Lobectomy in patients with differentiated thyroid cancer: experience of a Chilean tertiary center.

PURPOSE: Thyroid lobectomy (TL) is an appropriate treatment for up to 4 cm intrathyroidal differentiated thyroid cancer (DTC). There is scarce data regarding TL outside first-world centers. Our aim is to report a cohort of patients with DTC treated with TL in Chile. METHODS: We included DTC patients treated with TL, followed for at least 6 months, characterized their clinicopathological features and classified their risk of recurrence and response to treatment. RESULTS: Eighty-two patients followed for a median of 2.3 years (0.5-7.0). Seventy-three (89%) patients had papillary, 8 (9.8%) follicular and 1 (1.2%) high-grade DTC. The risk of recurrence was low in 56 (68.3%) and intermediate in 26 (31.7%). Eight (9.8%) patients required early completion thyroidectomy and radioiodine. At last follow-up, 52 (70.3%) had excellent, 19 (25.7%) had indeterminate, and 1 (1.4%) had structural incomplete response. CONCLUSION: In a developing country, TL is an adequate option for appropriately selected DTC patients.

ß-lactam-induced OMV release promotes polymyxin tolerance in Salmonella enterica sv. Typhi.

The rise of multidrug-resistant bacteria is a global concern, leading to a renewed reliance on older antibiotics like polymyxins as a last resort. Polymyxins, cationic cyclic peptides synthesized nonribosomally, feature a hydrophobic acyl tail and positively charged residues. Their antimicrobial mechanism involves initial interaction with Gram-negative bacterial outer-membrane components through polar and hydrophobic interactions. Outer membrane vesicles (OMVs), nano-sized proteoliposomes secreted from the outer membrane of Gram-negative bacteria, play a crucial role in tolerating harmful molecules, including cationic peptides such as polymyxins. Existing literature has documented environmental changes' impact on modulating OMV properties in Salmonella Typhimurium. However, less information exists regarding OMV production and characteristics in Salmonella Typhi. A previous study in our laboratory showed that S. Typhi ΔmrcB, a mutant associated with penicillin-binding protein (PBP, a ß-lactam antibiotic target), exhibited hypervesiculation. Consequently, this study investigated the potential impact of ß-lactam antibiotics on promoting polymyxin tolerance via OMVs in S. Typhi. Our results demonstrated that sub-lethal doses of ß-lactams increased bacterial survival against polymyxin B in S. Typhi. This phenomenon stems from ß-lactam antibiotics inducing hypervesiculation of OMVs with higher affinity for polymyxin B, capturing and diminishing its biologically effective concentration. These findings suggest that ß-lactam antibiotic use may inadvertently contribute to decreased polymyxin effectivity against S. Typhi or other Gram-negative bacteria, complicating the effective treatment of infections caused by these pathogens. This study emphasizes the importance of evaluating the influence of ß-lactam antibiotics on the interaction between OMVs and other antimicrobial agents.

Single-cell RNA sequencing identifies senescence as therapeutic target in rhabdomyolysis-induced acute kidney injury.

BACKGROUND: The role of macrophages in the development of rhabdomyolysis-induced acute kidney injury (RM-AKI) has been established, but an in-depth understanding of the changes in the immune landscape could help to improve targeted strategies. Whereas senescence is usually associated with chronic kidney processes, we also wished to explore whether senescence could also occur in AKI and whether senolytics could act on immune cells. METHODS: Single-cell RNA sequencing was used in the murine glycerol-induced RM-AKI model to dissect the transcriptomic characteristics of CD45+ live cells sorted from kidneys 2 days after injury. Public datasets from murine AKI models were reanalysed to explore cellular senescence signature in tubular epithelial cells (TECs). A combination of senolytics (dasatinib and quercetin, DQ) was administered to mice exposed or not to RM-AKI. RESULTS: Unsupervised clustering of nearly 17 000 single-cell transcriptomes identified seven known immune cell clusters. Sub-clustering of the mononuclear phagocyte cells revealed nine distinct cell sub-populations differently modified with RM. One macrophage cluster was particularly interesting since it behaved as a critical node in a trajectory connecting one major histocompatibility complex class IIhigh (MHCIIhigh) cluster only present in Control to two MHCIIlow clusters only present in RM-AKI. This critical cluster expressed a senescence gene signature, that was very different from that of the TECs. Senolytic DQ treatment blocked the switch from a F4/80highCD11blow to F4/80lowCD11bhigh phenotype, which correlated with prolonged nephroprotection in RM-AKI. CONCLUSIONS: Single-cell RNA sequencing unmasked novel transitional macrophage subpopulation associated with RM-AKI characterized by the activation of cellular senescence processes. This work provides a proof-of-concept that senolytics nephroprotective effects may rely, at least in part, on subtle immune modulation.

