Removal of metals and emergent contaminants from liquid digestates in constructed wetlands for agricultural reuse.

Given the increasing pressure on water bodies, it is imperative to explore sustainable methodologies for wastewater treatment and reuse. The simultaneous presence of multiples contaminants in complex wastewater, such as the liquid effluents from biogas plants, can compromise biological treatment effectiveness for reclaiming water. Vertical subsurface flow constructed wetlands were established as low-cost decentralized wastewater treatment technologies to treat the liquid fraction of digestate from municipal organic waste with metals, antibiotics, and antibiotic resistance genes, to allow its reuse in irrigation. Twelve lab-scale planted constructed wetlands were assembled with gravel, light expanded clay aggregate and sand, testing four different treating conditions (liquid digestate spiked with oxytetracycline, sulfadiazine, or ofloxacin, at 100 µg/ L, or without dosing) during 3 months. Physicochemical parameters (pH, chemical oxygen demand (COD), nutrients, metals, and antibiotics), the microbial communities dynamics (through 16S high-throughput sequencing) and antibiotic resistance genes removal (qPCR) were monitored in influents and effluents. Systems removed 85.8%-96.9% of organic matter (as COD), over 98.1% of ammonium and phosphate ions, and 69.3%-99.4% of nitrate and nitrite ions, with no significant differences between the presence or absence of antibiotics. Removal of Fe, Mn, Zn, Cu, Pb and Cr exceeded 82% in all treatment cycles. The treatment also removed oxytetracycline, sulfadiazine and ofloxacin over 99%, and decreased intl1, tetA, tetW, sul1 and qnrS gene copies. Nonetheless, after 3 months of ofloxacin dosing, qnrS gene started being detected. Removal processes relied on high HRT (14 days) and various mechanisms including sorption, biodegradation, and precipitation. Microbial community diversity in liquid digestate changed significantly after treatment in constructed wetlands with a decrease in the initial Firmicutes dominance, but with no clear effect of antibiotics on the microbial community structure. Removals above 85% and 94% were observed for Streptococcus and Clostridium, respectively. Results suggest that vertical subsurface flow constructed wetlands were a suitable technology for treating the liquid digestate to reuse it in irrigation agricultural systems, contributing to the circular bioeconomy concept. However, a more profound understanding of effective wastewater treatment strategies is needed to avoid antibiotic resistance genes dissemination.

Deep Learning and High-Resolution Anoscopy: Development of an Interoperable Algorithm for the Detection and Differentiation of Anal Squamous Cell Carcinoma Precursors-A Multicentric Study.

High-resolution anoscopy (HRA) plays a central role in the detection and treatment of precursors of anal squamous cell carcinoma (ASCC). Artificial intelligence (AI) algorithms have shown high levels of efficiency in detecting and differentiating HSIL from low-grade squamous intraepithelial lesions (LSIL) in HRA images. Our aim was to develop a deep learning system for the automatic detection and differentiation of HSIL versus LSIL using HRA images from both conventional and digital proctoscopes. A convolutional neural network (CNN) was developed based on 151 HRA exams performed at two volume centers using conventional and digital HRA systems. A total of 57,822 images were included, 28,874 images containing HSIL and 28,948 LSIL. Partial subanalyses were performed to evaluate the performance of the CNN in the subset of images acetic acid and lugol iodine staining and after treatment of the anal canal. The overall accuracy of the CNN in distinguishing HSIL from LSIL during the testing stage was 94.6%. The algorithm had an overall sensitivity and specificity of 93.6% and 95.7%, respectively (AUC 0.97). For staining with acetic acid, HSIL was differentiated from LSIL with an overall accuracy of 96.4%, while for lugol and after therapeutic manipulation, these values were 96.6% and 99.3%, respectively. The introduction of AI algorithms to HRA may enhance the early diagnosis of ASCC precursors, and this system was shown to perform adequately across conventional and digital HRA interfaces.

Artificial Intelligence and Colposcopy: Automatic Identification of Cervical Squamous Cell Carcinoma Precursors.

