The impact of extratropical transition (ET) on tropical cyclone (TC) tornadoes is not fully understood with no prior tornado climatologies for ET cases. Hence, this study investigates how ET impacts tornadoes and convective-scale environments within TCs using multidecadal tornado and radiosonde data from North Atlantic TCs. This study divides ET into three phases: tropical (i.e., pre-ET), transition (i.e., during ET), and extratropical (i.e., post-ET). These results show that the largest portion of tornadoes occur before and during ET, with the greatest frequencies during ET. As TCs undergo and complete ET, tornadoes tend to shift geographically north and east, farther south or more strongly downshear right relative to the TC center, occur later in the day, and are more likely to be associated with greater damage. Evaluation of radiosondes showed that the downshear right quadrant of the TC is frequently the most favorable for tornado production, having the best combination of entrainment CAPE (ECAPE) and storm-relative helicity (SRH) values. Specifically, the downshear right quadrant shows slower decreases in ECAPE (associated with large-scale cooling/drying) and increased low-level shear/SRH through ET, relative to quadrants left of the deeptropospheric (i.e.., 850-200-hPa) vertical wind shear vector. These results have ramifications for the physical model and prediction of ET-related TC evolution, both in terms of their environment and subsequent hazard production Suggested Reviewers:

Effect of the interaction between negative life events and brain-derived neurotrophic factor rs6265 polymorphism on adolescent Internet gaming disorder

