gait control.

Place cells in the claustrum remap under NMDA receptor control.

Place cells are cells that exhibit location-dependent responses; they have mostly been studied in the hippocampus. Place cells have also been reported in the rat claustrum, an underexplored paracortical region with extensive corto-cortical connectivity. It has been hypothesised that claustral neuronal responses are anchored to cortical visual inputs. We show rat claustral place cells remap when visual inputs are eliminated from the environment, and that this remapping is NMDA-receptor-dependent. Eliminating visual input decreases claustral delta-band oscillatory activity, increases theta-band oscillatory activity, and increases simultaneously recorded visual cortical activity. We conclude that, like the hippocampus, claustral place field remapping might be mediated by NMDA receptor activity, and is modulated by visual cortical inputs.

Evaluation of Fontan-associated Liver Disease and Ethnic Disparities in Long-term Survivors of the Fontan Procedure: A Population-based Study.

OBJECTIVES: Fontan-associated liver disease (FALD) has emerged as a nearly universal chronic comorbidity in patients with univentricular congenital heart disease who undergo the Fontan procedure. There is a paucity of data reporting long-term outcomes and the impact of FALD in this population. METHODS: Patients who underwent the Fontan procedure between 1992 and 2018 were identified using California registry data. Presumed FALD was assessed by a composite of liver disease codes. Primary outcomes were mortality and transplant. Multivariable regression and survival analyses were performed. RESULTS: Among 1436 patients post-Fontan, 75.9% studied were adults, with a median follow-up of 12.6 (8.4, 17.3) years. The population was 46.3% Hispanic. Overall survival at 20 years was >80%, but Hispanic patients had higher mortality risk compared with White patients [hazard ratio: 1.49 (1.09-2.03), P =0.012]. Only 225 patients (15.7%) had presumed FALD, although >54% of patients had liver disease by age 25. FALD was associated with later deaths [median: 9.6 (6.4-13.2) years post-Fontan] compared with patients who died without liver disease [4.1 (1.4-10.4) years, P =0.02]. Patients with FALD who underwent combined heart liver transplant had 100% survival at 5 years, compared with only 70.7% of patients who underwent heart transplant alone. CONCLUSIONS: In this population-based analysis of long-term outcomes post-Fontan, Hispanic ethnicity was associated with increased all-cause mortality. Further, the prevalence of FALD is underrecognized, but our data confirms that its incidence increases with age. FALD is associated with late mortality but excellent posttransplant survival. This emphasizes the need for FALD-specific liver surveillance strategies in patients post-Fontan.

Intratumoral γδ T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy which is often associated with a complex tumor microenvironment attributable to etiology-induced cellular inflammation. γδ T cells are known to detect and react to chronic inflammation, which is linked to cancer development, progression, and metastasis. Our recent genomic study revealed an increased infiltration of several immune cell types, including γδ T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis. APPROACH AND RESULTS: Here, we quantified the amount of γδ T cells using a γδ T-cell-specific gene signature in 247 Chinese HCC patients. We also validated the γδ T-cell signature in American HCC patients. Additionally, such an association was only found in tumor transcriptomic data, but not in adjacent nontumor transcriptomic data, suggesting a selective enrichment of γδ T cells in the tumor microenvironment. Moreover, the γδ T-cell signature was positively correlated with the expression of natural killer cell receptor genes, such as NKG2D and cytolytic T-cell genes granzymes and perforin, suggesting a stronger T-cell-mediated cytotoxic activity. Furthermore, we found that the γδ T-cell-specific gene expression is positively correlated with the expression of chemokine (C-C motif) ligand 4 (CCL4)/chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor type 1 (CCR1)/C-C chemokine receptor type 5 (CCR5), the receptors for γδ T cells. We validated these results using immunohistochemical analysis of formalin-fixed, paraffin-embedded tumor biopsies from 182 HCC patients. Moreover, we found evidence of CCL4/CCL5-mediated recruitment of γδ T cells both in vitro and in a murine orthotopic Hepa1-6 HCC model. CONCLUSIONS: We propose that CCL4/CCL5 may interact with their receptor, CCR1/CCR5, which may facilitate the recruitment of γδ T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of γδ T cells in tumors may enhance antitumor immunity and improve patients' prognosis.

