Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.

Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging and many age-related conditions. As such, complete control of mitochondrial function is critical to maintain cardiac efficiency in the aged heart. Lysine acetylation is a reversible post-translational modification shown to regulate several mitochondrial metabolic and biochemical processes. In the present study, we investigated how mitochondrial lysine acetylation regulates fatty acid oxidation (FAO) and cardiac function in the aged heart. We found a significant increase in mitochondrial protein acetylation in the aged heart which correlated with increased level of mitochondrial acetyltransferase-related protein GCN5L1. We showed that acetylation status of several fatty acid and glucose oxidation enzymes (long-chain acyl-coenzyme A dehydrogenase, hydroxyacyl-coA dehydrogenase, and pyruvate dehydrogenase) were significantly up-regulated in aged heart which correlated with decreased enzymatic activities. Using a cardiac-specific GCN5L1 knockout (KO) animal model, we showed that overall acetylation of mitochondrial proteins was decreased in aged KO animals, including FAO proteins which led to improved FAO activity and attenuated cardiac diastolic dysfunction observed in the aged heart. Together, these findings indicate that lysine acetylation regulates FAO in the aged heart which results in improved cardiac diastolic function and this is in part regulated by GCN5L1.

An implicit representation of stimulus ambiguity in pupil size.

To guide behavior, perceptual systems must operate on intrinsically ambiguous sensory input. Observers are usually able to acknowledge the uncertainty of their perception, but in some cases, they critically fail to do so. Here, we show that a physiological correlate of ambiguity can be found in pupil dilation even when the observer is not aware of such ambiguity. We used a well-known auditory ambiguous stimulus, known as the tritone paradox, which can induce the perception of an upward or downward pitch shift within the same individual. In two experiments, behavioral responses showed that listeners could not explicitly access the ambiguity in this stimulus, even though their responses varied from trial to trial. However, pupil dilation was larger for the more ambiguous cases. The ambiguity of the stimulus for each listener was indexed by the entropy of behavioral responses, and this entropy was also a significant predictor of pupil size. In particular, entropy explained additional variation in pupil size independent of the explicit judgment of confidence in the specific situation that we investigated, in which the two measures were decoupled. Our data thus suggest that stimulus ambiguity is implicitly represented in the brain even without explicit awareness of this ambiguity.

Gastrointestinal thickness, duration, and leak pressure of five intestinal anastomosis techniques in cats.

OBJECTIVE: To compare time to construct completion and resistance to leakage for five intestinal anastomosis techniques in cats and to report normal feline gastrointestinal thickness. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Grossly normal intestinal segments (n = 120) from 10 fresh cat cadavers. METHODS: A total of 8 cm segments of fresh feline cadaveric intestine were collected, and mural thickness was recorded. Segments were randomly allocated between a control group (n = 20 segments) and five treatment groups (20 segments/group with 2 segments/construct = 10 constructs per group): (1) hand-sewn anastomosis - simple interrupted (HSA-SI), (2) hand-sewn anastomosis - simple continuous (HSA-SC), (3) functional end-to-end stapled anastomosis (FEESA), (4) functional end-to-end stapled anastomosis with oversew (FEESA-O), (5) skin stapled anastomosis (SS). Time to construct completion, leakage location, initial leak pressure (ILP), and maximum intraluminal pressure (MIP) were compared. RESULTS: Mean mural thickness ± SD (mm) for the stomach, duodenum, jejunum, and ileum were 1.66 ± 0.28, 2.05 ± 0.18, 2.28 ± 0.30, and 2.11 ± 0.39, respectively. ILPs (mean ± SD) for HSA-SI (165 ± 122 mmHg), HSA-SC (149 ± 83), FEESA-O (63 ± 25, FEESA (84 ± 59), SS (77 ± 56), and control segments (>500) were compared. There was no statistically significant difference in ILP (p > .08) or MIP (p > .084) between any treatment groups. Nonoversewn FEESAs were 2.4 times faster to perform compared to oversewn FEESA and SS groups, and 4.7 times faster than HSA (p < .001). CONCLUSION: All anastomosis techniques provide resistance to leakage that is supraphysiological to that of the normal maximum intraluminal pressure. HSA take longer to complete than stapled anastomoses. CLINICAL SIGNIFICANCE: All anastomotic techniques may be appropriate in cats. Hand-sewn anastomoses result in a longer surgical time.