Integrated multimodal artificial intelligence framework for healthcare applications.

Artificial intelligence (AI) systems hold great promise to improve healthcare over the next decades. Specifically, AI systems leveraging multiple data sources and input modalities are poised to become a viable method to deliver more accurate results and deployable pipelines across a wide range of applications. In this work, we propose and evaluate a unified Holistic AI in Medicine (HAIM) framework to facilitate the generation and testing of AI systems that leverage multimodal inputs. Our approach uses generalizable data pre-processing and machine learning modeling stages that can be readily adapted for research and deployment in healthcare environments. We evaluate our HAIM framework by training and characterizing 14,324 independent models based on HAIM-MIMIC-MM, a multimodal clinical database (N = 34,537 samples) containing 7279 unique hospitalizations and 6485 patients, spanning all possible input combinations of 4 data modalities (i.e., tabular, time-series, text, and images), 11 unique data sources and 12 predictive tasks. We show that this framework can consistently and robustly produce models that outperform similar single-source approaches across various healthcare demonstrations (by 6-33%), including 10 distinct chest pathology diagnoses, along with length-of-stay and 48 h mortality predictions. We also quantify the contribution of each modality and data source using Shapley values, which demonstrates the heterogeneity in data modality importance and the necessity of multimodal inputs across different healthcare-relevant tasks. The generalizable properties and flexibility of our Holistic AI in Medicine (HAIM) framework could offer a promising pathway for future multimodal predictive systems in clinical and operational healthcare settings.

Potential use of n-3 PUFAs to prevent oxidative stress-derived ototoxicity caused by platinum-based chemotherapy.

Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.

Improving Clinical Outcomes in Cochlear Implantation Using Glucocorticoid Therapy: A Review.

Cochlear implant surgery is a successful procedure for auditory rehabilitation of patients with severe to profound hearing loss. However, cochlear implantation may lead to damage to the inner ear, which decreases residual hearing and alters vestibular function. It is now of increasing interest to preserve residual hearing during this surgery because this is related to better speech, music perception, and hearing in complex listening environments. Thus, different efforts have been tried to reduce cochlear implantation-related injury, including periprocedural glucocorticoids because of their anti-inflammatory properties. Different routes of administration have been tried to deliver glucocorticoids. However, several drawbacks still remain, including their systemic side effects, unknown pharmacokinetic profiles, and complex delivery methods. In the present review, we discuss the role of periprocedural glucocorticoid therapy to decrease cochlear implantation-related injury, thus preserving inner ear function after surgery. Moreover, we highlight the pharmacokinetic evidence and clinical outcomes which would sustain further interventions.

Relationship between infarct size and serum uric acid levels during the acute phase of stroke.

INTRODUCTION: Uric acid has gained considerable attention as a potential neuroprotective agent in stroke during the last decades, however, its role in the pathophysiology of ischemic stroke remains poorly understood. A serial evaluation of uric acid levels during the acute phase of stroke and its association with infarct size on magnetic resonance imaging is lacking. METHODS: We present a cohort study of 31 patients with ischemic stroke who were not candidates for thrombolysis according to current criteria at the time. We performed daily measurements of serum uric acid and total antioxidant capacity of plasma during the first week after symptoms onset and 30 days after. Infarct size was determined in the acute phase by a DWI sequence and the final infarct size with a control MRI (FLAIR) at day 30. RESULTS: Uric acid significantly decreases between days 2 to 6 compared to day 1, after adjustment by sex, age and DWI at diagnosis, with a nadir value at 72h. A mixed model analysis showed a negative association between DWI at diagnosis and uric acid evolution during the first week after stroke. Moreover, multivariable linear regression of uric acid values during follow up on DWI volumes demonstrated that DWI volume at diagnosis is negatively associated with uric acid levels at day 3 and 4. There were no significant associations between total antioxidant capacity of plasma and DWI at diagnosis, or FLAIR at any point. DISCUSSION: Patients with larger infarcts exhibited a significant decrease in serum uric acid levels, accounting for a more prominent reactive oxygen species scavenging activity with subsequent consumption and decay of this antioxidant. The different kinetics of total antioxidant capacity of plasma and serum uric acid levels suggests a specific role of uric acid in the antioxidant response in ischemic stroke.