The bidirectional association between depression and lower urinary tract symptoms (LUTS) in men: A systematic review and meta-analysis of observational studies.

BACKGROUND: Recent evidence from observational studies suggests a bidirectional association between lower urinary tract symptoms (LUTS) and depression in men. We sought to systematically quantify the effect of the presence of LUTS on depression symptoms, compared to those without LUTS, in adult males, and vice versa. METHODS: Electronic databases (MEDLINE, PsycINFO, SCOPUS, Embase) were examined for articles in English before March 2021. Observational studies of men aged over 18 years; reporting an association between LUTS and depression; including a validated scale for LUTS and depression symptoms were eligible for study inclusion. RESULTS: Seventeen studies out of 1787 records identified 163 466 men with reported depression symptoms by LUTS status, while 10 studies reported 72 363 men with LUTS by depression symptoms. Pooled estimates showed a strong effect of LUTS presence on depression risk (OR: 2.89, 95% CI: 2.50-3.33), with a high degree of heterogeneity among the examined studies (I2 = 83%; τ2 = 0,06; p < 0.001). Subgroup analyses demonstrated differences by study region (Q value:13.7, df:4, p = 0.003), setting (7.8(2), p = 0.020), design (7.2(1), p = 0.003), quality (6.2(1), p = 0.013), and LUTS measure (40.9(3), p < 0.001). Pooled estimates also showed a strong effect of depression presence on LUTS risk in men (OR: 3.13, 95% CI: 2.72-3.60), with only moderate heterogeneity between studies (I2 = 58%; τ2 = 0,02; p = 0.001). CONCLUSIONS: The strong relationship observed between LUTS and depression implies shared risk factors that cannot be solely attributed to the prostate. This has immediate implications for future studies and the assessment and management of patients with either condition.

Treatment and outcomes of hepatocellular carcinoma in patients with Sickle cell disease: a population-based study in the U.S.

BACKGROUND: Sickle cell disease (SCD) is a rare hemoglobinopathy which can result in chronic liver disease and cirrhosis. Patients with SCD have an increased risk of hematologic malignancy, but the prevalence of hepatocellular carcinoma (HCC) in this population is unknown. Herein, the association of SCD with HCC was examined using registry data. METHODS: The SEER-Medicare database was queried to identify patients diagnosed with HCC between 2000 and 2015, and further stratified by SCD status. Propensity matching was performed to examine cancer-related survival and treatment outcomes. RESULTS: Overall 56,934 patients with HCC were identified, including 81 patients with SCD. Patients with SCD more frequently had cirrhosis [48.1% (39/81) vs 23.5% (13,377/56,853), p < 0.01] yet presented with smaller tumors [<5 cm: 51.9% (42/81) vs 38.5% (21,898/56,853), p = 0.01]. After propensity matching, SCD was not associated with attenuated survival (aHR 0.73 95%CI 0.52-1.01). When stratified by treatment, patients with SCD had equivalent outcomes to chemotherapy (p = 0.65), TACE/TARE (p = 0.35), resection (p = 0.15) and transplantation (p = 0.67) when compared to non-SCD patients. CONCLUSION: This study confirms that a subset of patients with SCD will develop HCC. Importantly, therapeutic options for HCC should not be limited by pre-existing SCD, and similar survival should be expected when compared to non-SCD patients.

Sleep macroarchitecture but not obstructive sleep apnea is independently associated with cognitive function in only older men of a population-based cohort.