Consonance Perception in Congenital Amusia: Behavioral and Brain Responses to Harmonicity and Beating Cues.

Congenital amusia is a neurodevelopmental disorder characterized by difficulties in the perception and production of music, including the perception of consonance and dissonance, or the judgment of certain combinations of pitches as more pleasant than others. Two perceptual cues for dissonance are inharmonicity (the lack of a common fundamental frequency between components) and beating (amplitude fluctuations produced by close, interacting frequency components). Amusic individuals have previously been reported to be insensitive to inharmonicity, but to exhibit normal sensitivity to beats. In the present study, we measured adaptive discrimination thresholds in amusic participants and found elevated thresholds for both cues. We recorded EEG and measured the MMN in evoked potentials to consonance and dissonance deviants in an oddball paradigm. The amplitude of the MMN response was similar overall for amusic and control participants; however, in controls, there was a tendency toward larger MMNs for inharmonicity than for beating cues, whereas the opposite tendency was observed for the amusic participants. These findings suggest that initial encoding of consonance cues may be intact in amusia despite impaired behavioral performance, but that the relative weight of nonspectral (beating) cues may be increased for amusic individuals.

Quantitative Assessment of Regional Pulmonary Transit Times in Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) contributes to restricted flow through the pulmonary circulation characterized by elevated mean pulmonary artery pressure acquired from invasive right heart catheterization (RHC). MRI may provide a noninvasive alternative for diagnosis and characterization of PH. PURPOSE: To characterize PH via quantification of regional pulmonary transit times (rPTT). STUDY TYPE: Retrospective. POPULATION: A total of 43 patients (58% female); 24 controls (33% female). RHC-confirmed patients classified as World Health Organization (WHO) subgroups 1-4. FIELD STRENGTH/SEQUENCE: A 1.5 T/time-resolved contrast-enhanced MR Angiography (CE-MRA). ASSESSMENT: CE-MRA data volumes were combined into a 4D matrix (3D resolution + time). Contrast agent arrival time was defined as the peak in the signal-intensity curve generated for each voxel. Average arrival times within a vessel region of interest (ROI) were normalized to the main pulmonary artery ROI (t0 ) for eight regions to define rPTT for all subjects. Subgroup analysis included grouping the four arterial and four venous regions. Intraclass correlation analysis completed for reproducibility. STATISTICAL TESTS: Analysis of covariance with age as covariate. A priori Student's t-tests or Wilcoxon rank-sum test; α = 0.05. Results compared to controls unless noted. Significant without listing P value. ICC ran as two-way absolute agreement model with two observers. RESULTS: PH patients demonstrated elevated rPTT in all vascular regions; average rPTT increase in arterial and venous branches was 0.85 ± 0.15 seconds (47.7%) and 1.0 ± 0.18 seconds (16.9%), respectively. Arterial rPTT was increased for all WHO subgroups; venous regions were elevated for subgroups 2 and 4 (group 1, P = 0.86; group 3, P = 0.32). No significant rPTT differences were found between subgroups (P = 0.094-0.94). Individual vessel ICC values ranged from 0.58 to 0.97. DATA CONCLUSION: Noninvasive assessment of PH using standard-of-care time-resolved CE-MRA can detect increased rPTT in PH patients of varying phenotypes compared to controls. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Efficacy and safety of antiparasitic therapy for neurocysticercosis in rural Tanzania: a prospective cohort study.

PURPOSE: Neurocysticercosis is common in regions endemic for Taenia solium. Active-stage neurocysticercosis can be treated with antiparasitic medication, but so far no study on efficacy and safety has been conducted in Africa. METHODS: We conducted a prospective cohort study on treatment of neurocysticercosis in Tanzania between August 2018 and January 2022. Patients were initially treated with albendazole (15 mg/kg/d) for 10 days and followed up for 6 months. Additionally in July 2021, all participants who then still had cysts were offered a combination therapy consisting of albendazole (15 mg/kg/d) and praziquantel (50 mg/kg/d). Antiparasitic treatment was accompanied by corticosteroid medication and anti-seizure medication if the patient had experienced epileptic seizures before treatment. RESULTS: Sixty-three patients were recruited for this study, of whom 17 had a complete follow-up after albendazole monotherapy. These patients had a total of 138 cysts at baseline, of which 58 (42%) had disappeared or calcified by the end of follow-up. The median cyst reduction was 40% (interquartile range 11-63%). Frequency of epileptic seizures reduced considerably (p < 0.001). Three patients had all active cysts resolved or calcified and of the remaining 14, eight received the combination therapy which resolved 63 of 66 cysts (95%). Adverse events were infrequent and mild to moderate during both treatment cycles. CONCLUSION: Cyst resolution was unsatisfactory with albendazole monotherapy but was very high when it was followed by a combination of albendazole and praziquantel.