Title PageThiamine Deficiency and Refractory Shock: A Case Report Followed by a Literature ReviewYunyan Jing1; Bin Ni2; Hui Wang1; Ju Lin1; Linan Zhang1, Leqing Lin1*1: Department of Critical Care Medicine, Hangzhou Normal University Affiliated Hospital, #126 Wenzhou Road, Hangzhou, Zhejiang Province, 310000 China;2: Department of Cardiovascular Medicine, Hangzhou Normal University Affiliated Hospital, #126 Wenzhou Road, Hangzhou, Zhejiang Province, 310000 China;*Corresponding author: Leqing LinDepartment of Critical Care Medicine, Hangzhou Normal University Affiliated Hospital, Zhejiang province, China.Adress: #126 Wenzhou Road, Hangzhou, Zhejiang province, 310000 China.Tel: +86-13305710671. E-mail: happylin67@126.com. DRCID: 0009-0006-5941-8585.This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.The other authors’ emails:Yunyan Jing:jyy@hznu.edu.cn;Bin Ni: 20161102012011@hznu.edu.cn;Hui Wang: whk598@163.com;Ju Lin: 79238526@qq.com;Linan Zhang: zhanglinan1218@sina.com.Thiamine Deficiency and Refractory Shock: A Case Report Followed by a Literature ReviewKEYWORDScase report; thiamine deficiency; refractory shock; social withdrawal syndrome; metabolic resuscitation1. INTRODUCTIONThiamine (vitamin B1) is an essential nutrient that plays a critical role in glucose metabolism and the proper functioning of the cardiovascular, nervous, and other systems. A deficiency in thiamine can lead to various health issues, including dry beriberi, wet beriberi, and Wernicke encephalopathy(1). Among these, wet beriberi is a serious disease mainly characterized by damage to the cardiovascular system and can be manifested as acute flare-ups or chronic episodes(1). A fulminant form of wet beriberi is also known as ”Shoshin beriberi”, which is a rare and rapidly progressing condition that can cause death within hours or days if left untreated(1-3). A recent study showed that 79% of patients with Shoshin beriberi were admitted to the ICU, 23% died in the hospital, and more than one-third died within 24 hours of admission(1). Shoshin beriberi’s main characteristics include normal or increased cardiac output, reduced peripheral vascular resistance, and increased lactate levels(3, 4).Thiamine treatment can rapidly reverse the progression of Shoshin beriberi, and this is also an important basis for the diagnosis of the disease(1).The purpose of this article is to present the case of a 46-year-old male patient with thiamine deficiency resulting in associated clinical symptoms that rapidly progressed to refractory shock. The paper describes the difficulties of differential diagnosis, the importance of a thorough history, and the effectiveness of optimal medical treatments, including intravenous vitamin B1 and circulatory support. We emphasize the practical implications of this study and conclude with a summary review of the available literature on Shoshin syndrome.2. CASE PRESENTATIONA 46-year-old male patient was admitted to our emergency room with recurrent chest tightness and shortness of breath for 1 year and a relapse for 1 month. He reported experiencing similar symptoms a year ago at night, diagnosed with acute heart failure at a local hospital, and improved after treatment, discharged without long-term medication. He’s not limited in his daily activities. One month ago, the patient experienced chest tightness and shortness of breath again, which became more pronounced after physical activity, concomitant with significant edema in both lower extremities. As the persistence of the above symptoms without relief, he presented to emergency room of our hospital on August 8, 2024.After admission, the patient presented with dyspnea, a respiratory rate of 30 breaths per minute, accompanied by fever, a body temperature of 38 degrees Celsius, and a heart rate around 108 beats per minute. Physical examination revealed severe pitting edema in both lower extremities. Laboratory tests suggest varying degrees of elevation of indicators such as C-reactive protein (CRP) and brain natriuretic peptide (BNP)(Table1). Transthoracic echocardiography suggests pulmonary artery pressure of 60 mmHg (Figure1A), and chest computed tomography (CT) showed the presence of pulmonary edema (Figure2). Considering that the patient had acute heart failure, pulmonary hypertension, and pneumonia, he was given intravenous furosemide maintenance in combination with nesiritide to improve cardiac function and omadacycline for anti-infective therapy.After treatment, the patient ’s condition did not improve, but rather deteriorated dramatically, progressing to shock (blood pressure 80/49 mmHg) the next day. The patient was given norepinephrine to maintain his blood pressure and was transferred to Intensive Care Unit (ICU). Central venous pressure (CVP) was measured at 26 mmHg. Bedside ultrasound showed a cardiac output of 9.89 liters per minute, and pulmonary hypertension was still present. To rule out the possibility of pulmonary embolism, the patient underwent a CT pulmonary angiogram and received a negative result. Despite the norepinephrine dosage being 0.6ug/kg.min, it was still challenging to maintain blood pressure.3. METHODSTherefore, to further investigate the cause of shock, the patient was put on the Pulse indicator Continous Cadiac Output (PiCCO) monitoring, which indicated increased preload, extravascular lung water content and cardiac output, decreased systemic vascular resistance(Table2), suggesting haemodynamic disorders with high cardiac output and low peripheral vascular resistance.During this period, we ruled out tumors, hyperthyroidism, and pharmacological shock, but it remains a challenge to identify the etiology of refractory shock. A hyperdynamic hemodynamic disorder would seem to require the exclusion of distributive shock first. Septic shock is the most common type of distributive shock, but the patient’s low inflammatory status, as well as adequate preload without fluid resuscitation, do not seem to support this diagnosis. Additionally, the patient’s plasma cortisol level was relatively low (6 mmol/L), and although we administered hydrocortisone intravenously (200mg/d), this did not improve the patient’s condition. The patient’s difficult-to-maintain blood pressure forced us to administer terlipressin in combination with epinephrine.4. RESULTSEventually, we detected extremely low levels of vitamin B1 in the patient, specifically <1 ng/ml. We concluded that the patient had a thiamine deficiency, which led to Shoshin beriberi, and administered vitamin B1 at a dose of 10 mg intramuscularly three times a day for five days before switching to oral administration. From the second day of vitamin B1 treatment, the patient’s circulation miraculously and rapidly improved, blood lactate gradually decreased to normal levels (Figure3), and symptoms abated within days of treatment. Soon, the patient regained his normal activity endurance and was discharged from the hospital after two weeks. A cumulative negative fluid balance of 15,000 ml was achieved during his hospitalization, and at the time of discharge, a transthoracic echocardiogram showed complete resolution of his pulmonary hypertension (Figure1B).5. DISCUSSIONThiamine (vitamin B1) is an essential nutrient. Thiamine pyrophosphate, the active product of thiamine, is an important coenzyme of glucose metabolism(5). Impaired glucose metabolism caused by thiamine deficiency leads to a significant accumulation of pyruvic acid and lactic acid in the body, which can result in lactic acidosis in severe cases(4). The accumulation of pyruvic acid and lactic acid reduces peripheral vascular resistance and increases venous return, leading to an increase in cardiac preload and potentially resulting in the development of acute congestive heart failure(4). Shoshin beriberi is often accompanied by pulmonary hypertension(1). Impaired myocardial energy production and myocardial damage, which caus increased left ventricular end-diastolic pressure (LVEDP) and increased cardiac return volume, are possible mechanisms(3, 6) (Figure4). Complete recovery from pulmonary hypertension has been reported in the literature within 4-6 weeks(3).The hemodynamics of pediculosis are similar to, but not entirely consistent with, distributed shock, capillary leakage syndrome, and other forms of high-output heart failure. Table3 lists diseases that exhibit hyperdynamic hemodynamic disturbances. These diseases can also present concurrently with Shoshin beriberi, thereby complicating the diagnosis(6). In addition, conditions such as infections can predispose individuals to an increased demand for thiamine, leading to the rapid progression to Shoshine beriberi in patients with an existing thiamine deficiency that has not yet manifested clinically(3).Thiamine deficiency can be caused by a variety of factors, such as alcohol abuse, disease-related malnutrition, bariatric surgery, medications (e.g., omeprazole, metformin, furosemide, and thiazide diuretics), and refined foods(2, 7). However, patients with calorie-rich but nutritionally poor diets may not appear emaciated, thereby misleading clinicians(4). Furosemide exacerbates the risk of thiamine deficiency by increasing renal excretion of thiamine(5, 8). patients with social withdrawal syndrome, also known as hikikomori syndrome, may present a new population at risk of thiamine deficiency(9). Hikikomori syndrome was first identified in Japan and is now becoming a worldwide problem(9).The patient we reported was unmarried and childless, lived alone for a long time, and seldom interacted with friends, which was consistent with the features of social withdrawal syndrome. Although he denied being a partial eater and claimed to never drink alcohol, further questioning of his dietary history revealed that he preferred monotonous or restrictive diets, such as instant noodles, which could be the cause of his thiamine deficiency. Subsequent furosemide treatment promotes thiamine loss through the kidneys, further exacerbating this deficiency. A history of thiamine deficiency is one of the most important criteria for diagnosing hoshin beriberi. Clinicians should be aware of the potential risk of thiamine deficiency associated with hikikomori syndrome and should initiate thiamine replacement in cases of high-output heart failure associated with lactic acidosis(9).Currently, some scholars have reported cases of thiamine deficiency leading to Shoshin beriberi, similar to the case we reported(4, 10-14). The main clinical manifestation was intractable shock requiring high doses of vasoconstrictors, with most cases presenting as high cardiac output shock. However, a few patients experienced sharp hemodynamic deterioration after low cardiac output, even requiring ECMO support(4, 15, 16). The reported cases showed rapid improvement in circulation after thiamine supplementation, indicating that the condition can still be reversed with timely diagnosis, aggressive circulatory support, and thiamine supplementation.The blood test for thiamine levels is still the gold standard for diagnosing thiamine deficiency, but it has some limitations. Plasma thiamine levels are strongly influenced by recent caloric intake, and less than 1% of total body thiamine is found in whole blood, so a low level may not always be a sensitive indicator of true deficiency(4). In addition, it usually takes several days to obtain the results of laboratory assessment of blood thiamine levels. Some authors recommend obtaining thiamine levels prior to thiamine supplementation and not delaying treatment, i.e., starting thiamine administration immediately after blood is collected for analysis. This approach also implies diagnostic treatment(16).There is no recommended thiamine regimen for the treatment of Shoshin beriberi, which is primarily empirical and can vary depending on the severity of presentation(4). Studies have shown that the median maximum and initial doses of thiamine in patients with Shoshin beriberi are 200 mg/day (IQR, 100-500) and 100 mg/day (IQR, 60-300), respectively(1). Previous reports indicate that thiamine doses of 100-200 mg/day usually improve the symptoms of Shoshin beriberi(15, 16). It has also been reported that a loading dose of 100 to 500 mg of thiamine, followed by 25 to 100 mg/day orally for a course of 6 to 7 weeks, is effective(4). The patient we reported was initially given 300 mg of vitamin B1 intravenously daily for 3 days and then switched to 300 mg orally for 1 week of supplementation. The results of the treatment also indicate the effectiveness of this regimen.Targeted therapies aimed at improving mitochondrial function, termed “metabolic resuscitation,” have gained attention in recent years(17). In 2017, a retrospective study reported for the first time that the use of a combination “metabolic resuscitation cocktail” consisting of thiamine, ascorbic acid, and hydrocortisone resulted in favorable outcomes for patients with sepsis. Subsequently, related randomized controlled studies were conducted worldwide(18-24). Further meta-analyses found that the metabolic resuscitation cocktail improved organ failure recovery and decreased vasopressor duration(17). The physiological function of thiamine may explain this potential effect. Thiamine is a vitamin that serves as a cofactor for enzymes involved in the tricarboxylic acid cycle; therefore, a deficiency of thiamine results in decreased activity of thiamine-dependent enzymes, which leads to energy compromise, decreased ATP production, and increased ROS generation(17, 25). There is synergy between thiamine, ascorbic acid, and hydrocortisone(17). The hypermetabolic state of critically ill patients predisposes them to thiamine deficiency. Thiamine deficiency is frequently observed in critically ill patients and is associated with increased mortality(17). Although the current findings on metabolic resuscitation cannot prove that the improvement of organ function in critically ill patients is entirely attributable to thiamine supplementation, metabolic resuscitation, including thiamine, is still worthy of further attempts and research.6.CONCLUSIONThe case underscores the need to expand our vigilance for Shoshin beriberi to other populations that present with increased cardiac output, decreased peripheral vascular resistance, and elevated lactate levels. It also highlights the importance of obtaining a detailed history, even in patients without a clear history of drinking habits or drug use. Additionally, patients with social withdrawal syndrome should be considered for Shoshin beriberi when they exhibit the hemodynamic states described above. Of course, we must first rule out sepsis, poisoning, and other potential causes. Laboratory testing of vitamin B1 levels can help clarify the diagnosis. Shoshin beriberi progresses rapidly and has a high mortality rate, which can be reversed by early diagnosis and thiamine treatment. There are no agreed-upon standard therapeutic dose recommendations. It is also worth mentioning that vitamin B1, as part of metabolic resuscitation, deserves further research.TAKE-HOME MESSAGE1. Thiamine deficiency can lead to Shoshin beriberi;2. Shoshin beriberi is primarily characterized by refractory shock with high cardiac output;3. Shoshin beriberi has a high mortality rate, but it can still be reversed;4. People with social withdrawal syndrome are at high risk of Shoshin beriberi;5. Metabolic resuscitation still deserves application and further research.AUTHOR CONTRIBUTIONSYunyan Jing: Conceptualisation (lead), Methodology (supporting), Validation (equal), Writing - Original Draft (lead).Leqing Lin: Conceptualisation (supporting), Investigation (lead), Formal Analysis (lead), Data Curation (equal), Writing - Review & Editing (equal).Bin Ni: Writing - Review & Editing (equal).Hui Wang, Ju Lin and Linan Zhang: Resources (lead), Supervision (supporting).CONFLICT OF INTEREST STATEMENTThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.DATA AVAILABILITY STATEMENTAll raw data and code are available upon request.FUNDING INFORMATIONThis work was supported by Medical Science and Technology Project of Zhejiang Province[Grant Nos. 2025KY142].ETHICS STATEMENTThe authors take responsibility for all aspects of the work and ensure that issues related to the accuracy or completeness of any part of the work are properly investigated and resolved. All procedures performed in research involving human participants were in accordance with the ethical standards of the Western Michigan University School of Medicine institutional research committee and with the Helsinki Declaration (2013 Revision). Written informed consent was obtained from the patient for the publication of this case report and accompanying images.REFERENCES1. Mizuguchi Y, Mouri H, Jo T, Hashimoto Y, Matsui H, Fushimi K, et al. Clinical Features and Outcomes of Shoshin Beriberi. International Heart Journal. 2024;65(2):271-8.2. Gomes F, Bergeron G, Bourassa MW, Fischer PR. Thiamine deficiency unrelated to alcohol consumption in high‐income countries: a literature review. Annals of the New York Academy of Sciences. 2021;1498(1):46-56.3. Bhat JI, Rather HA, Ahangar AA, Qureshi UA, Dar P, Ahmed QI, et al. Shoshin beriberi-thiamine responsive pulmonary hypertension in exclusively breastfed infants: A study from northern India. Indian Heart Journal. 2017;69(1):24-7.4. Helali J, Park S, Ziaeian B, Han JK, Lankarani-Fard A. Thiamine and Heart Failure. Mayo Clinic Proceedings: Innovations, Quality & Outcomes. 2019;3(2):221-5.5. Ao M, Takabayashi K, Tomita R, Fujita R, Miyawaki T, Tanaka K. Vicious cycle of vitamin B1 insufficiency and heart failure in cardiology outpatients. J Clin Biochem Nutr. 2024 Nov;75(3):241-246.6. Samprathi M, Mohammad F, M S, Ramachandra P, Vemgal P. Case Report: Fulminant Infantile Beriberi: A Report of Six Cases. The American Journal of Tropical Medicine and Hygiene. 2021;104(6):2238-40.7. Scorza FA, de Almeida AC, Scorza CA. Thiamine deficiency to ward off cardiovascular dysfunction and SUDEP: Yay or nay? Epilepsy & behavior : E&B. 2016;56:48-9.8. Teigen LM, Twernbold DD, Miller WL. Prevalence of thiamine deficiency in a stable heart failure outpatient cohort on standard loop diuretic therapy. Clinical nutrition (Edinburgh, Scotland). 2016;35(6):1323-7.9. Tanabe N, Hiraoka E, Kataoka J, Naito T, Matsumoto K, Arai J, et al. Wet Beriberi Associated with Hikikomori Syndrome. Journal of General Internal Medicine. 2017;33(3):384-7.10. Kurisu S, Fujiwara H. A Case Report of Wet Beriberi Due to Excessive White Rice Consumption in an Elderly Male Patient: A Potentially Forgotten and Underrecognized Disease. Cureus. 2024.11. Kato TA, Sartorius N, Shinfuku N. Shifting the paradigm of social withdrawal: a new era of coexisting pathological and non-pathological hikikomori. Current opinion in psychiatry. 2024;37(3):177-84.12. Lim MS, Win W, Von Essen A, Gannon D, Ramali M. Lessons of the month 1: Shoshin beriberi: A case report of fulminant cardiovascular collapse, intractable hyperlactatemia and deteriorating consciousness. Clinical medicine (London, England). 2021;21(6):e670-e2.13. Cottini M, Ranucci M, Facciolo C, Satriano A, Kandill H, Bettini F, et al. An unusual case of cardiogenic shock in which thiamine administration led to reversal of lactic acidosis and heart function recovery: Shoshin beriberi in an adolescent. Int J Cardiol. 2016;222:401-3.14. Kim J, Park S, Kim JH, Kim SW, Kang WC, Kim SJ. A case of shoshin beriberi presenting as cardiogenic shock with diffuse ST-segment elevation, which dramatically improved after a single dose of thiamine. Cardiovascular journal of Africa. 2014;25(6):e1-5.15. Imamura T, Kinugawa K. Shoshin Beriberi With Low Cardiac Output and Hemodynamic Deterioration Treated Dramatically by Thiamine Administration. Int Heart J. 2015;56(5):568-70.16. Cottini M, Ranucci M, Facciolo C, Satriano A, Kandill H, Bettini F, et al. An unusual case of cardiogenic shock in which thiamine administration led to reversal of lactic acidosis and heart function recovery: Shoshin beriberi in an adolescent. International Journal of Cardiology. 2016;222:401-3.17. Reddy PR, Samavedam S, Aluru N, Yelle S, Rajyalakshmi B. Metabolic Resuscitation Using Hydrocortisone, Ascorbic Acid, and Thiamine: Do Individual Components Influence Reversal of Shock Independently? Indian J Crit Care Med. 2020 Aug;24(8):649-652. 18. Mohamed ZU, Prasannan P, Moni M, Edathadathil F, Prasanna P, Menon A, et al. Vitamin C Therapy for Routine Care in Septic Shock (ViCTOR) Trial: Effect of Intravenous Vitamin C, Thiamine, and Hydrocortisone Administration on Inpatient Mortality among Patients with Septic Shock. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2020;24(8):653-61.19. Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. Jama. 2020;324(7):642-50.20. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. Jama. 2020;323(5):423-31.21. Wani SJ, Mufti SA, Jan RA, Shah SU, Qadri SM, Khan UH, et al. Combination of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of sepsis: results from an open label randomised controlled clinical trial and a review of the literature. Infectious diseases (London, England). 2020;52(4):271-8.22. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest. 2020;158(1):164-73.23. Chang P, Liao Y, Guan J, Guo Y, Zhao M, Hu J, et al. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial. Chest. 2020;158(1):174-82.24. Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, et al. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. Jama. 2021;325(8):742-50.25. Montero VR, Ribes CM, Montell MP, Crespo RZ. [Corticosteroids and metabolic resuscitation (hydrocortisone, ascorbic acid and thiamine) in sepsis and septic shock]. Medicina intensiva. 2022;46 Suppl 1:49-59.