Background/Objectives: Proficient colposcopy is crucial for the adequate management of cervical cancer precursor lesions; nonetheless its limitations may impact its cost-effectiveness. The development of artificial intelligence models is experiencing an exponential growth, particularly in image-based specialties. The aim of this study is to develop and validate a Convolutional Neural Network (CNN) for the automatic differentiation of high-grade (HSIL) from low-grade dysplasia (LSIL) in colposcopy. Methods: A unicentric retrospective study was conducted based on 70 colposcopy exams, comprising a total of 22,693 frames. Among these, 8729 were categorized as HSIL based on histopathology. The total dataset was divided into a training (90%, n = 20,423) and a testing set (10%, n = 2270), the latter being used to evaluate the model's performance. The main outcome measures included sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiving operating curve (AUC-ROC). Results: The sensitivity was 99.7% and the specificity was 98.6%. The PPV and NPV were 97.8% and 99.8%, respectively. The overall accuracy was 99.0%. The AUC-ROC was 0.98. The CNN processed 112 frames per second. Conclusions: We developed a CNN capable of differentiating cervical cancer precursors in colposcopy frames. The high levels of accuracy for the differentiation of HSIL from LSIL may improve the diagnostic yield of this exam.

Heterogeneity in families with ATTRV30M amyloidosis: a historical and longitudinal Portuguese case study impact for genetic counselling.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an inherited disease, where the study of family history holds importance. This study evaluates the changes of age-of-onset (AOO) and other age-related clinical factors within and among families affected by ATTRv amyloidosis. METHODS: We analysed information from 934 trees, focusing on family, parents, probands and siblings relationships. We focused on 1494 female and 1712 male symptomatic ATTRV30M patients. Results are presented alongside a comparison of current with historical records. Clinical and genealogical indicators identify major changes. RESULTS: Overall, analysis of familial data shows the existence of families with both early and late patients (1/6). It identifies long familial follow-up times since patient families tend to be diagnosed over several years. Finally, results show a large difference between parent-child and proband-patient relationships (20-30 years). CONCLUSIONS: This study reveals that there has been a shift in patient profile, with a recent increase in male elderly cases, especially regarding probands. It shows that symptomatic patients exhibit less variability towards siblings, when compared to other family members, namely the transmitting ancestors' age of onset. This can influence genetic counselling guidelines.

Real-World Evidence of the Long-Term Effectiveness of 0.2 µg/Day Fluocinolone Acetonide Implant in Persistent and Recurrent Diabetic Macular Edema - A Single Center Study.

Purpose: To report the long-term functional, anatomical and safety outcomes of 0.2 µg/day fluocinolone acetonide 0.19mg in patients with persistent or recurrent diabetic macular edema (DME). Methods: Retrospective, observational, single-center study of patients with recurrent or persistent DME. All patients received 0.2 µg/day of fluocinolone acetonide 0.19mg, and data were collected at baseline and months 1, 3, 6, 12, 24 and 36 after implantation. Outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), and safety outcomes. Results: A total of 28 eyes from 28 patients were included. The mean age was 66.5 years (95% CI 62.8-70.2) with a mean duration of DME of 8.8 years (95% CI 7.7-10.0). Only two eyes were phakic. Mean follow-up was 25.4 months (95% CI 21.2-29.6). Mean BCVA at baseline was 48.6 ETDRS letters (95% CI 41.3-55.8) and improved as early as month 1 of follow-up with a mean gain in BCVA of 7.8 (95% CI 4.3-11.3) ETDRS letters (p<0.001). Statistically significant improvements in BCVA were also observed at months 6, 12 and 24. At baseline, patients had a mean CMT of 530.5µm (95% CI 463.0-598.0), and a decrease in CMT was observed, starting at the first month of follow-up (mean CMT reduction of -170.5µm, 95% CI -223.8- -117.1; p<0.001). Statistically significant decreases in CMT were also observed at months 6, 12, 24, and 36, with the maximum decrease observed at month 12 (p<0.001). Mean IOP at baseline was 16.4mmHg (95% CI 15.3-17.5) and nine eyes (32.1%) had an IOP ≥21mmHg during follow-up. Conclusion: Our results support the effectiveness and safety profile of fluocinolone acetonide. Although additional long-term real-world evidence is required, fluocinolone acetonide may represent a safe strategy for daily, low-dose, sustained and localized release to the posterior segment of the eye, providing both functional and anatomical benefits in DME.

Novel method for chlorine determination in biofuel lipid feedstock by coupling a total sample introduction system (hTISIS) to an inductively coupled plasma tandem mass spectrometry (ICP-MS/MS).