CRISPR base editing of cis-regulatory elements enables the perturbation of neurodegeneration-linked genes.

CRISPR technology has demonstrated broad utility for controlling target gene expression; however, there remains a need for strategies capable of modulating expression via the precise editing of non-coding regulatory elements. Here, we demonstrate that CRISPR base editors, a class of gene-modifying proteins capable of creating single-base substitutions in DNA, can be used to perturb gene expression via their targeted mutagenesis of cis-acting sequences. Using the promoter region of the human huntingtin (HTT) gene as an initial target, we show that editing of the binding site for the transcription factor NF-κB led to a marked reduction in HTT gene expression in base-edited cell populations. We found that these gene perturbations were persistent and specific, as a transcriptome-wide RNA analysis revealed minimal off-target effects resulting from the action of the base editor protein. We further demonstrate that this base-editing platform could influence gene expression in vivo as its delivery to a mouse model of Huntington's disease led to a potent decrease in HTT mRNA in striatal neurons. Finally, to illustrate the applicability of this concept, we target the amyloid precursor protein, showing that multiplex editing of its promoter region significantly perturbed its expression. These findings demonstrate the potential for base editors to regulate target gene expression.

MRA of the Supraaortic Vasculature: Comparison of Gadobutrol and Gadoterate Meglumine at 1.5 T.

BACKGROUND: Gadobutrol (GB) and gadoterate meglumine (GM) are contrast agents used for contrast-enhanced magnetic resonance angiography (CEMRA). Supraaortic vasculature (SAV) CEMRAs are used to evaluate stroke risk and neurologic symptoms. There is a need to compare the SAV CEMRA image quality obtained with GB and GM. PURPOSE: To intra-individually compare MRA images obtained with equimolar GB and GM at 1.5 T in the SAV. STUDY TYPE: Prospective, crossover. POPULATION: Twenty-eight subjects (54 ± 13 years; 17 female). FIELD STRENGTH/SEQUENCE: 1.5 T; three-dimensional (3D) gradient recalled echo. ASSESSMENT: Quantitative image quality was measured by normalized signal intensity (SIn ) [SIn  = SI blood/SD blood] and contrast ratio (CR) [CR = SI blood/SI muscle], determined by an observer (JWC) with 1 year of vascular imaging experience. Three radiologists (AS, PA, and MU) with (5, 5, and 6 years of) vascular imaging experience evaluated image quality by Likert-scale ratings (of image impression, wall conspicuity, and artifact absence). STATISTICAL TESTS: SIn and CR were compared with paired t-tests or Wilcoxon signed-rank tests and Bland-Altman plots. Qualitative ratings were compared with Wilcoxon signed-rank test. RESULTS: No significant difference in SIn was found between GB and GM. CRs with GB were significantly higher than GM at the right common carotid (6.9 ± 2.5 vs. 4.8 ± 1), left internal carotid (7.3 ± 2 vs. 4.4 ± 1.2), right internal carotid (7.7 ± 2.2 vs. 5 ± 1.1), and left vertebral (6.6 ± 2.2 vs. 4.5 ± 1.1) arteries. Bland-Altman plots showed relatively greater differences between GB and GM at higher CRs and SIn s. GM showed significantly higher artifact than GB (3.56 ± 0.52 vs. 3.36 ± 0.46) and significantly lower overall image quality (10.73 ± 1.45 vs. 11.26 ± 1.58) at the left vertebral artery. DATA CONCLUSION: At 1.5 T and equimolar demonstration, GB (0.1 mL/kg, i.e., 0.1 mmol/kg) showed higher CRs in the SAV compared to GM (0.2 mL/kg, i.e., 0.1 mmol/kg) at most vessels. Subjective image quality was not significantly different between the two agents for most vessels. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Spontaneous surface adsorption of aqueous graphene oxide by synergy with surfactants.

