Inappropriate Acetazolamide Use for a Hiker Who Developed Acute Kidney Injury.

Prophylactic use of acetazolamide (ACZ) to prevent acute mountain sickness (AMS) is a common practice among high altitude travelers and mountaineers. With its use comes a possible risk of acute kidney injury (AKI). We present a case in which a 56-year-old male hiker in Grand Canyon National Park developed acute exertional rhabdomyolysis and subsequent AKI while taking prophylactic ACZ to prevent AMS. This medication was prescribed despite the hiker encountering only moderate altitude at Grand Canyon with a planned descent within <24 h. The resulting AKI was determined to be the combined result of acute exertional rhabdomyolysis and dehydration/hypovolemia, with the ACZ, a diuretic, as a contributing factor. Medical providers need to recognize the risks/benefits with ACZ use for AMS prophylaxis and avoid prescribing it to individuals whose altitude exposure and activity fall outside the clinical practice guidelines recommended for use.

Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures.

Connexins (Cxs) are a family of integral membrane proteins, which function as both hexameric hemichannels (HCs) and dodecameric gap junction channels (GJCs), behaving as conduits for the electrical and molecular communication between cells and between cells and the extracellular environment, respectively. Their proper functioning is crucial for many processes, including development, physiology, and response to disease and trauma. Abnormal GJC and HC communication can lead to numerous pathological states including inflammation, skin diseases, deafness, nervous system disorders, and cardiac arrhythmias. Over the last 15 years, high-resolution X-ray and electron cryomicroscopy (cryoEM) structures for seven Cx isoforms have revealed conservation in the four-helix transmembrane (TM) bundle of each subunit; an αß fold in the disulfide-bonded extracellular loops and inter-subunit hydrogen bonding across the extracellular gap that mediates end-to-end docking to form a tight seal between hexamers in the GJC. Tissue injury is associated with cellular Ca2+ overload. Surprisingly, the binding of 12 Ca2+ ions in the Cx26 GJC results in a novel electrostatic gating mechanism that blocks cation permeation. In contrast, acidic pH during tissue injury elicits association of the N-terminal (NT) domains that sterically blocks the pore in a "ball-and-chain" fashion. The NT domains under physiologic conditions display multiple conformational states, stabilized by protein-protein and protein-lipid interactions, which may relate to gating mechanisms. The cryoEM maps also revealed putative lipid densities within the pore, intercalated among transmembrane α-helices and between protomers, the functions of which are unknown. For the future, time-resolved cryoEM of isolated Cx channels as well as cryotomography of GJCs and HCs in cells and tissues will yield a deeper insight into the mechanisms for channel regulation. The cytoplasmic loop (CL) and C-terminal (CT) domains are divergent in sequence and length, are likely involved in channel regulation, but are not visualized in the high-resolution X-ray and cryoEM maps presumably due to conformational flexibility. We expect that the integrated use of synergistic physicochemical, spectroscopic, biophysical, and computational methods will reveal conformational dynamics relevant to functional states. We anticipate that such a wealth of results under different pathologic conditions will accelerate drug discovery related to Cx channel modulation.

Wilderness Medical Society Clinical Practice Guidelines for Spinal Cord Protection: 2024 Update.

The Wilderness Medical Society reconvened an expert panel to update best practice guidelines for spinal cord protection during trauma management. This panel, with membership updated in 2023, was charged with the development of evidence-based guidelines for management of the injured or potentially injured spine in wilderness environments. Recommendations are made regarding several parameters related to spinal cord protection. These recommendations are graded based on the quality of supporting evidence and balance the benefits and risks/burdens for each parameter according to American College of Chest Physicians methodology. Key recommendations include the concept that interventions should be goal-oriented (spinal cord/column protection in the context of overall patient and provider safety) rather than technique-oriented (immobilization). An evidence-based, goal-oriented approach excludes the immobilization of suspected spinal injuries via rigid collars or backboards.

Discovery of Novel Rhizoctonia solani DHFR Inhibitors as Fungicides Using Virtual Screening.