BACKGROUND: Chlorine concentrations above 1 mg kg-1 in lipid feedstocks for biofuel production can generate corrosion issues in the different refining units as well as catalyst deactivation by clogging or fouling. To reach accurate analyses by inductively coupled plasma (ICP) techniques at low concentration levels, dilution in organic solvents rises as a simpler and more straightforward sample preparation methodology than conventional sample decomposition procedures (e.g., microwave-assisted acid digestion). However, matrix effects and the impact of the Cl chemical form on the signal must be overcome to obtain accurate results. RESULTS: In this work, the high temperature torch integrated sample introduction system (hTISIS) operated at 350 °C is coupled to an inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) for the determination of Cl in lipid biofuel feedstock samples diluted in xylene and these results are compared with those reported by a conventional sample introduction system. Under optimal conditions of the hTISIS-ICP-MS/MS configuration, matrix effects are efficiently overcome (recovery values ranged from 101 to 104%) as well as the effect of the Cl chemical form on the signal for 6 organochloride compounds. Thus, an external calibration approach can be set to carry out the quantification of this element in real samples. The method is successfully validated, obtaining a good agreement in the Cl concentration reported in a standard reference material (SRM NIST 1634c) and also by comparing the concentration results obtained by external calibration and standard addition approaches in two biofuel feedstock samples. SIGNIFICANCE AND NOVELTY: The hTISIS coupled to an ICP-MS/MS system is used for the first time to overcome not only matrix effects but also the impact of the Cl chemical form in biofuel feedstock samples. This novel method, with a limit of quantification (LOQ) of 7.1 µg kg-1, give access to an accurate Cl determination in all kind of lipid feedstocks for clean fuel production.

Treatment strategies and treatment-related adverse events in MG according to the age of onset.

Introduction: Early-onset (EOMG) and late-onset (LOMG) are distinct groups of MG patients. It is unclear if treatment strategies and treatment-related adverse events may differ according to the age of MG onset. Methods: This single-center retrospective study includes all MG patients followed at a tertiary center since 2007. We reviewed the electronic clinical records. Results: In total, 212 patients were identified, 142 (67.0%) females, with a median disease duration of 10 years. The median age of symptom onset was 42.0 (26.0-64.5) years, with 130 (61.3%) EOMG cases and 82 (38.7%) LOMG. EOMG were more frequently female, had longer disease duration and often more generalized MG (p < 0.001). Comorbidities were significantly more frequent in LOMG (67.1%) compared to EOMG (53.1%) (p = 0.002). Steroid-related adverse effects motivating the switch to steroid-sparing agents (82.0%) were different between groups, with hypertension, hypercholesterolemia, diabetes mellitus and malignancies being more common in LOMG. At the same time, osteoporosis and dyspepsia were more frequent in EOMG (p < 0.001). The most common first-line choice was azathioprine (45.8%), and rituximab was used in 4 patients (1.9%). Conclusion: Our study shows that treatment modalities are similar between EOMG and LOMG, while steroid-related adverse events appear to be distinct.

Squid meal and shrimp hydrolysate as novel protein sources for dog food.

The world's growing pet population is raising sustainability and environmental concerns for the petfood industry. Protein-rich marine by-products might contribute to mitigating negative environmental effects, decreasing waste, and improving economic efficiency. The present study evaluated two marine by-products, squid meal and shrimp hydrolysate, as novel protein sources for dog feeding. Along with the analysis of chemical composition and antioxidant activity, palatability was evaluated by comparing a commercial diet (basal diet) and diets with the inclusion of 150 g kg-1 of squid meal or shrimp hydrolysate using 12 Beagle dogs (2.2 ± 0.03 years). Two in vivo digestibility trials were conducted with six dogs, three experimental periods (10 days each) and three dietary inclusion levels (50, 100 and 150 g kg-1) of squid meal or shrimp hydrolysate in place of the basal diet to evaluate effects of inclusion level on apparent total tract digestibility (ATTD), metabolizable energy content, fecal characteristics, metabolites, and microbiota. Both protein sources presented higher protein and methionine contents than ingredients traditionally used in dog food formulation. Shrimp hydrolysate showed higher antioxidant activity than squid meal. First approach and taste were not affected by the inclusion of protein sources, but animals showed a preference for the basal diet. Effects on nutrient intake reflected the chemical composition of diets, and fecal output and characteristics were not affected by the increasing inclusion levels of both protein sources. The higher ATTD of dry matter, most nutrients and energy of diets with the inclusion of both by-products when compared to the basal diet, suggests their potential to be included in highly digestible diets for dogs. Although not affected by the inclusion level of protein sources, when compared to the basal diet, the inclusion of squid meal decreased butyrate concentration and shrimp hydrolysate increased all volatile fatty acids, except butyrate. Fecal microbiota was not affected by squid meal inclusion, whereas inclusion levels of shrimp hydrolysate significantly affected abundances of Oscillosperaceae (UCG-005), Firmicutes and Lactobacillus. Overall, results suggest that squid meal and shrimp hydrolysate constitute novel and promising protein sources for dog food, but further research is needed to fully evaluate their functional value.