Admixture is common in nature, and can serve as a crucial source of adaptive potential through the generation of novel genotype combinations and phenotypes. Conversely, the presence of hybrid incompatibilities can decrease the fitness of hybrids. Due to the pervasiveness of admixture in nature and its potential role in facilitating adaptation, understanding how admixture affects the rate and repeatability of evolution is important for furthering our understanding of evolutionary dynamics. However, few studies have assessed how patterns of evolutionary parallelism in admixed lineages are affected by the presence of strong ecological pressure. In this experiment, we assessed patterns of evolution and parallelism across admixed and non-admixed cowpea seed beetles (Callosobruchus maculatus) during adaptation to a novel, stressful host: lentil. Specifically, we asked (1) whether admixture facilitates adaptation to lentil, (2) whether parallelism was higher in admixed or non-admixed lineages, and (3) to what degree parallelism in admixed lineages was associated with selection on globally adaptive alleles versus epistatic effects and hybrid incompatibilities. We found that admixture facilitated adaptation to lentil, and evolutionary rescue–defined as adaptation that prevents population extinction–occurred in all lineages. The degree of evolutionary parallelism was highest in two admixed lineages, but notable in all lineages. Adaptation to lentil appeared to be driven by selection on alleles that were globally adaptive. However, even during evolutionary rescue in a marginal environment, the purging of hybrid incompatibilities appeared to contribute substantially to evolutionary parallelism in admixed lineages.