Dihydrofolate reductase (DHFR) is an essential enzyme in the folate pathway and has been recognized as a well-known target for antibacterial and antifungal drugs. We discovered eight compounds from the ZINC database using virtual screening to inhibit Rhizoctonia solani (R. solani), a fungal pathogen in crops. These compounds were evaluated with in vitro assays for enzymatic and antifungal activity. Among these, compound Hit8 is the most active R. solani DHFR inhibitor, with the IC50 of 10.2 µM. The selectivity of inhibition is 22.3 against human DHFR with the IC50 of 227.7 µM. Moreover, Hit8 has higher antifungal activity against R. solani (EC50 of 38.2 mg L-1) compared with validamycin A (EC50 of 67.6 mg L-1), a well-documented fungicide. These results suggest that Hit8 may be a potential fungicide. Our study exemplifies a computer-aided method to discover novel inhibitors that could target plant pathogenic fungi.

Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs.

To mediate cell-to-cell communication via gap junction channels (GJCs), connexins (Cx) traffic as hexameric hemichannels to the plasma membrane, which dock end-to-end between adjacent cell membranes, thereby forming a dodecameric intercellular conduit. Hemichannels also function independently to mediate the passage of contents between the cytoplasm and extracellular space. To generate hemichannels, the mutation N176Y was introduced into the second extracellular loop of Cx26. The electron cryomicroscopy structure of the hexameric hemichannel in lipid bilayer nanodiscs displays an open pore and a 4-helix bundle transmembrane design that is nearly identical to dodecameric GJCs. In contrast to the high resolution of the transmembrane α-helices, the extracellular loops are less well resolved. The conformational flexibility of the extracellular loops may be essential to facilitate surveillance of hemichannels in apposed cells to identify compatible Cx isoforms that enable intercellular docking. Our results also provide a structural foundation for previous electrophysiologic and permeation studies of Cx hemichannels.

Capturing the Catalytic Proton of Dihydrofolate Reductase: Implications for General Acid-Base Catalysis.

Acid-base catalysis, which involves one or more proton transfer reactions, is a chemical mechanism commonly employed by many enzymes. The molecular basis for catalysis is often derived from structures determined at the optimal pH for enzyme activity. However, direct observation of protons from experimental structures is quite difficult; thus, a complete mechanistic description for most enzymes remains lacking. Dihydrofolate reductase (DHFR) exemplifies general acid-base catalysis, requiring hydride transfer and protonation of its substrate, DHF, to form the product, tetrahydrofolate (THF). Previous X-ray and neutron crystal structures coupled with theoretical calculations have proposed that solvent mediates the protonation step. However, visualization of a proton transfer has been elusive. Based on a 2.1 Å resolution neutron structure of a pseudo-Michaelis complex of E. coli DHFR determined at acidic pH, we report the direct observation of the catalytic proton and its parent solvent molecule. Comparison of X-ray and neutron structures elucidated at acidic and neutral pH reveals dampened dynamics at acidic pH, even for the regulatory Met20 loop. Guided by the structures and calculations, we propose a mechanism where dynamics are crucial for solvent entry and protonation of substrate. This mechanism invokes the release of a sole proton from a hydronium (H3O+) ion, its pathway through a narrow channel that sterically hinders the passage of water, and the ultimate protonation of DHF at the N5 atom.

Management of Hypothermia in Tactical Combat Casualty Care: TCCC Guideline Proposed Change 20-01 (June 2020).

As an outcome of combat injury and hemorrhagic shock, trauma-induced hypothermia (TIH) and the associated coagulopathy and acidosis result in significantly increased risk for death. In an effort to manage TIH, the Hypothermia Prevention and Management Kit™ (HPMK) was implemented in 2006 for battlefield casualties. Recent feedback from operational forces indicates that limitations exist in the HPMK to maintain thermal balance in cold environments, due to the lack of insulation. Consequently, based on lessons learned, some US Special Operations Forces are now upgrading the HPMK after short-term use (60 minutes) by adding insulation around the casualty during training in cold environments. Furthermore, new research indicates that the current HPMK, although better than no hypothermia protection, was ranked last in objective and subjective measures in volunteers when compared with commercial and user-assembled external warming enclosure systems. On the basis of these observations and research findings, the Committee on Tactical Combat Casualty Care decided to review the hypothermia prevention and management guidelines in 2018 and to update them on the basis of these facts and that no update has occurred in 14 years. Recommendations are made for minimal costs, low cube and weight solutions to create an insulated HPMK, or when the HPMK is not readily available, to create an improvised hypothermia (insulated) enclosure system.