Measurement Invariance of the Multidimensional Jealousy Scale and Quality of Relationships Inventory (Friend).

The aim of this study is to measure the invariance of the Multidimensional Jealousy Scale (MJS) and of the Quality of Relationships Inventory (Friend) (QRI-F) across gender, age, education, and being in a romantic relationship in a Portuguese sample (N = 662). A confirmatory factor analysis was performed to test the fit of different potential factor structures. The results pointed out that both MJS and QRI-F were most suitable if represented by three first-order factors correlated between them. Results from multi-group analyses suggested there was factorial invariance for these structures across groups, suggesting that the MJS and the QRI-F provide, respectively, an assessment of romantic jealousy and quality of relationship that are equivalent across gender, age, education, and being in a romantic relationship. The study established the strong psychometric properties of its instruments, validating reliability and convergent and discriminant validity, thereby bolstering the research's overall credibility. Additionally, cognitive jealousy is primarily influenced by heightened conflict values, with education, relationship status, and gender moderating the associations between QRI-F dimensions and MJS behavioral and cognitive jealousy. The research offered in-depth perspectives on jealousy, underscoring its diverse manifestations across demographic variables and illuminating the complexities within the dynamics of friendships.

Discrepancies among equations to estimate the glomerular filtration rate for drug dosing decision making in aged patients: a cross sectional study.

BACKGROUND: Patients often require adjustments to drug doses due to impaired renal function. Glomerular filtration rate (GFR) estimation using various equations can result in discrepancies, potentially leading to different dose adjustment recommendations. AIM: To determine the clinical significance of discrepancies observed between different equations used to estimate GFR for drug dose adjustments in a real-world group of patients over 65 years in primary care. METHOD: The Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Berlin Initiative Study 1 equations were applied to estimate GFR in a group of patients over 65 years old attending a primary care center. Results were compared using Bland-Altman plots, and limits of agreement (LoA) and overall bias were calculated. Regression analyses were conducted to identify the null difference GFR and the slope of differences for each pairwise comparison. RESULTS: A total of 1886 patients were analyzed. Differences between patient-adjusted and body surface area (BSA)-normalized versions of the equations were not clinically relevant for dose adjustments, with LoAs below 20 mL/min. However, discrepancies among the original versions of several equations presented LoAs over 30 mL/min. Greater differences were found between CG and MDRD or CKD-EPI equations. CONCLUSION: Clinically relevant differences in GFR estimation were observed among different equations, potentially impacting drug dose adjustments. However, discrepancies were not considered significant when comparing patient-adjusted and BSA-normalized versions of the equations, particularly for patients with BSA close to the average.

Key factors for effective implementation of healthcare workers support interventions after patient safety incidents in health organisations: a scoping review.

OBJECTIVES: This study aims to map and frame the main factors present in support interventions successfully implemented in health organisations in order to provide timely and adequate response to healthcare workers (HCWs) after patient safety incidents (PSIs). DESIGN: Scoping review guided by the six-stage approach proposed by Arksey and O'Malley and by PRISMA-ScR. DATA SOURCES: CINAHL, Cochrane Library, Embase, Epistemonikos, PsycINFO, PubMed, SciELO Citation Index, Scopus, Web of Science Core Collection, reference lists of the eligible articles, websites and a consultation group. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Empirical studies (original articles) were prioritised. We used the Mixed Methods Appraisal Tool Version 2018 to conduct a quality assessment of the eligible studies. DATA EXTRACTION AND SYNTHESIS: A total of 9766 records were retrieved (last update in November 2022). We assessed 156 articles for eligibility in the full-text screening. Of these, 29 earticles met the eligibility criteria. The articles were independently screened by two authors. In the case of disagreement, a third author was involved. The collected data were organised according to the Organisational factors, People, Environment, Recommendations from other Audies, Attributes of the support interventions. We used EndNote to import articles from the databases and Rayyan to support the screening of titles and abstracts. RESULTS: The existence of an organisational culture based on principles of trust and non-judgement, multidisciplinary action, leadership engagement and strong dissemination of the support programmes' were crucial factors for their effective implementation. Training should be provided for peer supporters and leaders to facilitate the response to HCWs' needs. Regular communication among the implementation team, allocation of protected time, funding and continuous monitoring are useful elements to the sustainability of the programmes. CONCLUSION: HCWs' well-being depends on an adequate implementation of a complex group of interrelated factors to support them after PSIs.