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Background and Clinical Significance: Granular cell tumor (GCT), also known as Abrikossoff tumor, is a rare, typically benign neoplasm of Schwannian origin. Although these tumors can occur in various locations, breast involvement is uncommon, accounting for up to 15% of cases. Case Presentation: We report the case of a 23-year-old female who presented with a firm, non-tender, 1 cm palpable lump in the upper outer quadrant of the left breast, detected during routine examination without skin changes or axillary lymphadenopathy. Ultrasound imaging revealed a hypoechoic, well-defined nodule, while MRI demonstrated minimal contrast enhancement, supporting a benign process despite features that may mimic malignancy. A core needle biopsy showed a proliferation of polygonal cells with abundant granular eosinophilic cytoplasm, mild nuclear pleomorphism, and low mitotic activity (Ki-67 ≤2%). Immunohistochemical analysis confirmed the diagnosis with strong positivity for S100, SOX10, and vimentin, and negativity for carcinoma-associated markers. Conclusions: This case highlights the diagnostic challenges of breast GCT in young patients and underscores the importance of integrating imaging, histopathology, and immunohistochemistry to distinguish it from malignant lesions and guide appropriate management. Regular follow-up is recommended to monitor for recurrence.

Emerging as a game-changing technology, generative artificial intelligence (GenAI) impacts various sectors, including healthcare, finance, education, and the creative arts. These systems are excellent at producing text, images, audio, and other modalities that resemble those of a human being because sophisticated deep learning architectures like transformer models drive them. Hallucination in AI, particularly in Large Language Models (LLMs), refers to the generation of plausible but inaccurate or fabricated responses. These errors can be categorized as intrinsic hallucinations (internal reasoning errors) and extrinsic hallucinations (outputs lacking justification from incoming data). Hallucinations present in three forms: factual inaccuracies, semantic distortions, and fluency-related discrepancies. Addressing hallucination entails various research methodologies, including prompt engineering like Retrieval-Augmented Generation, which retrieves authoritative information; self-refinement, where models iteratively enhance their responses for precision; model development utilizing context-aware decoding and knowledge graphs; and fine-tuning with factually accurate datasets. Methods like R-Tuning and Faithfulness-Based Loss Functions also help in improving factual alignment and minimizing hallucinations. Hallucinations in content generation diminish the usefulness and legitimacy of AI-generated content. Although prompt engineering has made significant strides, a structured understanding of how prompts affect hallucinations and consistent nomenclature are still lacking. Additionally, current mitigation strategies frequently focus on post-processing or superficial changes to prompts, failing to address the underlying causes of hallucinations that are ingrained in the training data and model design.

