Xanthelasma Palpebrarum is Not Associated with Dyslipidemia or Cardiovascular Disease: A Case Control Study.

OBJECTIVE: To determine whether Xanthelasma palpebrarum (XP) is associated with dyslipidemia, cardiovascular disease (CVD) and other systemic conditions in a large population. DESIGN: Case-control study conducted at a single tertiary care center. PARTICIPANTS: Individuals who were examined at a medical screening institute from 2001 to 2020. METHODS: Medical records were reviewed to extract data on ophthalmic evaluations, blood tests, and systemic diagnoses. Patients identified with XP in at least one eye comprised the study group. A control group without XP was established matched by age and sex at a 10:1 ratio to allow robust statistical analysis. MAIN OUTCOME MEASURES: Associations between XP and dyslipidemia and CVD. Lipid profiles, diagnosis of dyslipidemia and CVD were compared between the case and control groups. RESULTS: The database included 35,452 individuals, 24,287 males (69%), mean age 52.2±12.2 years. The study population included 203 XP patients (0.6%) and 2030 matched controls. The prevalence of dyslipidemia diagnosis and the usage rates of statins, fibrates, or other cholesterol-lowering medications was similar between the two groups. Lipid profiles were similar between the groups, including median total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels (187 controls vs. 192 XP, 48 controls vs. 47 XP, 120 controls vs. 125 XP, 111 controls vs. 105 XP, respectively, P>0.05 for all). The rate of CVD was similar as well (10% controls vs. 8.9%, XP P=0.56). The prevalences of related conditions, including hypertension, diabetes mellitus, and history of cerebrovascular accident, were similar between groups (24% controls vs. 23% XP, 14% controls vs. 10% XP, 1.3% controls vs. 1% XP, respectively P>0.05). CONCLUSIONS: XP was not associated with increased rates of dyslipidemia or CVD. This questions the extent to which XP serves as an indicative marker for heightened systemic risk.

Exploring the Role of Masturbation as a Coping Strategy in Women.

Objectives: Recent findings suggest that individuals tend to engage in masturbation more frequently when experiencing elevated levels of psychological stress, and there appears to be distinguishable effects on stress response based on clitoral and vaginal stimulation. In this concurrent mixed-method study, we aimed to investigate this association in more detail using a convenience sample of 370 women. Methods: Quantitative data were used to examine whether higher psychological distress was associated with higher levels of masturbation frequency depending on the mode of stimulation, while qualitative data gave further insight into this association. Results: In regression analysis, higher levels of general and subscale-specific psychological distress were significantly associated with higher clitoral, but not combined clitoral and vaginal masturbation frequency. Qualitative content analysis showed that masturbation was used as a reliable coping strategy and self-care strategy which induced positive affective states, such as happiness and relaxation. Very few women reported negative feelings associated with masturbation. Mixed-method analysis revealed that women who indicated to use of masturbation for coping or self-care or who reported negative feelings did not differ in their level of psychological distress from women who did not report using it. The positive effects of masturbation were not related to the mode of stimulation. Conclusions: Results showed the complexity of how psychological distress is related to sexual activity and point to the potential benefits of masturbation for dealing with psychological distress and for enhancing general well-being. Our results have various implications for researchers, clinicians, and society.

Impact of surgical specialization on emergency upper gastrointestinal surgery outcomes: A systematic review and meta-analysis.

BACKGROUND: Emergency presentations make up a large proportion of a general surgeon's workload. Patients who have emergency surgery carry a higher rate of mortality and complications. We aim to review the impact of surgical subspecialization on patients following upper gastrointestinal (UGI) emergency surgery. METHODS: A systematic search of Ovid Embase, Ovid MEDLINE, and Cochrane databases using a predefined search strategy was completed reviewing studies published from 1st of January 1990 to August 27, 2023. The study was prospectively registered with PROSPERO (CRD42022359326). Studies were reviewed for the following outcomes: 30-day mortality, in-hospital mortality, conversion to open, length of stay, return to theater, and readmission. RESULTS: Of 5181 studies, 24 articles were selected for full text review. Of these, seven were eligible and included in this study. There was a statistically significant improvement in 30-day mortality favoring UGI specialists (OR 0.71 [95% CI 0.55-0.92 and p = 0.009]) and in-hospital mortality (OR 0.29 [95% CI 0.14-0.60 and p = 0009]). There was a high degree of study heterogeneity in 30-day mortality; however, a low degree of heterogeneity within in-hospital mortality. There was no statistical significance when considering conversion to open and insufficient data to allow meta-analysis for return to theater or readmission rates. CONCLUSION: In emergency UGI surgery, there was improved 30-day and in-hospital mortality for UGI specialists. Therefore, surgeons should consider early involvement of a subspecialist team to improve patient outcomes.