Chronic Intermittent Hypoxia-Induced Dysmetabolism Is Associated with Hepatic Oxidative Stress, Mitochondrial Dysfunction and Inflammation.

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O2) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.

Effects of microalgae as dietary supplement on palatability, digestibility, fecal metabolites, and microbiota in healthy dogs.

The current trend of dog owners increasingly favoring the functional value of food to assure preventive health and wellbeing of their pets has been raising the interest in microalgae as natural additives with bioactive properties. However, scientific studies addressing the effects of microalgae supplementation in diets for dogs are scarce. This study aimed to evaluate the effects of dietary supplementation with three microalgae species (Chlorella vulgaris, Nannochloropsis oceanica, and Tetradesmus obliquus) on diet palatability, total tract digestibility, metabolizable energy content, fecal metabolites and microbiota of dogs. Twelve adult Beagle dogs were used in three two-bowl tests to compare the palatability of a commercial complete diet for adult dogs without (reference diet) and with 1.5% supplementation of each microalgae. From the results obtained, three digestibility trials were performed according to a replicated Latin square 3 × 3, with six adult Beagle dogs, three experimental periods of 10 days each, and three dietary supplementation levels of microalgae (0.5, 1.0, and 1.5%). In each trial, effects of microalgae supplementation levels on total tract digestibility, metabolizable energy content, fecal metabolites and microbiota of dogs were evaluated. First diet approached or tasted was not significantly affected by microalgae inclusion, but dogs showed a preference for the reference diet over the diets with 1.5% inclusion of C. vulgaris and N. oceanica, no difference being observed with 1.5% T. obliquus. In all digestibility trials, dietary supplementation with microalgae up to 1.5% did not greatly affected the dietary chemical composition and kept unaffected food intake, fecal output and metabolites, and digestibility of nutrients and energy. Compared with the reference diet, supplementation with C. vulgaris increased protein digestibility. Fecal characteristics and metabolites were affected by microalgae supplementation, being the effects dependent on the species. Fecal microbiota composition of dogs fed with microalgae-supplemented diets was modified by promoting the beneficial Turicibacter and Peptococcus genera associated with gut health and activation of the immune system. Overall, the results support C. vulgaris, N. oceanica, and T. obliquus as sustainable functional supplements that potentially enhance gastrointestinal health of dogs through the selective stimulation of microbiota without detrimental effects on food intake and digestibility.

Idiopathic acute exudative polymorphous vitelliform maculopathy: the importance of multimodal imaging, systemic workup and genetic testing.

The authors describe a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) in an otherwise healthy man in his 60s complaining of subacute bilateral blurred vision. At examination, best-corrected visual acuity was 20/32 in the right eye and 20/40 in the left eye. Bilateral central large serous detachments with inferior meniscus-like deposition of a vitelliform-like material were observed at funduscopy and confirmed by spectral-domain optical coherence tomography. Small vitelliform-like lesions along the temporal superior vascular arcades were also seen. The lesions with vitelliform appearance appeared hyperautofluorescent on fundus autofluorescence. A complete systemic workup and genetic testing were performed and the diagnosis of idiopathic AEPVM was established. Six months later, a complete resolution of the lesions was observed.

Thermal tolerance limits and physiological traits as indicators of Hediste diversicolor's acclimation capacity to global and local change drivers.