Clomiphene citrate treatment for late onset hypogonadism: rise and fall

ABSTRACT Objective: Previous series have demonstrated that Clomiphene Citrate (CC) is an effective treatment to increase Total Testosterone (TT) in Late Onset Hypogonadism (LOH) patients. However, what happens to TT levels after ending CC treatment is still debatable. The objective of this study is to evaluate TT levels 3 months after the discontinuation of CC in patients with LOH who were previously successfully treated with the same drug. Materials and Methods: Twenty-seven patients with LOH that were successfully treated (achieved TT levels >11nmol/l) with CC 50mgs daily for 50 days were prospectively recruited in our Andrological outpatient clinic. CC was then stopped for 3 months and TT levels were measured at the end of this period. Results: Mean TT level before discontinuation of CC was 22.7±8.1nmol/L (mean±SD). Three months after discontinuation, mean TT level significantly decreased in all patients, 10.2±3.9nmol/l (p<0.01). Twenty-one patients (78%) decreased TT levels under 11nmol/L. Six patients (22%) had TT levels that remained within the normal recommended range (≥11nmol/l). No statistical significant differences were observed between both groups. Conclusion: In the short term LOH does not seem to be a reversible condition in most patients after CC treatment. More studies with longer follow-up are needed to evaluate the kinetics of TT in LOH.

Clomiphene citrate treatment for late onset hypogonadism: rise and fall.

OBJECTIVE: Previous series have demonstrated that Clomiphene Citrate (CC) is an effective treatment to increase Total Testosterone (TT) in Late Onset Hypogonadism (LOH) patients. However, what happens to TT levels after ending CC treatment is still debatable. The objective of this study is to evaluate TT levels 3 months after the discontinuation of CC in patients with LOH who were previously successfully treated with the same drug. MATERIALS AND METHODS: Twenty-seven patients with LOH that were successfully treated (achieved TT levels >11nmol/l) with CC 50mgs daily for 50 days were prospectively recruited in our Andrological outpatient clinic. CC was then stopped for 3 months and TT levels were measured at the end of this period. RESULTS: Mean TT level before discontinuation of CC was 22.7±8.1nmol/L (mean±SD). Three months after discontinuation, mean TT level significantly decreased in all pa¬tients, 10.2±3.9nmol/l (p < 0.01). Twenty-one patients (78%) decreased TT levels under 11nmol/L. Six patients (22%) had TT levels that remained within the normal recommended range (≥11nmol/l). No statistical significant differences were observed between both groups. CONCLUSION: In the short term LOH does not seem to be a reversible condition in most patients after CC treatment. More studies with longer follow-up are needed to evaluate the kinetics of TT in LOH.

Capacity of the aquatic fern (Salvinia minima Baker) to accumulate high concentrations of nickel in its tissues, and its effect on plant physiological processes.

An experiment was designed to assess the capacity of Salvinia minima Baker to uptake and accumulate nickel in its tissues and to evaluate whether or not this uptake can affect its physiology. Our results suggest that S. minima plants are able to take up high amounts of nickel in its tissues, particularly in roots. In fact, our results support the idea that S. minima might be considered a hyper-accumulator of nickel, as it is able to accumulate 16.3 mg g(-1) (whole plant DW basis). Our results also showed a two-steps uptake pattern of nickel, with a fast uptake of nickel at the first 6 to 12h of being expose to the metal, followed by a slow take up phase until the end of the experiment at 144 h. S. minima thus, may be considered as a fern useful in the phytoremediation of residual water bodies contaminated with this metal. Also from our results, S. minima can tolerate fair concentrations of the metal; however, at concentrations higher than 80 µM Ni (1.5 mg g(-1) internal nickel concentration), its physiological performance can be affected. For instance, the integrity of cell membranes was affected as the metal concentration and exposure time increased. The accumulation of high concentrations of internal nickel did also affect photosynthesis, the efficiency of PSII, and the concentration of photosynthetic pigments, although at a lower extent.