The spontaneous adsorption of graphene oxide (GO) sheets at the air-water interface is explored using X-ray reflectivity (XRR) measurements. As a pure aqueous dispersion, GO sheets do not spontaneously adsorb at the air-water interface due to their high negative surface potential (-60 mV) and hydrophilic functionality. However, when incorporated with surfactant molecules at optimal ratios and loadings, GO sheets can spontaneously be driven to the surface. It is hypothesised that surfactant molecules experience favourable attractive interactions with the surfaces of GO sheets, resulting in co-assembly that serves to render the sheets surface active. The GO/surfactant composites then collectively adsorb at the air-water interface, with XRR analysis suggesting an interfacial structure comprising surfactant tailgroups in air and GO/surfactant headgroups in water for a combined thickness of 30-40 Å, depending on the surfactant used. Addition of too much surfactant appears to inhibit GO surface adsorption by saturating the interface, and low loadings of GO/surfactant composites (even at optimal ratios) do not show significant adsorption indicating a partitioning effect. Lastly, surfactant chemistry is also a key factor dictating adsorption capacity of GO. The zwitterionic surfactant oleyl amidopropyl betaine causes marked increases in GO surface activity even at very low concentrations (≤0.2 mM), whereas non-ionic surfactants such as Triton X-100 and hexaethyleneglycol monododecyl ether require higher concentrations (ca. 1 mM) in order to impart spontaneous adsorption of the sheets. Anionic surfactants do not enhance GO surface activity presumably due to like-charge repulsions that prevent co-assembly. This work provides useful insight into the synergy between GO sheets and molecular amphiphiles in aqueous systems for enhancing the surface activity of GO, and can be used to inform system formulation for developing water-friendly, surface active composites based around atomically thin materials.

Correlated structure of neuronal firing in macaque visual cortex limits information for binocular depth discrimination.

Variability in cortical neural activity potentially limits sensory discriminations. Theoretical work shows that information required to discriminate two similar stimuli is limited by the correlation structure of cortical variability. We investigated these information-limiting correlations by recording simultaneously from visual cortical areas primary visual cortex (V1) and extrastriate area V4 in macaque monkeys performing a binocular, stereo depth discrimination task. Within both areas, noise correlations on a rapid temporal scale (20-30 ms) were stronger for neuron pairs with similar selectivity for binocular depth, meaning that these correlations potentially limit information for making the discrimination. Between-area correlations (V1 to V4) were different, being weaker for neuron pairs with similar tuning and having a slower temporal scale (100+ ms). Fluctuations in these information-limiting correlations just prior to the detection event were associated with changes in behavioral accuracy. Although these correlations limit the recovery of information about sensory targets, their impact may be curtailed by integrative processing of signals across multiple brain areas.NEW & NOTEWORTHY Correlated noise reduces the stimulus information in visual cortical neurons during experimental performance of binocular depth discriminations. The temporal scale of these correlations is important. Rapid (20-30 ms) correlations reduce information within and between areas V1 and V4, whereas slow (>100 ms) correlations between areas do not. Separate cortical areas appear to act together to maintain signal fidelity. Rapid correlations reduce the neuronal signal difference between stimuli and adversely affect perceptual discrimination.

Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients.

BACKGROUND: Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy. METHODS: Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry. RESULTS: TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival. CONCLUSIONS: Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.

Treatment of a Mouse Model of ALS by In Vivo Base Editing.

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal disorder that can be caused by mutations in the superoxide dismutase 1 (SOD1) gene. Although ALS is currently incurable, CRISPR base editors hold the potential to treat the disease through their ability to create nonsense mutations that can permanently disable the expression of the mutant SOD1 gene. However, the restrictive carrying capacity of adeno-associated virus (AAV) vectors has limited their therapeutic application. In this study, we establish an intein-mediated trans-splicing system that enables in vivo delivery of cytidine base editors (CBEs) consisting of the widely used Cas9 protein from Streptococcus pyogenes. We show that intrathecal injection of dual AAV particles encoding a split-intein CBE engineered to trans-splice and introduce a nonsense-coding substitution into a mutant SOD1 gene prolonged survival and markedly slowed the progression of disease in the G93A-SOD1 mouse model of ALS. Adult animals treated by this split-intein CRISPR base editor had a reduced rate of muscle atrophy, decreased muscle denervation, improved neuromuscular function, and up to 40% fewer SOD1 immunoreactive inclusions at end-stage mice compared to control mice. This work expands the capabilities of single-base editors and demonstrates their potential for gene therapy.

The experience of D/deaf healthcare professionals during the coronavirus pandemic.