Wilderness Medical Society Clinical Practice Guidelines for the Management of Exercise-Associated Hyponatremia: 2019 Update.

Exercise-associated hyponatremia (EAH) is defined by a serum or plasma sodium concentration below the normal reference range of 135 mmol·L-1 that occurs during or up to 24 h after prolonged physical activity. It is reported to occur in individual physical activities or during organized endurance events conducted in environments in which medical care is limited and often not available, and patient evacuation to definitive care is often greatly delayed. Rapid recognition and appropriate treatment are essential in the severe form to increase the likelihood of a positive outcome. To mitigate the risk of EAH mismanagement, care providers in the prehospital and in hospital settings must differentiate from other causes that present with similar signs and symptoms. EAH most commonly has overlapping signs and symptoms with heat exhaustion and exertional heat stroke. Failure in this regard is a recognized cause of worsened morbidity and mortality. In an effort to produce best practice guidelines for EAH management, the Wilderness Medical Society convened an expert panel in May 2018. The panel was charged with updating the WMS Practice Guidelines for Treatment of Exercise-Associated Hyponatremia published in 2014 using evidence-based guidelines for the prevention, recognition, and treatment of EAH. Recommendations are made based on presenting with symptomatic EAH, particularly when point-of-care blood sodium testing is unavailable in the field. These recommendations are graded on the basis of the quality of supporting evidence and balanced between the benefits and risks/burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians.

Is Community Relevance Enough? Civic and Science Identity Impact of Microbiology CUREs Focused on Community Environmental Justice.

Course-based undergraduate research experiences (CUREs) often involve a component where the outcomes of student research are broadly relevant to outside stakeholders. We wanted to see if building courses around an environmental justice issue relevant to the local community would impact students' sense of civic engagement and appreciation of the relevance of scientific research to the community. In this quasi-experimental study, we assessed civic engagement and scientific identity gains (N = 98) using pre- and post-semester surveys and open-ended interview responses in three different CUREs taught simultaneously at three different universities. All three CURES were focused on an environmental heavy metal pollution issue predominantly affecting African-Americans in Birmingham, Alabama. While we found increases in students' sense of science efficacy and identity, our team was unable to detect meaningful changes in civic engagement levels, all of which were initially quite high. However, interviews suggested that students were motivated to do well in their research because the project was of interest to outside stakeholders. Our observations suggest that rather than directly influencing students' civic engagement, the "broadly relevant" component of our CUREs engaged their pre-existing high levels of engagement to increase their engagement with the material, possibly influencing gains in science efficacy and science identity. Our observations are consistent with broader community relevance being an important component of CURE success, but do not support our initial hypothesis that CURE participation would influence students' attitudes toward the civic importance of science.

Wilderness Medical Society Clinical Practice Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia: 2019 Update.

To provide guidance to clinicians, the Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for the out-of-hospital evaluation and treatment of victims of accidental hypothermia. The guidelines present the main diagnostic and therapeutic modalities and provide recommendations for the management of hypothermic patients. The panel graded the recommendations based on the quality of supporting evidence and a balance between benefits and risks/burdens according to the criteria published by the American College of Chest Physicians. The guidelines also provide suggested general approaches to the evaluation and treatment of accidental hypothermia that incorporate specific recommendations. This is the 2019 update of the Wilderness Medical Society Practice Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia: 2014 Update.

Wilderness Medical Society Clinical Practice Guidelines for Spinal Cord Protection.

