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Craniotomies represent one of the oldest surgical procedures in human history and have evolved significantly through centuries of medical innovation and wartime necessity. From prehistoric trepanation practices to modern neurosurgical interventions, military conflicts have repeatedly accelerated advances in cranial surgery. This historical review examines the evolution of craniotomies across major historical periods, including prehistoric civilizations, the Renaissance, and modern warfare. Emphasis was placed on the influence of battlefield medicine, technological innovation, and ethical considerations in shaping contemporary neurosurgical practice. Early civilizations such as the Egyptians, Greeks, and Incas performed trepanation for therapeutic, traumatic, and ritualistic purposes, demonstrating surprising procedural sophistication and postoperative survival. During the Renaissance and subsequent military conflicts, including World Wars I and II, the Korean War, Vietnam War, and recent Middle Eastern conflicts, craniotomy techniques rapidly advanced due to the urgent demands of combat-related neurotrauma. Innovations including standardized debridement techniques, mobile neurosurgical units, rapid evacuation systems, neuroimaging, minimally invasive procedures, and robotic-assisted surgery significantly improved survival and neurological outcomes. Modern military neurosurgery additionally recognizes the importance of integrating psychological and rehabilitative care alongside surgical intervention. The evolution of craniotomies reflects the continuous interaction between warfare, technological progress, and medical innovation. Although modern neurosurgery has achieved remarkable precision and improved outcomes, ongoing ethical and logistical challenges remain, particularly in military settings. Understanding the historical development of craniotomies highlights both the resilience of surgical innovation and the enduring pursuit of improved care for patients with traumatic brain injury.

There has been a recent renaissance in the use of peptides as therapeutic agents across a range of indications, sparking significant demand for the development of sustainable and cost-effective alternatives to solid-phase peptide synthesis (SPPS) for the production of these molecules, particularly in the pharmaceutical industry. While tag-assisted peptide synthesis (TAPS) has offered promise, this methodology cannot be routinely used to assemble longer peptide targets (>20 residues), limiting its utility for most peptide therapeutics. Fragment condensation of side-chain-protected peptides using coupling reagents is typically used to prepare larger targets, but this approach usually leads to unacceptable levels of epimerization without significant optimization. Herein, we report an efficient platform for the synthesis of pharmaceutically relevant peptides through direct aminolysis of peptide aryl selenoesters generated via TAPS. Notably, this novel ligation method circumvents the limitations of peptide length associated with TAPS, leads to minimal epimerization, and significantly reduces reagent and solvent use, making it attractive from an environmental standpoint. By integrating the aryl selenoester aminolysis ligation (ASAL) into the TAPS workflow, the convergent synthesis of several therapeutic peptides of increasing complexity was successfully accomplished, including osteoporosis drug teriparatide (34 residues), sulfated tsetse fly-derived thrombin-inhibiting anticoagulant TTI (32 residues), and tirzepatide (39 residues), used for the treatment of type 2 diabetes and weight management. When used in concert with TAPS, the ASAL reaction developed here can serve as a robust method for the ligation-based assembly of tagged peptides, creating a scalable route to access peptide-based therapeutics across academia and industry with a low environmental impact.

State-of-the-art rodent models have aided researchers in the refinement of a holistic understanding of the mechanistic insights related to metastasis, which will eventually lead to the discovery of new multi-targeted therapeutic options. More recently, extraordinary breakthroughs in the genomics, proteomics and mouse modeling have significantly fostered a renaissance of cutting-edge researches on metastasis, leading to conceptually conceivable frameworks to gain insights about its molecular underpinnings. Exciting field of cervical cancer metastasis has moved to the forefront of studies in the past few decades. In this review we have set spotlight on pivotal role of TGF/SMAD, Wnt/β-catenin, AKT/mTOR and Notch signaling in cervical cancer progression. This review also provides an intriguing summary of quintessential role of ubiquitination in regulation of cervical cancer. By integration of mechanistic insights with multi-scale computational studies, basic researchers and clinicians have started to develop previously unprecedented understanding about disease aggressiveness of cervical cancer. More importantly, rational integration of multi-omics and single-cell sequencing technologies into clinical trial designs will enable researchers to gather refined scientific data for result-oriented clinical decision-making.