Evidence linking obstructive sleep apnea with cognitive dysfunction predominantly comes from clinical or select community samples. We investigated the independent cross-sectional association of obstructive sleep apnea and sleep macroarchitecture parameters with cognitive function in unselected community-dwelling middle-aged and older men. Four hundred and seventy-seven Florey Adelaide Male Ageing Study participants underwent successful home-based polysomnography. They also completed cognitive testing, including the inspection time task, Fuld object memory evaluation, trail-making test A and B, and mini-mental state examination. Multivariable regression models examined independent cross-sectional associations of obstructive sleep apnea and sleep macroarchitecture parameters with cognitive function. In univariable analyses, a higher apnea-hypopnea index and percentage of total sleep time with oxygen saturation <90% were associated with worse trail-making test A performance (both p < .05). A higher apnea-hypopnea index was also associated with worse trail-making test B performance and slower inspection time (both p < .05). In adjusted analyses, obstructive sleep apnea and sleep macroarchitecture parameters were not associated with cognitive function (all p > .05). In age-stratified analysis in men ≥65 years, greater stage 1 sleep was independently associated with worse trail-making test A performance, whereas greater stage 3 sleep was independently associated with better trail-making test A performance (both p < .05). Our findings suggest that obstructive sleep apnea is not independently associated with cognitive function. In older, but not younger, men, light sleep was associated with worse attention, whereas deep sleep was associated with better attention. Longitudinal population-based cohort studies are needed to determine if obstructive sleep apnea and disrupted sleep macroarchitecture independently predict prospective cognitive dysfunction and decline.

Negative pressure wound therapy following excision of pilonidal sinus disease: A retrospective review.

AIM: There is no agreed definitive surgical treatment for pilonidal sinus disease (PSD) with several techniques in use with varying success. Negative pressure wound therapy (NPWT) is used to accelerate wound healing but literature in the context of PSD remains sparse. The aim of this study was to evaluate outcomes in patients with PSD treated by a standardised technique of complete surgical excision followed by the application of NPWT. METHODS: A retrospective observational cohort study of all patients with PSD managed by complete surgical excision followed by application of NPWT was performed over a five year period. The primary endpoints were PSD recurrence and failed wound healing. RESULTS: Sixty-one patients underwent treatment during the study period. There was 100% compliance with NPWT. All patients' wounds healed successfully, with the median time to healing being 28 days. One patient (1.6%) developed recurrent PSD and required further surgery. Two patients (3.3%) developed postoperative wound infections. Five patients, who had been managed previously by other operative approaches and subsequently developed recurrence, were successfully managed by this technique. Most patients (52.4%) were managed as a day case procedure. CONCLUSIONS: Surgery for PSD should have low recurrence rates, prompt wound healing, minimal complications, short inpatient lengths of stay and be tolerated by the patient. Our results demonstrate that our technique meets these criteria. To our knowledge, this study contains the largest number of patients with PSD managed by excision and NPWT in the literature.

A case-control study examining the association of smad7 and TLR single nucleotide polymorphisms on the risk of colorectal cancer in ulcerative colitis.

AIM: Ulcerative colitis (UC) is characterized by chronic mucosal inflammation and an increased risk of colorectal cancer. smad7, TLR2 and TLR4 modulate intestinal inflammation and their polymorphisms affect the risk of development of sporadic colorectal cancer. The aim of the current study was to examine the association between single nucleotide polymorphisms (SNPs) in smad7, TLR2 and TLR4 and the development of colorectal cancer in patients with UC. METHOD: DNA was extracted from formalin-fixed, paraffin-embedded tissue from 90 patients with UC who had undergone panproctocolectomy between 1985 and 2013 (30 with UC-associated colorectal cancer and 60 control UC patients). Control cases were matched 2:1 for age at diagnosis of colitis, duration of disease and gender. Genotyping was performed for the smad7 rs4464148, rs11874392, rs12953717 and rs4939827 SNPs, the TLR2 rs5743704 and rs5743708 SNPs and the TLR4 rs4986790 and rs4986791 SNPs. RESULTS: Sixty three of the 90 patients (70%) were men and the mean age at diagnosis of UC was 38.6 ± 1.6 years. The mean time to the diagnosis of UC-associated colorectal cancer was 13.5 ± 1.9 years. The 5-year recurrence-free and cancer-specific survival rates were 76% and 88%, respectively. All eight SNPs were in Hardy-Weinberg equilibrium. None of the eight SNPs assessed in smad7, TLR2 or TLR4 were associated with the development of UC-associated colorectal cancer at an allelic or genotypic level. CONCLUSIONS: These data do not support an association between polymorphisms in smad7, TLR2 or TLR4 and the development of UC-associated colorectal cancer.