BACKGROUND: The coronavirus pandemic, in particular the introduction of masks, presented a huge challenge for the UK's D/deaf community, many of whom rely on visual cues in lipreading and sign language. This particularly affected D/deaf healthcare professionals (HCPs), who faced significant communication challenges at work due to the lack of transparent masks or other reasonable adjustments. AIMS: To determine the impact that a lack of transparent masks and reasonable adjustments had on communication, confidence at work and well-being among D/deaf HCPs during the coronavirus pandemic. METHODS: A survey was sent to all members of the 'UK Deaf Healthcare Professionals Group' on Facebook, the 'Healthcare Professionals with Hearing Loss' listserver and promoted on Social Media. RESULTS: Eighty-three responses were received. Nine (11%) individuals had access to transparent masks. Over three-quarters of respondents reported feeling anxious and fearful of making a mistake due to communication difficulties. Fourteen (17%) were removed from clinical roles due to a lack of reasonable adjustments. One-third felt they would need to consider an alternative career if improvements were not made. Seventy-eight per cent felt the communication needs of D/deaf HCPs had not been met during the pandemic. CONCLUSIONS: D/deaf HCPs felt left behind, isolated and frustrated by a lack of transparent masks and reasonable adjustments to meet their communication needs. Loss of experienced, qualified HCPs has a significant economic and workforce impact, particularly during a pandemic. Urgent action is needed to ensure D/deaf HCPs are provided with the workplace support required under the Equality Act (2010).

Safety and efficacy of teriparatide treatment for severe osteoporosis in patients with Duchenne muscular dystrophy.

Osteoporosis is a major concern in patients with Duchenne muscular dystrophy. In this novel study of teriparatide treatment in 6 patients with severe osteoporosis, bone health (fractures, vertebral morphometry, and DXA) remained stable, with no adverse events. These findings will help inform future osteoporosis research in this challenging population. INTRODUCTION: Despite standard therapy with vitamin D and bisphosphonates (BP), many patients with Duchenne muscular dystrophy (DMD) continue to sustain fragility fractures due to long-term glucocorticoid treatment and limited mobility. We aimed to evaluate the safety and efficacy of teriparatide for the treatment of severe osteoporosis in adolescent and young adult patients with DMD. METHODS: We prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20 mcg subcutaneously daily for 1-2 years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. We examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, bone mineral density and content, bone formation markers, safety indices, and adverse events. RESULTS: The mean age at teriparatide start was 17.9 years (range 13.9-22.1 years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5 years) and 5 were non-ambulatory. Five patients had been treated with BP for 7.9 ± 4.2 years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); one patient sustained a long bone fracture at 6 months of treatment. Trajectories for change in bone mineral density and content were not different post- vs. pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning. No adverse events were observed. CONCLUSION: In six patients with DMD treated with teriparatide for severe osteoporosis, we observed stable bone health and modest increases in P1NP, without safety concerns. Further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.

Pain management for medical and surgical termination of pregnancy between 13 and 24 weeks of gestation: a systematic review.

BACKGROUND: High-quality care for termination of pregnancy (TOP) requires pain to be effectively managed; however, practices differ, and the available guidelines do not specify optimal strategies. OBJECTIVE: To guide providers in effective pain management for second-trimester medical and surgical TOP. SEARCH STRATEGY: We searched PubMed, Cochrane and Embase databases, and the US National Library of Medicine clinical trials registry, from inception to the end of June 2019, and hand-searched reference lists. SELECTION CRITERIA: Trials comparing pain management strategies with no treatment, placebo or active interventions during induced medical or surgical TOP, occurring between 13 and 24 weeks of gestation, and reporting direct or indirect measures of pain. DATA COLLECTION AND ANALYSIS: Both authors summarised and systematically assessed the evidence and risk of bias using standard tools. MAIN RESULTS: We included seven medical and four surgical TOP studies, with 453 and 349 participants, respectively. The heterogeneity of interventions and outcomes prevented pooled analyses. Medical TOP: women receiving routine or continuous epidural analgesia experienced mild pain. The prophylactic use of nonsteroidal anti-inflammatory drugs (NSAIDs) decreased pain (mean difference -0.5, P < 0.001) and additional opioid requirements (3.5 versus 7 mg, P = 0.04) compared with placebo/other treatment. Paracervical block was ineffective. No studies assessed intramuscular (IM)/intravenous (IV) opioid or nonpharmacological treatment. Surgical TOP: general anaesthesia/deep IV sedation alleviated pain. Nitrous oxide was ineffective. No studies assessed moderate IV sedation, IV/IM opioid, paracervical block without sedation, NSAID or nonpharmacological treatment. CONCLUSION: Based on limited data, regional analgesia and NSAIDs mitigated second-trimester medical TOP pain; general anaesthesia/deep IV sedation alleviated surgical TOP pain. TWEETABLE ABSTRACT: Although women experience intense pain during second-trimester termination of pregnancy, few data are available to inform their treatment.