Manganese (Mn) has lingered in the shadows as a mere enzymatic cofactor, with its profound role in regulating the most fundamental life processes largely overlooked. This review heralds a "manganese renaissance" - a paradigm shift that elevates Mn from a passive trace element to a dynamic architect of metabolic homeostasis and a critical driver of disease. We synthesize breakthroughs that redefine its biological significance. In addition to enabling reactions for enzymes such as MnSOD, Mn actively governs lipid trafficking via the modulation of the COPII complex, facilitates cGAS/STING signaling for host immune responses, and precisely activates ion transporters and sensors to maintain cellular homeostasis. Dysregulated Mn homeostasis - whether stemming from genetic defects in key transporters (SLC30A10, SLC39A8, SLC39A11, and SLC39A14) or environmentally induced overload - fuels a spectrum of pathologies, including metabolic syndrome, Parkinsonism-like neurodegeneration, hepatic dysfunction, cardiovascular disease, and immune dysfunction. This disruption underscores the irreplaceable role of Mn as a biological linchpin, as its balance is not merely supportive but also central to sustaining health. In the future, we outline translational frontiers - from dietary Mn modulation and transporter-specific therapies for genetic Mn disorders to the elucidation of Mn signaling and the development of exposure guidelines to safeguard public health. This synthesis reaffirms that Mn is far more important than simply functioning as a nutrient. Research into Mn functions has been conducted across biology, environmental science, and medicine, and Mn acts as a master regulator whose emerging mechanisms will reshape our understanding of metabolic health and disease pathogenesis.

The origins of music therapy for psychiatric treatment are typically traced back to the mid-20th century, following World War II, and even further back to post-Renaissance Europe and ancient Greece within contemporary literature. However, these historical works often rely on philosophical and theological sources outside the medical field and do not address actual therapeutic practices. This article aims to rectify this oversight by shedding light on the unexplored realm of Ottoman music therapy (OMT) during the early modern Islamic period (ca. 14th-18th centuries). By delving into the utilization of OMT as a treatment for psychiatric disorders, this study seeks to provide valuable insights into the missing therapeutic practices of the era. We demonstrate how Ottoman physicians used music as a medical tool to target illnesses and restore health by prescribing makams (i.e., melodic modes) and implementing music as a treatment modality within hospitals (i.e., maristans). Gaining insight into the OMT theories and practices is necessary to bridge a significant gap in the chronology of contemporary music therapy. Furthermore, the resurgence of makams (also spelled as maqams, makām, or maqām) by the Ottomans in contemporary times has the potential to diversify the range of therapeutic modalities available within the clinical sphere. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Excitatory amino acid transporters (EAATs) are critical regulators of synaptic glutamate levels in the central nervous system. Dysregulated central nervous system glutamatergic homeostasis is implicated in many neurological diseases, highlighting the key role of EAATs in neurological health. We previously identified a library of small compounds that function as either positive allosteric modulators (PAMs) or negative allosteric modulators of EAATs, with diverse selectivity for subtypes EAAT1, EAAT2, and EAAT3, including astrocytic EAAT1 and EAAT2 and neuronal EAAT3. In this work, we characterized compounds from our library using molecular modeling, mutagenesis, and pharmacologic approaches. We focused on 3 representative compounds: NA-014, an EAAT2-selective PAM, DA-038, an EAAT1-3 PAM, and NA-010, an EAAT2-selective negative allosteric modulators. Binding studies demonstrated that these compounds do not interact with the orthosteric glutamate-binding site, confirming an allosteric action. Docking studies suggested several potential binding poses of NA-014 between the scaffold and transport domains of EAAT2, which we then studied with mutagenesis approaches. We identified potential binding sites of representative compounds in transmembrane domains 1, 5, 8, and hairpin 2 and demonstrated that these are necessary for their activity. Ten key amino acid residues within a subdomain of EAAT2 substituted into EAAT1 conferred EAAT2-selective PAM activity, demonstrating these residues are required and sufficient to enable selective PAM function. Collectively, these studies identified crucial subdomains and key amino acids linked to PAM activity, advancing our understanding of how to modulate EAAT activity. This knowledge can be integrated into future studies to develop EAAT allosteric modulators for neurological disorders. SIGNIFICANCE STATEMENT: We identified modulators of glutamate transporters, key regulators of central nervous system excitability and neuronal health. Using molecular modeling, mutagenesis, and pharmacology, we mapped their allosteric binding sites and identified ten residues that confer selective transport enhancement. This mechanism of transporter activation may guide development of therapies for disorders involving glutamatergic dysregulation, including stroke, neuropathic pain, and substance use disorders.