This paper presents an improved Dynamic Window Approach (DWA) for omnidirectional mobile robots, aimed at optimizing local path planning and posture adjustment in narrow and complex environments. Traditional DWA faces challenges such as inadequate dynamic obstacle avoidance and unstable postures when applied to omnidirectional robots. To address these issues, this paper introduces a three-dimensional velocity vector V ̵⃗ = [ V x V y ω ̵⃗ ] , replacing the conventional ( v, ω) framework. This optimizes the calculation of the dynamic window according to the characteristics of omnidirectional robots and incorporates mutual constraints between linear and angular velocities. Moreover, the evaluation function of the traditional DWA is enhanced by adding a new posture evaluation function, and the normalization process is eliminated to improve computational efficiency. A triangular region scanning algorithm is also designed for capturing optimal posture angles in dynamic environments. Through extensive experiments involving random dynamic obstacles, the improved algorithm achieves a path planning success rate of over 98% and it maintains a collision occurrence probability below 5% in both simulation and real-world tests. The robot can successfully navigate narrow obstacle environments with optimal posture, validating the repeatability and robustness of the improved DWA in path planning and posture adjustment. This study holds potential for further application in broader dynamic and unpredictable environments.

*Correspondence: AAAnikin@kantiana.ruAbstractThe work is devoted to the magnetic layered microdisks synthesized by tear-off optical lithography combined with electron-beam deposition of metal layers that are considered to be the microagents for the anti-cancer treatments. Two types of microdisks were studied with different layers sequences with thicknesses in nm: Au(10)/Fe(70)/Au(10) and Fe(50)/Au(10)/Fe(50). First type of disks showed slightly higher optical absorption and lower magnetic susceptibility, the photothermal conversion coefficient is 27%. The second type showed higher magnetic susceptibility and the photothermal conversion coefficient is 30%. The single photothermal and magnetomechanical therapies conducted with the microdisks showed mild decrease of cell viability. For the photothermal therapy ~10% cells viability decrease was achieved. For the magnetomechanical therapy it reached ~17% cells viability decrease. However, if photothermal therapy is conducted after the magnetomechanical stimulation the viability decreases by ~30%. In combinational treatment with simultaneous photothermal and magnetomechanical impact the viability decreased by 50%.1. Introduction Magnetic particles (MPs) find wide application in biomedical field, including cancer treatment using magnetic hyperthermia [\cite{Kafrouni2016}], or magnetically controlled delivery and release of antitumor drugs to the target area [\cite{Oliveira2013}]. Recently, methods of cancer cell destruction based on movement of magnetic particles in changing magnetic fields have been actively developed [\cite{Naud2020}, \cite{Golovin_2018}]. The most suitable materials should have high mechanical moment under the influence of changing magnetic fields. In particular, microdisks with vortex magnetic structure in the ground state, created using magnetron sputtering and subsequent optical lithography [\cite{Kilinc_2016},\cite{therapy}], nanowires and nanotubes obtained by electrochemical synthesis in porous membranes [\cite{Contreras_2015},\cite{Anikin_2024}], ultrathin magnetic particles with perpendicular magnetization [\cite{Mansell_2017}], as well as synthetic antiferromagnetic microdisks with zero residual magnetization are considered. The main difficulties in preparing such materials arise in obtaining stable colloidal solutions of nanoparticles with their optimal magnetomechanical and hysteresis properties, in reducing cytotoxicity, and in scaling up the synthesis methods.Photothermal and magnetomechanical therapies with nanoparticles are among novel approaches to cancer treatment [\cite{Ali_2019}, \cite{Vines_2019}, \cite{Naud_2020}, \cite{Subramanian_2019}]. Photothermal therapy (PTT) involves heating by incident light of cancer cells loaded with plasmonic nanoparticles that achieves the temperature required for cell destruction. Magnetomechanical therapy (MMT) can be divided into magnetic drug delivery and magnetomechanical cell destruction, both requiring the use of magnetic nanoparticles.Using only one method of influencing cells may not be effective enough. Of interest is the study of the combined action of mechanical forces and heating, both due to magnetic hyperthermia and photothermia [\cite{Efremova_2018}, \cite{Shi_2022},\cite{Espinosa_2018}]. However, magnetic materials, as a rule, do not heat up well enough when interacting with light, especially in the near IR range, at wavelengths of about 800 nm, which is the first transparency window of biological tissues. On the other hand, in order to improve the biocompatibility and stability of MPs, as well as to reduce their agglomeration, coatings of various biocompatible materials, including gold, are used [\cite{Subekin_2024}]. This leads to an increase in optical absorption and the efficiency of photothermal heating, which makes it possible to combine several anticancer therapies using one type of particles. This is especially relevant in the context of the emerging field of nanomedicine, where such particles can be used to generate local forces or moments on biological samples at different temperatures and study the cellular response.In this work, we investigated the optical, photothermal and magnetic properties of layered microdisks in two configurations, Au/Fe/Au (Au/Fe/Au) and Fe/Au/Fe (Fe/Au/Fe), fabricated by lift-off optical lithography. The first type of discs has high optical absorption up to the IR region and photothermal efficiency. While the second type has greater potential for use in magnetomechanical therapy. Single photothermal and magnetomechanical therapies were performed, as well as combined therapies. The results show potential of the biomedical use of the microdisks.