NO FACE-DOWN POSITIONING SURGERY FOR THE REPAIR OF CHRONIC IDIOPATHIC MACULAR HOLES.

PURPOSE: To report visual and anatomical outcomes after the repair of chronic idiopathic macular holes (MHs) with no face-down positioning. METHODS: We conducted a retrospective review of chronic MH cases of greater than 1-year duration that were repaired through pars plana vitrectomy with broad internal limiting membrane peeling and no face-down positioning between March 2009 and December 2017. There were 18 eyes of 18 patients that met inclusion criteria. Patients with MH duration of less than 1 year and without at least 1 month of follow-up were excluded. Macular hole staging and measurements were performed with spectral domain optical coherence tomography. RESULTS: Mean MH duration was 5.0 ± 6.9 years. Two-thirds of MHs had a basal diameter of more than 1,000 µm. Mean preoperative Snellen visual acuity was 20/302 and improved to a mean postoperative visual acuity of 20/112 (P ≤ 0.0001). Visual acuity improved in all patients who achieved successful anatomical closure, 94.4% (17/18) of eyes. CONCLUSION AND RELEVANCE: Patients in this series with chronic MH who underwent no-face-down MH repair demonstrated a high single-surgery anatomical closure rate with a significant improvement in visual acuity.

INCREASED INCIDENCE OF CUTANEOUS KERATINOCYTIC AND MELANOCYTIC MALIGNANCIES IN PATIENTS WITH AGE-RELATED MACULAR DEGENERATION.

PURPOSE: The relationship between age-related macular degeneration (AMD) and malignancy, especially cutaneous malignancies, is not well studied. We investigated a possible association between AMD and cutaneous malignancies. METHODS: A retrospective, consecutive review of all patients who had received at least 1 intravitreal injection for wet AMD between January 1, 2004, and December 31, 2013, was conducted using the Rochester Epidemiology Project in Olmsted County, Minnesota. Age- and sex-matched control groups included 473 pre-anti-vascular endothelial growth factor era wet AMD patients, 504 concurrent time dry AMD patients, and 504 patients with no AMD. The rates of AMD and overall malignancy, cutaneous malignancies, and specific types of cutaneous malignancies were compared between groups of patients. RESULTS: Patients with wet AMD incurred an increased rate of overall malignancies compared to patients with dry AMD {52.8% wet AMD (confidence interval [CI]: 48.3-57.2) vs. 43.7% dry AMD (CI: 39.3-48.1); P= 0.003} or those without AMD (52.8% wet AMD [CI: 48.3-57.2] vs. 35.3% no AMD [CI: 31.1-39.7]; P = <0.001). Patients with dry AMD also had higher rates of malignancy than those without AMD (43.7% dry AMD [CI: 39.3-48.1] vs. 35.3% no AMD [CI: 31.1-39.7]; P = 0.007). Rate of cutaneous malignancies was increased in patients with wet AMD compared to patients with dry AMD (24.4% wet AMD [CI: 20.7-28.4] vs. 14.6% dry AMD [CI: 11.5-17.9]; P = <0.001) and those with no AMD (24.4% wet AMD [CI: 20.7-28.4] vs. 9.7% no AMD [CI: 7.3-12.7]; P = <0.001). CONCLUSION AND RELEVANCE: To the best of our knowledge, this is the first report to establish an association between AMD and cutaneous malignancies, supporting a possible discussion of the association when a patient presents with one of the two conditions.

Health care engagement behaviors of men who use performance- and image-enhancing drugs in Australia.