Intestinal and hepatic expression of cytochrome P450 3A4 (CYP3A4) is essential to the oxidative metabolism of many steroids, environmental toxins, and pharmaceutical drugs. The enzyme also produces 4β-hydroxycholesterol (4β-OHC) from cholesterol, an oxysterol involved in several metabolic signaling pathways and detectable in human circulation. Circulating 4β-OHC is increasingly used in drug development research as an endogenous biomarker of CYP3A4 activity to understand agent metabolism and the potential for drug-drug interactions. The relatively long half-life of 4β-OHC in blood provides temporal stability, while still retaining sensitivity to increase 2- to 4-fold within a week in response to a strong CYP3A4 inducer. Beyond pharmacometric studies, circulating 4β-OHC is emerging as a biomarker of cumulative CYP3A4-related detoxification capacity in epidemiologic studies of liver disease, renal disease, hypertension, diabetes, cancer, and other conditions. Discoveries in lipid biology have distinguished 4β-OHC from other oxysterols, revealing mechanisms by which endobiotic and xenobiotic metabolism can disrupt the homeostasis of cholesterol, fatty acids, and glucose. This review summarizes the expanding relevance of circulating 4β-OHC in epidemiologic research, focusing on clinical and demographic characteristics as sources of variation. Consistent with between-person variability in CYP3A4 activity, circulating 4β-OHC is typically higher for women, lean individuals, and genetically-determined CYP3A5 expressers, factors potentially affecting its application in both drug optimization and disease phenotyping.

Exposure to the heavy metal lead (Pb) is linked with postural balance in workers with elevated exposure, but risks from heavy metals at levels observed in the general population are uncertain. Using a refined balance examination with enhanced sensitivity for a broad age range of participants available in the 2021-2023 National Health and Nutrition Examination Survey (NHANES), we assessed associations between blood Pb and Cd and vestibular dysfunction. There were 3153 participants ages 20-69 with data on blood metals and vestibular dysfunction employing the improved Modified Romberg Test for postural balance. Associations were tested using log-binomial regression for pass/fail balance tests and hazard regression for time-to-failure analysis. After adjusting for age, race, sex, education, and smoking history, the highest quartile of cadmium (&#x2265;0.445&#x202f;&#x3bc;g/L) was marginally associated with balance dysfunction compared to the lowest quartile (<0.158&#x202f;&#x3bc;g/L): prevalence ratio (PR)=&#x202f;1.16 (95% Cl: 0.97, 1.38) for failing one of the first 4 balance tests, and PR=&#x202f;1.06 (95% Cl: 0.99, 1.14) for failing one of the 5 balance tests. No associations were observed with blood Pb or in failure time models. After incorporating sample weights and a more complete set of covariates in logistic regression models, odds ratio (OR) =&#x202f;1.77 (95% CI: 1.10, 2.84) for upper quartile Cd with failing one of the first 4 balance tests, and OR=&#x202f;1.43 (95% CI: 0.96, 2.13) for failing one of the 5 balance tests. Low levels of blood cadmium may be associated with vestibular dysfunction.

Loss of locus coeruleus (LC) integrity, a debilitating feature of Alzheimer's disease (AD), can be visualized in vivo with MRI. Longitudinal investigation across the AD spectrum can elucidate the timing of LC damage and its behavioral correlates.Cognitively normal adults (n=153), individuals with mild cognitive impairment (n=73), and with AD (n=43) underwent MR imaging to assess LC integrity, PET imaging to assess tau and A&#x3b2; ([18F]MK6240 and [18F]AZD4694, respectively) and completed a battery of cognitive tests. For a subset of participants, these assessments were repeated annually for up to four years. Linear mixed effects analysis examined the association of time and cognitive performance with LC signal.Reduction in LC integrity over time was significant for patients early in the course of AD (t95=-3.72, p=0.0003) but not in later AD phases or healthy aging. In AD participants, several cognitive measures correlated with LC integrity including logical memory (t64=2.57, p=0.013) and object recognition (t64=3.41, p=0.001).LC imaging reveals degeneration of the LC-norepinephrine system within subjects over time in early AD phases. LC damage correlates to cognitive impairment and the strong relationship observed of LC signal to object recognition could suggest an important role of this system in novelty detection in AD.