Deferring diagnostic evaluation of suspected deep vein thrombosis using direct oral anticoagulant or low-molecular-weight heparin as a single dose anticoagulant: A prospective real-world study in a regionwide care pathway.

BACKGROUND: Patients with suspected deep vein thrombosis (DVT) are typically referred to the emergency department for immediate evaluation. To enhance efficiency, our hospital implemented a regional, general practitioner (GP)-driven DVT care pathway, deferring diagnostic evaluation to a scheduled outpatient DVT clinic appointment the following day. Patients receive a single dose anticoagulant from their GP to prevent thrombosis progression while awaiting diagnostic workup. This prospective study aimed to evaluate the safety and patient preferences regarding the DVT care pathway and the type of single dose anticoagulant (low-molecular-weight heparin (LMWH) vs. direct oral anticoagulant (DOAC)). METHODS: Patients enrolled in the DVT care pathway between June 2021 and July 2023 were eligible. Until July 2022, LMWH was administered, and thereafter, the protocol recommended DOAC as the single dose anticoagulant. Patients completed questionnaires, incorporating patient-reported outcome and experience measures (PROMs/PREMs), during their DVT clinic visit and after five days. The primary endpoint was bleeding events within 72 h of receiving the single dose anticoagulant. RESULTS: Of 460 included patients, 229 received LMWH and 231 received DOAC as the single dose anticoagulant. DVT was confirmed in 24.8 % of patients. No major or clinically relevant non-major bleeding were reported. LMWH was associated with more minor bleedings (22.3 % vs. DOAC 13.4 %), primarily attributed to injection site hematomas. Patients reported high satisfaction with the DVT care pathway (96.5 %) and generally preferred DOAC over LMWH. CONCLUSION: Deferring diagnostic evaluation for DVT using a single dose of either LMWH or DOAC in a real-world population is deemed safe. Considering practical advantages, patient preferences, and fewer skin hematomas, we favor DOACs as the single dose anticoagulant in this care pathway.

Effect of lixisenatide on liquid gastric emptying in type 2 diabetes - Implications for the use of GLP-1 receptor agonists before procedures.

Gastric emptying of a glucose drink was measured in people with type 2 diabetes given lixisenatide (20 µg/day or placebo) for 8 weeks. Intragastric retention at 240 min (2 (0-11)% vs 48 (3-97)%; P < 0.0001) was much greater with lixisenatide than placebo. Accordingly, lixisenatide may delay liquid gastric emptying markedly.

Association Between Acquired Punctal Stenosis and Ocular Surface Disease: the Egg and the Chicken Story.

PURPOSE: This study explores the relationship between acquired punctal stenosis (PS) and ocular surface disease (OSD), assessing causal mechanisms and clinical impacts, utilizing a combination of a comprehensive literature review and a detailed analysis of a patient cohort from a tertiary care center. METHODS: Data from 213 PS patients at Sheba Medical Center were retrospectively analyzed, evaluating various OSD symptoms and treatment effectiveness through standardized clinical assessments and statistical tests. RESULTS: Predominantly older and female, many patients exhibited bilateral PS. OSD symptoms were found in 35.2% of all patients. Treatments like punctoplasty with stents significantly alleviated symptoms. Significant associations between treatment modalities and symptom improvement were identified. CONCLUSIONS: PS and OSD have acomplex, bidirectional relationship that complicates treatment outcomes. This study underscores the need for thorough diagnostic approaches and personalized treatments to improve PS management. Further research is essential to deepen understanding of PS-OSD interactions and develop effective therapies.

ER-export and ARFRP1/AP-1-dependent delivery of SARS-CoV-2 Envelope to lysosomes controls late stages of viral replication.

The ß-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global COVID-19 pandemic. Coronaviral Envelope (E) proteins are pentameric viroporins that play essential roles in assembly, release, and pathogenesis. We developed a nondisruptive tagging strategy for SARS-CoV-2 E and find that, at steady state, it localizes to the Golgi and to lysosomes. We identify sequences in E, conserved across Coronaviridae, responsible for endoplasmic reticulum-to-Golgi export, and relate this activity to interaction with COP-II via SEC24. Using proximity biotinylation, we identify an ADP ribosylation factor 1/adaptor protein-1 (ARFRP1/AP-1)-dependent pathway allowing Golgi-to-lysosome trafficking of E. We identify sequences in E that bind AP-1, are conserved across ß-coronaviruses, and allow E to be trafficked from Golgi to lysosomes. We show that E acts to deacidify lysosomes and, by developing a trans-complementation assay for SARS-CoV-2 structural proteins, that lysosomal delivery of E and its viroporin activity is necessary for efficient viral replication and release.

Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides.

Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.

Semiautomated MRI-Based Method for Orbital Volume and Contour Analysis.