Global projections predict significant increases in ocean temperature and changes in ocean chemistry, including salinity variations by 2100. This has led to a substantial interest in the study of thermal ecophysiology, as temperature is a major factor shaping marine ectotherm communities. However, responses to temperature may be influenced by other factors such as salinity, highlighting the relevance of multiple stressor studies. In the present work, we experimentally evaluated the thermal tolerance of the marine ragworm Hediste diversicolor under predicted global change scenarios. Organisms were subjected to an experimental trial under control (24 °C), and two temperature treatment scenarios (ocean warming +3 °C - (27 °C) and heat wave +6 °C - (30 °C)), combined with salinity variations (20 and 30) in a full factorial design for 29 days. Environmental data from the field were collected during 2019 and 2020. At day 30 post exposure, upper thermal limits (Critical Thermal Maximum - CTMax), thermal safety margins (TSM) and acclimation capacity were measured. Higher acclimation temperatures led to higher thermal tolerance limits, confirming that H. diversicolor features some physiological plasticity, acclimation capacity and a positive thermal safety margin. This margin was greater considering in situ temperature data from 2019 than maximum temperatures for 2020 (CTMax > maximum habitat temperature-MHT). Moreover, smaller organisms displayed higher upper thermal limits suggesting that thermal tolerance is size dependent. Ragworms subjected to higher salinity also showed a higher CTMax than those acclimated to lower salinity. However, temperature and salinity showed an additive effect on CTMax, as no significant interaction was detected. We conclude that H. diversicolor can easily acclimate to increased water temperature, independently of salinity variations. Given the key role of ragworms in food webs in estuaries and coastal lagoons, substrate bioturbation and aquaculture, this information is relevant to support conservation actions, optimize culture protocols and identify thermal resistant strains.

Automated macular segmentation can distinguish glaucomatous from compressive optic neuropathy.

PURPOSE: To compare macular damage in glaucomatous optic neuropathy (GON) and compressive optic neuropathy (CON) and assess its diagnostic accuracy in distinguishing between diseases. METHODS: Observational, cross-sectional, single-center study. Patients with GON, CON, and healthy controls were included according to the eligibility criteria. An automated spectral-domain optical coherence tomography (SD-OCT) algorithm was used to segment the circumpapilary retinal nerve fiber layer (cpRNFL) and macula. The layer thickness was measured in each sector according to the Early Treatment Diabetic Retinopathy Study and the 6-sector Garway-Heath-based grids. Data was compared across all study groups, and the significance level was set at 0.05. RESULTS: Seventy-five eyes of 75 participants, 25 with GON, 25 with CON, and 25 healthy controls (CG), were included. Macular thickness was diminished in the ganglion cell complex of GON and CON patients compared to CG (p<0.05). The best Garway-Heath-based grid parameters for distinguishing GON and CON were the nasal-inferior (NI) and nasal-superior sectors and the NI/temporal inferior (TI) damage ratios in the macular ganglion cell (mGCL) and inner plexiform (IPL) layers. Moreover, the combination of the NI sector and NI/TI damage ratios in both layers had higher discriminative power (AUC 0.909; 95% CI 0.830-0.988; p<0.001) than combining parameters in each layer separately. CONCLUSION: Our findings suggest that the evaluation of macular segmented layers damage by SD-OCT may be a helpful add-on tool in the differential diagnosis between GON and CON.

Effect of depression and anxiety on sexual functioning in couples trying to conceive with and without an infertility diagnosis.

OBJECTIVE: This study examined the effects of anxiety and depression on sexual functioning in couples trying to conceive, and tested the moderating role of infertility diagnosis on this association. DESIGN: An online questionnaire was completed by 1453 individuals in a heterosexual relationship for more than one year. The final sample had 107 couples who were actively attempting a pregnancy (63 had an infertility diagnosis; 44 were presumably fertile). Data was analyzed with the Actor-Partner Interdependence Model (APIM). MAIN OUTCOME MEASURES: Depression and anxiety symptoms were assessed by the Hospital Anxiety and Depression Scale (HADS), and male and female sexual functioning were assessed through the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI), respectively. RESULTS: Actor effects were found between depression and sexual functioning in both men (ß= -.28, p= .003) and women (ß= -.43, p < .001), with no significant partner effects. The moderation analysis showed that the relationship between depression and sexual functioning is stronger in infertile men than in presumably fertile men (ß= -.29; p= .002). CONCLUSION: Psychological interventions with couples trying to conceive should address the role of depression in sexual functioning, particularly in infertile men.

Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant.

BACKGROUND: Cognitive dysfunction is part of the broad spectrum of clinical manifestations in older untreated hereditary transthyretin amyloidosis patients with peripheral polyneuropathy. OBJECTIVE: The objective of this study is to systematically explore cognitive dysfunction in ATTRV30M amyloidosis patients whose disease course was modified by liver transplant (LT). METHODS: A series of 269 carriers of TTRVal30Met mutation treated with LT underwent a neuropsychological assessment. Clinical charts were reviewed to identify focal neurological episodes (FNEs), cognitive complaints and laboratory results. Chi-square and Mann-Whitney tests explored potential predictors of cognitive dysfunction. RESULTS: Cognitive dysfunction was identified in 35 patients (13%)-14 (5%) had mild and 21 (8%) had moderate dysfunction. In comparison to normal cognition, both mild and moderate cognitive dysfunction patients had older age, higher mPND score and elevated NT-proBNP and Cystatin C values. Mild cognitive dysfunction was associated with longer disease duration and history of FNEs, whereas moderate dysfunction was related to older age at disease onset and more cognitive complaints and depression symptoms. CONCLUSIONS: Consistent with the natural history of the disease, older age and higher severity of the disease are significantly associated and potentially predictors of cognitive dysfunction in ATTRV30M patients treated with LT. The level of cognitive dysfunction may depend on some clinical variables.

Tafamidis polyneuropathy amelioration requires modest increases in transthyretin stability even though increases in plasma native TTR and decreases in non-native TTR do not predict response.

BACKGROUND: TTR aggregation causes hereditary transthyretin (TTR) polyneuropathy (ATTRv-PN) in individuals with destabilised TTR variants. ATTRv-PN can be treated with ligands that bind TTR and prevent aggregation. One such ligand, tafamidis, is widely approved to treat ATTRv-PN. We explore how TTR stabilisation markers relate to clinical efficacy in 210 ATTRv-PN patients taking tafamidis. METHODS: TTR concentration in patient plasma was measured before and after tafamidis treatment using assays for native or combined native + non-native TTR. TTR tetramer dissociation kinetics, which are slowed by tafamidis binding, were also measured. RESULTS: Native TTR levels increased by 56.8% while combined native + non-native TTR levels increased by 3.1% after 24 months of tafamidis treatment, implying that non-native TTR decreased. Accordingly, the fraction of native TTR increased from 0.54 to 0.71 with tafamidis administration. Changes in native and non-native TTR levels were uncorrelated with clinical response to tafamidis. TTR tetramer dissociation generally slowed to an extent consistent with ∼40% of TTR being tafamidis-bound. Male non-responders had a lower extent of binding. CONCLUSIONS: Native and non-native TTR concentration changes cannot be used as surrogate measures for therapeutic efficacy. Also, successful tafamidis therapy requires only moderate TTR stabilisation. Male patients may benefit from higher tafamidis doses.

ß-Lactam Dosing in Critical Patients: A Narrative Review of Optimal Efficacy and the Prevention of Resistance and Toxicity.

Antimicrobial prescription in critically ill patients represents a complex challenge due to the difficult balance between infection treatment and toxicity prevention. Underexposure to antibiotics and therapeutic failure or, conversely, drug overexposure and toxicity may both contribute to a worse prognosis. Moreover, changes in organ perfusion and dysfunction often lead to unpredictable pharmacokinetics. In critically ill patients, interindividual and intraindividual real-time ß-lactam antibiotic dose adjustments according to the patient's condition are critical. The continuous infusion of ß-lactams and the therapeutic monitoring of their concentration have both been proposed to improve their efficacy, but strong data to support their use are still lacking. The knowledge of the pharmacokinetic/pharmacodynamic targets is poor and is mostly based on observational data. In patients with renal or hepatic failure, selecting the right dose is even more tricky due to changes in drug clearance, distribution, and the use of extracorporeal circuits. Intermittent usage may further increase the dosing conundrum. Recent data have emerged linking overexposure to ß-lactams to central nervous system toxicity, mitochondrial recovery delay, and microbiome changes. In addition, it is well recognized that ß-lactam exposure facilitates resistance selection and that correct dosing can help to overcome it. In this review, we discuss recent data regarding real-time ß-lactam antibiotic dose adjustment, options in special populations, and the impacts on mitochondria and the microbiome.