While pediatric ear foreign bodies are well described, injuries related to headphone earbud use have not been reported. As earbuds (and especially wireless ones) continue to increase in popularity, understanding the risks associated with earbud use becomes increasingly important. We conducted a retrospective review of earbud-related injuries in patients &#x2264;21 y using the National Electronic Injury Surveillance System from January 1, 2005, to December 31, 2024. Cases were identified with keyword search terms. Manual review of narratives was used to identify presenting complaints and associated symptoms. We identified 784 earbud-related cases, representing a national estimate of approximately 27,893 cases. Interestingly, cases increased significantly over time (4.2 cases/year; R2 = 0.85; P < 0.001). Ninety-eight percent of children were treated in the emergency department and discharged home. The most common presenting complaint was ear foreign body (61%), followed by nasal foreign body (13%) and swallowed foreign body (8%). Age-related differences were significant for both involved anatomical site and mechanism of injury (P < 0.001). Younger children (&#x2264;7) were more likely to swallow earbuds or insert them into the nose, while older children were more likely to sustain injuries from inserting them into the ear. Earbud-related injuries in children have increased significantly over the last 20 y. Younger children are more likely to ingest earbuds or insert them into their noses, whereas older children are more likely to experience ear injuries. These findings may reduce preventable harm through improved product design, age-specific safety precautions, and expanded education.

Burnout, elevated psychological distress, and reduced flourishing undermine the well-being of physician trainees and may ultimately compromise patient care. Exposure to ethno-racial trauma (ERT) can disrupt trainees' personal and professional identity formation and impede their learning experiences. This scoping review aims to synthesize the existing literature on how ERT affects the well-being of medical trainees. This review was conducted according to JBI methodology. A literature search of six bibliographic databases and one grey literature source was conducted in August 2023, and updated in June 2024, without time restriction applied. All English language studies conducted in the US that assessed the impact of ERT on physicians and/or physician trainees were included. Of the 4656 manuscripts identified for initial screening, 534 studies underwent full-text review, and 92 studies met inclusion criteria, with 45 studies focused on physician trainees alone and 18 focused on both physicians and physician trainees. Included studies were published between 1987 and 2024, with the majority of quantitative (49%) or qualitative (30%) methodology. Most frequently reported forms of ERT experienced by physician trainees included microaggressions, discrimination, implicit bias, invisibility, lack of belonging, devaluation of works, and disrespectful actions. Faculty, peers, patients, other practitioners and staff, community members, and medical school administrators were identified as sources of ERT. ERT was most often associated with burnout, isolation, and stress, and negatively impacted confidence, emotions, learning experience, and mental health. ERT impacted all domains of PERMA in this literature review. Current literature indicates that ERT has profound negative effects on physician trainees' well-being, contributing to burnout, psychological distress, and diminished sense of belonging. These impacts erode professional identity, hinder learning, and threaten long-term career satisfaction. Prospective, interventional studies are needed to further delineate the effects of ERT on trainees' well-being and inform strategies to mitigate these effects.

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Tonsillectomy is the most common pediatric surgery performed globally, yet little is known about how tonsillectomy outcomes vary worldwide. Although generally considered a safe surgery, tonsillectomy carries significant risks. Approximately 3% of US children require hospital readmission within 30 days due to life-threatening complications. While mortality rates in high-income countries (HICs) are relatively low (~0.0005%), mortality rates in low- and middle-income countries (LMICs) are not well characterized, with some reports suggesting rates many times higher (~3%). Despite the frequency and significance of tonsillectomy, it remains unclear how surgical indications, techniques, and settings may impact outcomes worldwide. In addition, there is currently no mechanism to perform a prospective investigation of global tonsillectomy outcomes. We hypothesize that the morbidity and mortality of routine tonsil surgery vary significantly according to geographic region and healthcare setting, as well as surgical indications and techniques. We aim 1) to quantify global variation in 30-day major postoperative complications and mortality following pediatric tonsillectomy across World Health Organization (WHO) regions and 2) to characterize global variation in pediatric tonsillectomy surgical indications and operative techniques across WHO regions. OtoSurg 1 will be an international, multi-site, prospective cohort study. The central IRB is approved and hosted by Emory University (IRB ID: STUDY00009113). All healthcare facilities globally that perform pediatric tonsillectomy will be invited to participate. Participating investigators will be trained to collect data on patients undergoing primary tonsillectomy over a 90-day period at their respective institutions. Site-based teams will record demographic data, surgical indication(s), surgical technique(s), postoperative complications, and mortality directly into a global de-identified tonsillectomy outcomes data registry. We will leverage existing relationships and professional networks to recruit participants from 30 sites in each of the six WHO regions for a target of 180 partner sites. This study will highlight potential opportunities for intervention to standardize and improve outcomes for the world's most common pediatric surgery, focusing on LMICs. Beyond its primary objectives, this project will also seek 1) to recruit and train a collaborative research network of otolaryngology surgeons from around the world and 2) to build the digital infrastructure necessary to support this network sustainably. This collaborative research network will serve as the foundation for future large-scale research initiatives and for the development and implementation of novel, data-driven interventions.