Metabolic reprogramming is a hallmark of cancer cells, enabling them to meet the heightened energetic and biosynthetic demands required for rapid growth and proliferation. Recently, non-canonical functions of metabolic enzymes have garnered significant attention in cancer research. Pyruvate kinase 2 (PKM2) has been identified as a key player in transcriptional regulation within the nucleus, presenting new opportunities for therapeutic interventions in cancer. Here, we discovered that triclabendazole, a novel benzimidazole derivative，commonly used against Fasciola hepatolithiasis, effectively inhibited the nuclear translocation of PKM2. This inhibition resulted in the downregulation of glycolytic flux, ultimately suppressing lung cancer cell proliferation. Notably, triclabendazole reduced PKM2 acetylation by promoting the interaction between PKM2 and histone deacetylase 6 (HDAC6), thus blocking PKM2 nuclear localization. Moreover, we also demonstrated that triclabendazole-mediated inhibition of cell proliferation is driven by the downregulation of glycolysis, which enhanced AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling. Consistently, triclabendazole administration significantly inhibited tumor growth in vivo, correlating with the blockade of PKM2 nuclear translocation and lactate production decreased. Together, our findings revealed that triclabendazole inhibits PKM2 nuclear localization and glycolysis through an HDAC6-dependent mechanism, leading to the activation of AMPK/mTOR signaling and suppression of lung cancer cell proliferation. These results suggested that triclabendazole holds promise as a potential therapeutic agent, with the HDAC6-PKM2 axis representing a novel target for lung cancer treatment.

I.Background: Male infertility is a global issue with few remedies, particularly for testicular damage caused by radiation. Investigating new medications to treat radiation-induced testicular damage was the goal of this study. II.Methods: Six male mice (n = 6) received 0.5 Gy whole-body irradiation for 5 consecutive days and were then intraperitoneally injected with telmisartan (1.2 mg/kg). The therapeutic effect of telmisartan was evaluated using quantitative real-time PCR. A drug affinity reactivity target stability (DARTS) assay was used to identify target proteins and pathways. Western blot, CCK-8, EdU 594 and ubiquitination assays were used to investigate the mechanism involved. Finally, rescue experiments were performed by combining telmisartan with ESR1 antagonists and agonists. III.Results: The telmisartan treatment group presented significantly higher mRNA levels of spermatogenic cell markers than did the irradiation treatment group (P < 0.05). The DARTS assay and Western blotting results revealed that telmisartan increased the expression of connexin in Sertoli cells and increased proliferation and activated downstream signalling pathways by controlling ESR1 expression. Ubiquitination pull-down assays revealed that the degradation of ESR1 after irradiation was inhibited by telmisartan. Telmisartan combined with PPT/AZD9496 further upregulated ESR1 expression, which was beneficial for reducing radiation-induced testicular injury. IV.Conclusions: In conclusion, our findings suggest that telmisartan reduces radiation-induced testicular damage in mice by upregulating ESR1 in Sertoli cells. These findings may lead to the development of new approaches for treating testicular damage caused by radiation.

Background and Purpose: Developing potent, broad-spectrum antimicrobial peptides with rapid onset of action can mitigate the growing threat of antimicrobial resistance posed by conventional antibiotics. We designed a cyclic antimicrobial peptide named as SAP 2.8 to evaluate the antibacterial activity and mechanism of action against pathogens. Experimental approach: The antimicrobial activity of various antibiotics and antimicrobial peptides against pathogens was assessed by measuring their minimal inhibitory concentration (MIC). Time kills kinetics, scanning electron microscopy, transmission electron microscopy, and membrane integrity studies were conducted to know the mechanism of action of the peptide. Balb/C and C57BL/6 mice were utilized for the wound infection model and peritonitis model to evaluate the therapeutic potential of the SAP 2.8 peptide in in vivo experiments. Key Results: SAP 2.8 antimicrobial peptide was observed more potent against Staphylococcus aureus and Methicillin-resistant staphylococcus aureus clinical isolates (MICs; 1.25-2.5 µg/mL). SAP 2.8 showed advantages of rapid bactericidal properties within 30 min. Additionally, SAP 2.8 inhibited bacteria biofilm formation and disrupted preformed biofilms in vitro. Mechanistic studies indicated that SAP 2.8 disrupts bacterial cell membranes and leads to an increase in intracellular reactive oxygen species, eventually resulting in bacterial death. Notably, SAP 2.8 demonstrated significant in vivo efficacy against S. aureus and MRSA infections. Conclusion and implications: SAP 2.8 peptide is an excellent candidate to combat bacterial infections both in vitro and in vivo. This shows SAP 2.8, might represent a promising candidate for the treatment of S.aureus skin infections.

Estimate of land use land cover change and its impact on landscape structure through using Landsat Satellite data and techniques: The case of Bagmundi C.D. Block, Purulia District, West Bengal.First author and Corresponding author: Rajesh HansdaJunior Research Fellow, Department of Geography, The University of Burdwan, Burdwan Pin-713104, West Bengal, India, E-mail address: hansdarajesh19@gmail.comORCID ID: 0009-0002-5943-7584

not-yet-known not-yet-known not-yet-known unknown Introduction. Acute Pancreatitis is a widespread condition, considered by health care professionals that impacts the pancreas and is regarded to be the most intricate disease of gastrointestinal tract. Diagnosing and treating diseases of this glandular organ is critical for maintaining well-being of digestive and endocrine system impacting the overall health of the body1. The cause of acute pancreatitis (AP) should be determined upon admission and is achieved through a comprehensive medical history, physical exam, lab tests, and imaging. Additionally, assessing risk factors and the patient’s response to initial treatment helps forecast the AP outcome2. This potentially life threatening condition typically triggered by factors such as alcohol use, gallstones, acute on chronic pancreatitis, or idiopathic cause. It can also occur as a complication following surgeries, particularly those involving the pancreas, including hepatobiliary, gastric surgeries, splenorenal shunts, splenectomies and certain cardiac procedures3-6. Research indicates that microlithiasis and sludge could be responsible for a large proportion of idiopathic acute pancreatitis (IAP). These small stones and sludge, particularly when located in the common bile duct, are often challenging to detect with transabdominal ultrasound. Consequently, patients initially diagnosed with IAP may actually have biliary pancreatitis. Lower the risk of recurrent acute pancreatitis, performing Laparoscopic/Open Cholecystectomy during the same hospital admission is recommended for cases of mild biliary pancreatitis7. Endoscopic retrograde cholangiopancreatography (ERCP) is associated with a 2-10% risk of post-ERCP pancreatitis (PEP), which can increase to 30-50% in high-risk individuals. In up to 5% of cases, PEP may become severe, leading to potentially fatal complications such as multi-organ failure, acute peripancreatic fluid collections, and, in rare instances, death, which occurs in about 1% of cases8. We are reporting the case after Laparoscopic cholecystectomy pancreatitis which is a very rare entity. Acute pancreatitis essentially requires the presence of at least two of the three mentioned criteria: (A) abdominal pain (More on epigastric region) characteristic of the condition, (B) Three folds elevation of serum amylase and/or lipase, and (C) typical results from abdominal radiological studies9. Serum pancreatic enzymes are considered the most reliable method for diagnosing acute pancreatitis10.