Background: Although people who inject performance- and image-enhancing drugs (PIEDs) report fewer unsafe injecting practices, stigma and discrimination may negatively impact their access to help and information. Engagement with health care services, compared with social networks (friends, relatives, and gym associates) and the Internet and media (steroid user forums, information sites, and magazines), may be important for harm minimization. Methods: A cross-sectional Internet or in-person survey of men who use PIEDs in Australia in 2014-2015 examined differences in sources for PIEDs, injecting equipment, and anabolic-androgenic steroids (AAS) information and factors associated with having periodical medical checks related to PIEDs issues using multivariate logistic regression. Results: In total, 267 men (mean age: 25 years, SD: 8.7 years; 246 of 267 [92%] reported recent AAS injection) were recruited. Most participants sourced injecting equipment from health professionals, PIEDs from their social networks, and AAS information from the Internet and media. Self-reported AAS knowledge was high and frequent. Higher income (adjusted odds ratio [AOR]: 2.04, 95% confidence interval [CI]: 1.03, 4.00), ≥2 different PIEDs used in addition to AAS (AOR: 1.94, 95% CI: 1.08, 3.49), and sourcing AAS information from health care professionals (AOR: 3.14, 95% CI: 1.81, 5.46) were independently associated with periodical medical checks. Participants nominated preference for improved health services through needle-syringe programs, primary care services, and peer educator support groups. Conclusion: Men who use PIEDs in Australia consider themselves well informed but tend to use Internet and media sources, providing potentially misleading or inaccurate information. Increasing trust between men who use PIEDs and health care providers may enable delivery of PIEDs-specific information to those at greatest need.

Adenosine production in mesenchymal stromal cells in relation to their developmental status.

BACKGROUND: Mesenchymal stromal cells (MSC) are multipotent progenitor cells found in the tumor microenvironment. They have an innate and regulatory immune activity, and they are able to produce immunosuppressive adenosine (ADO) via their ectonucleotidases CD39 and CD73. The present study explores ADO metabolism of MSC in relation to their developmental status. METHODS: We analyzed MSC (n = 6), chondrogenic progenitor cells (CPC, n = 8), and chondrocytes (n = 8) for surface markers by flow cytometry. The ability to hydrolyze ATP and to produce ADO was tested by luminescence assays and mass spectrometry. RESULTS: Significant differences in the surface marker expression of MSC, CPC, and chondrocytes were seen. While the expression of CD73 was observed to be the same on all cell types, the expression of the ectonucleotidase CD39 was significantly increased on MSC. Consequently, production of ADO was most abundant in MSC as compared with chondrocytes and CPC. CONCLUSION: Mesenchymal stromal cells are potent producers of ADO and are, therefore, able to increase immunosuppression. As MSC differentiate into chondrocytes, they lose this ability and may take on other functions.

The Magnitude, But Not the Sign, of MT Single-Trial Spike-Time Correlations Predicts Motion Detection Performance.

Spike-time correlations capture the short timescale covariance between the activity of neurons on a single trial. These correlations can significantly vary in magnitude and sign from trial to trial, and have been proposed to contribute to information encoding in visual cortex. While monkeys performed a motion-pulse detection task, we examined the behavioral impact of both the magnitude and sign of single-trial spike-time correlations between two nonoverlapping pools of middle temporal (MT) neurons. We applied three single-trial measures of spike-time correlation between our multiunit MT spike trains (Pearson's, absolute value of Pearson's, and mutual information), and examined the degree to which they predicted a subject's performance on a trial-by-trial basis. We found that on each trial, positive and negative spike-time correlations were almost equally likely, and, once the correlational sign was accounted for, all three measures were similarly predictive of behavior. Importantly, just before the behaviorally relevant motion pulse occurred, single-trial spike-time correlations were as predictive of the performance of the animal as single-trial firing rates. While firing rates were positively associated with behavioral outcomes, the presence of either strong positive or negative correlations had a detrimental effect on behavior. These correlations occurred on short timescales, and the strongest positive and negative correlations modulated behavioral performance by ∼9%, compared with trials with no correlations. We suggest a model where spike-time correlations are associated with a common noise source for the two MT pools, which in turn decreases the signal-to-noise ratio of the integrated signals that drive motion detection.SIGNIFICANCE STATEMENT Previous work has shown that spike-time correlations occurring on short timescales can affect the encoding of visual inputs. Although spike-time correlations significantly vary in both magnitude and sign across trials, their impact on trial-by-trial behavior is not fully understood. Using neural recordings from area MT (middle temporal) in monkeys performing a motion-detection task using a brief stimulus, we found that both positive and negative spike-time correlations predicted behavioral responses as well as firing rate on a trial-by-trial basis. We propose that strong positive and negative spike-time correlations decreased behavioral performance by reducing the signal-to-noise ratio of integrated MT neural signals.