PURPOSE: The architecture of the orbital cavity is intricate, and precise measurement of its growth is essential for managing ocular and orbital pathologies. Most methods for those measurements are by CT imaging, although MRI for soft tissue assessment is indicated in many cases, specifically pediatric patients. This study introduces a novel semiautomated MRI-based approach for depicting orbital shape and dimensions. DESIGN: A retrospective cohort study. PARTICIPANTS: Patients with at least 1 normal orbit who underwent both CT and MRI imaging at a single center from 2015 to 2023. METHODS: Orbital dimensions included volume, horizontal and vertical lengths, and depth. These were determined by manual segmentation followed by 3-dimensional image processing software. MAIN OUTCOME MEASURES: Differences in orbital measurements between MRI and CT scans. RESULTS: Thirty-one patients (mean age 47.7 ± 23.8 years, 21 [67.7%]) females, were included. The mean differences in delta values between orbital measurements on CT versus MRI were: volume 0.03 ± 2.01 ml, horizontal length 0.53 ± 2.12 mm, vertical length, 0.36 ± 2.53 mm, and depth 0.97 ± 3.90 mm. The CT and. MRI orbital measurements were strongly correlated: volume (r = 0.92, p < 0.001), horizontal length (r = 0.65, p < 0.001), vertical length (r = 0.57, p = 0.001), and depth (r = 0.46, p = 0.009). The mean values of all measurements were similar on the paired-samples t test: p = 0.9 for volume (30.86 ± 5.04 ml on CT and 30.88 ± 4.92 ml on MRI), p = 0.2 for horizontal length, p = 0.4 for vertical length, and p = 0.2 for depth. CONCLUSIONS: We present an innovative semiautomated method capable of calculating orbital volume and demonstrating orbital contour by MRI validated against the gold standard CT-based measurements. This method can serve as a valuable tool for evaluating diverse orbital processes.

Tuning the photoactivated anticancer activity of Pt(iv) compounds via distant ferrocene conjugation.

Photoactive prodrugs offer potential for spatially-selective antitumour activity with minimal effects on normal tissues. Excited-state chemistry can induce novel effects on biochemical pathways and combat resistance to conventional drugs. Photoactive metal complexes in particular, have a rich and relatively unexplored photochemistry, especially an ability to undergo facile intersystem crossing and populate triplet states. We have conjugated the photoactive octahedral Pt(iv) complex trans, trans, trans-[Pt(N3)2(OH)2(py)2] to ferrocene to introduce novel features into a candidate photochemotherapeutic drug. The X-ray crystal structure of the conjugate Pt-Fe confirmed the axial coordination of a ferrocene carboxylate, with Pt(iv) and Fe(ii) 6.07 Å apart. The conjugation of ferrocene red-shifted the absorption spectrum and ferrocene behaves as a light antenna allowing charge transfer from iron to platinum, promoting the photoactivation of Pt-Fe with light of longer wavelength. Cancer cellular accumulation is enhanced, and generation of reactive species is catalysed after photoirradiation, introducing ferroptosis as a contribution towards the cell-death mechanism. TDDFT calculations were performed to shed light on the behaviour of Pt-Fe when it is irradiated. Intersystem spin-crossing allows the formation of triplet states centred on both metal atoms. The dissociative nature of triplet states confirms that they can be involved in ligand detachment due to irradiation. The Pt(ii) photoproducts mainly retain the trans-{Pt(py)2}2+fragment. Visible light irradiation gives rise to micromolar activity for Pt-Fe towards ovarian, lung, prostate and bladder cancer cells under both normoxia and hypoxia, and some photoproducts appear to retain Pt(iv)-Fe(ii) conjugation.

Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. CRC liver metastases (CRLM) are often resistant to conventional treatments, with high rates of recurrence. Therefore, it is crucial to identify biomarkers for CRLM patients that predict cancer progression. This study utilised matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to spatially map the CRLM tumour proteome. CRLM tissue microarrays (TMAs) of 84 patients were analysed using tryptic peptide MALDI-MSI to spatially monitor peptide abundances across CRLM tissues. Abundance of peptides was compared between tumour vs stroma, male vs female and across three groups of patients based on overall survival (0-3 years, 4-6 years, and 7+ years). Peptides were then characterised and matched using LC-MS/MS. A total of 471 potential peptides were identified by MALDI-MSI. Our results show that two unidentified m/z values (1589.876 and 1092.727) had significantly higher intensities in tumours compared to stroma. Ten m/z values were identified to have correlation with biological sex. Survival analysis identified three peptides (Histone H4, Haemoglobin subunit alpha, and Inosine-5'-monophosphate dehydrogenase 2) and two unidentified m/z values (1305.840 and 1661.060) that were significantly higher in patients with shorter survival (0-3 years relative to 4-6 years and 7+ years). This is the first study using MALDI-MSI, combined with LC-MS/MS, on a large cohort of CRLM patients to identify the spatial proteome in this malignancy. Further, we identify several protein candidates that may be suitable for drug targeting or for future prognostic biomarker development.