Ichthyosis hystrix Lambert Type: A rare form of Keratinopathic IchthyosesPeter J. Chapa1*, Magdalena Dennis2, Amina Omary1, Russel Halama1Dodoma Regional Referral Hospital, P.O Box 904, Dodoma, TanzaniaMuhimbili National Hospital, P.O Box 6500, Dar Es Salaam, Tanzania*Corresponding author: Peter J. Chapa, Dodoma Regional Referral Hospital, P.O Box 904, Dodoma, Tanzania, chapapj@yahoo.com

In this era of rapid climate change, understanding the adaptive potential of organisms is imperative for buffering biodiversity loss. Genomic forecasting provides invaluable insights into population vulnerability and adaptive potential under diverse climatic conditions, thereby facilitating management interventions and bolstering shaping species-specific germplasm conservation strategies. We integrated population genomics and landscape genomics approaches, leveraging single-nucleotide polymorphisms obtained through whole-genome resequencing of 201 individuals across 43 Rheum palmatum complex populations, to pinpoint adaptive variation and its significance in the context of future climates, delineate seed zones, and established guidelines for ex situ germplasm conservation. The species complex exhibited strong signatures of local adaptation and differential genomic vulnerabilities across its distribution range, with eastern lineage populations facing significant maladaptation risks under future climate scenarios. Using diverse datasets of putatively adaptive loci and climate change scenarios, we delineated three distinct seed zones within the species' range, estimated varying sample sizes per zone to capture most adaptive diversity, and predicted shifts in seed zone centroids ranging from 48.3 km to 359.3 km from historical distributions to mitigate climate change impacts. Overall, our findings provide a genome-wide perspective on climate adaptation and valuable insights into germplasm conservation strategies aimed at enhancing population resilience in future climates, serving as a blueprint for restoration plans of other vulnerable species.

Assisted gene flow is used to counteract genetic erosion in small populations of endangered species, yet an evaluation of genetic compatibility of potential donor populations and recipient populations is rare. We developed new metrics for assessing genetic impact of genetic augmentation based on genotype identity of functional variants between donor and recipient genomes and used these metrics to evaluate options for assisted gene flow in Eastern Massasauaga rattlesnake (Sistrutus catenatus) populations in Ohio, USA. We used putatively deleterious variants, and genetic variants likely under positive selection (termed “adaptive” variants) as the two components of functional variation. For potential donor and recipient populations, we estimated three key aspects of genetic compatibility – (a) introduction of novel variants, (b) masking or unmasking of existing deleterious variants, and (c) potential for outbreeding depression through disruption of local adaptation. The main impact of augmentation from diverse donor populations was to introduce novel deleterious variants and to a lesser extent novel adaptive variants into each recipient population. Both donor populations had a similar minor impact in terms of masking existing deleterious variants. Finally, only ~ 7% of adaptive variants show evidence for local adaptation arguing that the negative effect of outbreeding depression would be small. These results draw attention to the importance of considering the potential impact of both deleterious and adaptive genetic variants in augmentation efforts and suggest that in case of these endangered rattlesnakes, the net effect of proposed assisted gene flow may lead to an increase in absolute levels of mutation load.

The insect-pathogenic fungal genus Strongwellsea (Entomophthorales) contains specialist species infecting only adult flies from cyclorrhaphan adult flies. Flies with infection develop one, two or even three abdominal holes, through which conidia are discharged while the fly is still alive. We describe three new species from Strongwellsea infecting adult flies from the family Anthomyiidae. Strongwellsea caulis infects cabbage root fly, Delia radicum (Linnaeus), Strongwellsea lata infects Anthomyia liturata, and Strongwellsea potentia infects Hylemya vagans. The descriptions of the three new species are based on a) pathobiology as revealed by natural host species, b) the morphologies of primary conidia and resting spores, and c) DNA as revealed by ITS2 sequence analysis. Of particular importance is that the two pest species cabbage fly D. radicum and bean seed fly Delia platura (Meigen), are infected by different species from Strongwellsea, namely S. caulis and Strongwellsea castrans respectively. Our findings suggest the existence of a high and still little known diversity of highly specialized Strongwellsea species infecting adult flies from Anthomyiidae.

not-yet-known not-yet-known not-yet-known unknown A substantial community variation of free-living bacterioplankton and their main predator heterotrophic nanoflagellates (HNFs) is often unexplained because their mutual dependency through presumed trophic interactions is often overlooked. Here, we collected bacterioplankton and HNFs from the surface layer and depth of chlorophyll-a maximum (DCM) along 13 degrees of latitude in the Kuroshio from Taiwan to Japan. We performed three-way variation partitioning analyses to unravel their reciprocal influences, in addition to dispersal limitation and environmental dissimilarity. Our analyses reveal that bacterioplankton and HNFs mutually and uniquely explain over 10% of compositional variation when both layers are analyzed collectively, underscoring the significance of trophic interactions. The vertical compositional variations of bacterioplankton and HNFs also reciprocally explain each other. Whereas, considering the surface layer alone, bacterioplankton uniquely explains 12.9% of HNF composition, but HNF makes a non-significant unique contribution to bacterial composition. In the DCM layer, the two trophic levels do not mutually explain each other. Dispersal limitation uniquely accounts for more than 20% of the compositional variation in each layer but does not significantly explain vertical variations. Environmental dissimilarity makes a minor contribution to both trophic levels. Our results suggest that influences of trophic interactions are more pronounced when considering vertical rather than horizontal variations. The horizontal dispersal limitation dominates the compositional variation within a water layer, while trophic interactions between bacterioplankton and HNFs mediate their compositional variation across depths. By considering two trophic levels, this study advances our understanding of metacommunity dynamics of free-living bacterioplankton and HNFs.