Orbital Development in Children with Retinoblastoma: An Imaging-Based Study.

PURPOSE: To examine whether children treated for Retinoblastoma (Rb) have impaired orbital development. METHODS: A retrospective case series was performed among children with Rb treated at a single medical center from 2004 to 2020. Orbital volumes and measurements were assessed by 3-dimensional image processing software. The main outcome measures were differences in orbital growth between Rb and non-Rb eyes assessed at last follow-up. RESULTS: Among 44 patients included (mean age 16.09 ± 18.01 months), a positive correlation between age and orbital volume was observed only in the uninvolved, healthy eyes (p = .03). In unilateral cases, orbital growth in the horizontal, vertical, and depth planes was smaller on the affected side compared to the healthy eyes (p < .05). Orbits that underwent enucleation showed decreased growth over time compared to those treated conservatively (p = .017). CONCLUSIONS: Orbital growth rate is slower in the orbits of children treated for Rb compared to healthy orbits. Enucleation negatively affects orbital growth.

Regio- and Enantioselective Asymmetric Transfer Hydrogenation of One Carbonyl Group in a Diketone through Steric Hindrance.

On the basis of steric hindrance, one carbonyl group in a diketone can be reduced in a regioselective manner, with high enantioselectivity. The methodology can be extended to ketones with varied length of hydrocarbon chain spacing, and the products can be converted by oxidation to hydroxy esters or lactones without loss of enantiopurity.

Prevalence of common and rare ophthalmic findings in adults attending a medical survey institute.

PURPOSE: To examine the ophthalmic data from a large database of people attending a general medical survey institute, and to investigate ophthalmic findings of the eye and its adnexa, including differences in age and sex. METHODS: Retrospective analysis including medical data of all consecutive individuals whose ophthalmic data and the prevalences of ocular pathologies were extracted from a very large database of subjects examined at a single general medical survey institute. RESULTS: Data were derived from 184,589 visits of 3676 patients (mean age 52 years, 68% males). The prevalence of the following eye pathologies were extracted. Eyelids: blepharitis (n = 4885, 13.3%), dermatochalasis (n = 4666, 12.7%), ptosis (n = 677, 1.8%), ectropion (n = 73, 0.2%), and xanthelasma (n = 160, 0.4%). Anterior segment: pinguecula (n = 3368, 9.2%), pterygium (n = 852, 2.3%), and cataract or pseudophakia (n = 9381, 27.1%). Cataract type (percentage of all phakic patients): nuclear sclerosis (n = 8908, 24.2%), posterior subcapsular (n = 846, 2.3%), and capsular anterior (n = 781, 2.1%). Pseudophakia was recorded for 697 patients (4.6%), and posterior subcapsular opacification for 229 (0.6%) patients. Optic nerve head (ONH): peripapillary atrophy (n = 4947, 13.5%), tilted disc (n = 3344, 9.1%), temporal slope (n = 410, 1.1%), ONH notch (n = 61, 0.2%), myelinated nerve fiber layer (n = 94, 0.3%), ONH drusen (n = 37, 0.1%), optic pit (n = 3, 0.0%), and ON coloboma (n = 4, 0.0%). Most pathologies were more common in males except for ONH, and most pathologies demonstrated a higher prevalence with increasing age. CONCLUSIONS: Normal ophthalmic data and the prevalences of ocular pathologies were extracted from a very large database of subjects seen at a single medical survey institute.

Generation and assessment of cytokine-induced killer cells for the treatment of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Cytokine-induced killer (CIK) cells are an adoptive immunotherapy reported to have strong anti-tumour activity across a range of cancers. They are a heterogeneous mix of lymphoid cells generated by culturing human peripheral blood mononuclear cells with cytokines and monoclonal antibodies in vitro. In this study, we investigated the yield and function of CIK cells generated from patients with CRC liver metastases. We first showed that CIK cells generated in serum free medium X-VIVO 15 were comparable to those from RPMI medium with 10% FBS in terms of the number and percentages of the main subsets of cells in the CIK culture, and the intracellular levels of granzyme B and perforin, and the pro-inflammatory cytokines IL-2, IFN-γ and TNF-α. The CIK cells were cytotoxic to CRC cell lines grown in 2D cultures or as spheroids, and against autologous patient-derived tumour organoids. Donor attributes such as age, sex, or prior chemotherapy exposure had no significant impact on CIK cell numbers or function. These results suggest that functional CIK cells can be generated from patients with CRC liver metastatic disease, and support further investigations into the therapeutic application of autologous CIK cells in the management of patients with CRC liver metastases.