Chinese hamster ovary (CHO) cell is a widely used cell line for the production of therapeutic proteins. Customarily, CHO host cell line is established through random integration, which requires multiple rounds of screening to identify the optimal producer. In contrast, site-specific integration (SSI) technology can boost cell line development efficiency by directing gene of interest (GOI) to certain genomic loci that supports sustained and stable expression. In this study, by utilizing AI algorithms and robotic systems, we have identified several CHO host cell lines carrying marker gene by Bxb1-mediated SSI technology. After the substitution of marker gene with different types of GOI at specific sites, some of the monoclonal cells delivered a titer exceeding 15 g/L. Thanks to the uniformity of SSI cell lines, protein titer and quality of monoclonal cells can be predicted based on the performance of corresponding minipools. Different monoclonal cells originated from the same minipool also showed consistent protein quality. Furthermore, it was observed that the monoclonal cells obtained by SSI demonstrated consistency in protein titer, quality and genetic stability after 26 consecutive passages (approximately 90 days). In summary, we have successfully developed an effective platform for the construction of SSI cell lines, which allows the rapid and efficient expression of various proteins while maintaining consistency in stability and product quality.

not-yet-known not-yet-known not-yet-known unknown Cicada (Hemiptera; Cicadidae) is one of the most important insect preys for many vertebrate predators, including birds and mammals due to its large body and high nutrition. Although mammals have often been observed to prey on cicadas, there is no comprehensive summary such as the geographical patterns and its predator species. Here, I summarized the published literatures reporting cicada consumption by mammals worldwide. I found 75 records from 61 the published papers from 1937 to 2023 across all continents (except for Para arctic). There were 50 mammalian consumer and 14 cicada species. The most reported predator order was Carnivora, followed by Primates, and then Chiroptera. The highest recorded cicada species was periodical cicada (Magicicada spp.) which are well-known as the primary prey for insectivorous birds during their mass emergence year. Based on the literatures, I proposed five modes explaining that mammals prey on cicadas across both nymphal and adult stages. I summarized behavioral- and population- responses of mammalian predators to cicada emergence and proposed the role of cicada as a driver of forest ecological networks. Finally, I discussed on ecological functions of cicadas as prey under the changing world. Future research should tackle to understand how behavioral- and population- level responses of mammalian predators to changes in cicada availability and phenology.

Background: The syndrome defined by cerebellar ataxia, neuropathy and vestibular areflexia (CANVAS) was previously described as a cause of late-onset ataxia. With the discovery of biallelic expansion in the RFC1 gene as its underlying genetic cause, CANVAS and the broader RFC1-disease became more clinically heterogeneous and one of adult’s most common genetic cause of ataxia. Methods: Retrospective cohort comprising patients with a genetic diagnosis of CANVAS. Data related to neurological examination, video Head Impulse Test (VHIT), caloric tests, posturography, electromyography/nerve conduction studies and brain magnetic resonance imaging (MRI) were considered. Results: We included 15 patients, with a current mean age of 65.8±12.8 years. Ten (66.6%) patients presented with the complete clinical triad. At neurological examination, 13 patients showed signs of peripheral neuropathy. Cerebellar dysfunction was observed in 12 patients, whereas postural instability was seen in 11 patients. Electromyography/nervous conduction studies revealed peripheral neuropathy in all of the cases. Bilateral vestibular dysfunction was confirmed in approximately one-half of the patients. Mean balance values from the posturography were decreased in the majority (n=14). In the imaging assessment (n=11), 6 patients displayed significant vermian atrophy, predominantly in the anterior/dorsal regions, while the other 5 patients showed moderate atrophy. Conclusions: With the discovery of the genetic cause of CANVAS, it was possible to identify many patients in the absence of the classic triad. Detailed characterization/phenotyping through clinic and multimodal integration if the complementary diagnostic tests, allows a better understanding of the entire spectrum of RCF1-related disorder.

Characterizing temporal niche is integral to understanding eco-evolutionary interactions of species, but research into the timing of species’ daily activity patterns (diel activity) has remained challenging due to data limitations. In timing their activity, organisms face trade-offs such as maximizing foraging and reproduction during favorable conditions while minimizing predation and competition. We assembled large-scale daily activity data across hundreds of butterfly species, broad geographic regions, and seasons using research-grade iNaturalist observations in the conterminous United States. The activity of butterflies is known to be temperature-dependent, and this clade contains a wide range of body sizes, enabling tests of key thermoregulatory trade-offs related to diel activity, climate, season, and morphology. In particular, we predicted that day length and temperature increase activity duration, and that smaller butterflies will be more sensitive to temperature extremes at both daily and annual timescales. We apply an analysis pipeline that addresses observer biases in iNaturalist data and test our predictions using phylogenetic linear mixed models. As expected, we found that day length and temperature increase activity duration, and that the activity of larger butterflies occurs later in the day, when temperature is the highest. Yet temperature does not interact with body size - that is, larger butterflies show these patterns regardless of their climatic environments. Our study, the first for diel activity at the macroecological scale, informs our understanding of interactions of phylogenetic, trait and thermal constraints on daily activity and how species may be able to respond to a warming climate. This work also showcases the enormous potential of community science data to address questions at hitherto unprecedented scales.

Alcohol Use Disorder (AUD) is a chronic, multifaceted condition defined by compulsive alcohol consumption and its detrimental effects on health and society. This article explores the neurobiological mechanisms and behavioural cycles associated with AUD, highlighting the three interconnected stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages illustrate the complex interplay between psychological dependence and neurobiological adaptations, contributing to the persistence of the disorder. The global prevalence of AUD is significant, with millions affected, yet a substantial treatment gap exists, driven largely by stigma and lack of access to care. Current treatment modalities, including psychosocial interventions and pharmacological options, are reviewed, revealing the need for enhanced strategies to address AUD effectively. Future directions in AUD management are discussed, emphasizing the promise of personalized medicine and advancements in neurobiological research to tailor treatments to individual needs. Additionally, the article advocates for the integration of digital health technologies and telehealth solutions to improve treatment accessibility and engagement. Community-based strategies play a crucial role in reducing stigma and fostering supportive environments that promote recovery. Ultimately, this review underscores the urgency of a comprehensive, multi-dimensional approach to AUD that combines clinical research, innovative treatment methods, and community involvement to improve outcomes for individuals and reduce the societal burden of alcohol use disorders.