The Wilderness Medical Society reconvened an expert panel to update best practice guidelines for spinal cord protection during trauma management. This panel, with membership updated in 2018, was charged with the development of evidence-based guidelines for management of the injured or potentially injured spine in wilderness environments. Recommendations are made regarding several parameters related to spinal cord protection. These recommendations are graded based on the quality of supporting evidence and balance the benefits and risks/burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians. Key recommendations include the concept that interventions should be goal oriented (spinal cord/column protection in the context of overall patient and provider safety) rather than technique oriented (immobilization). This evidence-based, goal-oriented approach does not support the immobilization of suspected spinal injuries via rigid collars or backboards.

Management of Hemorrhage From Craniomaxillofacial Injuries and Penetrating Neck Injury in Tactical Combat Casualty Care: iTClamp Mechanical Wound Closure Device TCCC Guidelines Proposed Change 19-04 06 June 2019.

The 2012 study Death on the battlefield (2001-2011) by Eastridge et al.1 demonstrated that 7.5% of the prehospital deaths caused by potentially survivable injuries were due to external hemorrhage from the cervical region. The increasing use of Tactical Combat-Casualty Care (TCCC) and other medical interventions have dramatically reduced the overall rate of combat-related mortality in US forces; however, uncontrolled hemorrhage remains the number one cause of potentially survivable combat trauma. Additionally, the use of personal protective equipment and adaptations in the weapons used against US forces has caused changes in the wound distribution patterns seen in combat trauma. There has been a significant proportional increase in head and neck wounds, which may result in difficult to control hemorrhage. More than 50% of combat wounded personnel will receive a head or neck wound. The iTClamp (Innovative Trauma Care Inc., Edmonton, Alberta, Canada) is the first and only hemorrhage control device that uses the hydrostatic pressure of a hematoma to tamponade bleeding from an injured vessel within a wound. The iTClamp is US Food and Drug Administration (FDA) approved for use on multiple sites and works in all compressible areas, including on large and irregular lacerations. The iTClamp's unique design makes it ideal for controlling external hemorrhage in the head and neck region. The iTClamp has been demonstrated effective in over 245 field applications. The device is small and lightweight, easy to apply, can be used by any level of first responder with minimal training, and facilitates excellent skills retention. The iTClamp reapproximates wound edges with four pairs of opposing needles. This mechanism of action has demonstrated safe application for both the patient and the provider, causes minimal pain, and does not result in tissue necrosis, even if the device is left in place for extended periods. The Committee on TCCC recommends the use of the iTClamp as a primary treatment modality, along with a CoTCCC-recommended hemostatic dressing and direct manual pressure (DMP), for hemorrhage control in craniomaxillofacial injuries and penetrating neck injuries with external hemorrhage.

The iTClamp in the treatment of prehospital craniomaxillofacial injury: a case series study.

BACKGROUND: Craniomaxillofacial (CMF) injuries are very common in both civilian and military settings. Nearly half of all civilian trauma incidents include a scalp laceration and historical rates of CMF battle injuries increased from 16%-21% to 42.2%. The scalp is highly vascular tissue and uncontrolled bleeding can lead to hypotension, shock and death. Therefore, enabling on-scene providers, both military and civilian, to immediately manage scalp and face lacerations, in a manner that allows them to still function in a tactical way, offers operational advantages. This case series examines how effectively a wound-clamp (iTClamp) controlled bleeding from CMF injuries pre-hospital environment. METHODS: The use of the iTClamp for CMF (scalp and face laceration) was extracted from iTrauma Care's post market surveillance database. Data was reviewed and a descriptive analysis was applied. RESULTS: 216 civilian cases of iTClamp use were reported to iTrauma Care. Of the 216 cases, 37% (n=80) were for control of CMF hemorrhage (94% scalp and 6% face). Falls (n=24) and MVC (n=25) accounted for 61% of the mechanism of injury. Blunt accounted for 66% (n=53), penetrating 16% (n=13) and unknown 18% (n=14). Adequate hemorrhage control was reported in 87.5% (n=70) of cases, three respondents reported inadequate hemorrhage control and in seven cases hemorrhage control was not reported. Direct pressure and packing was abandoned in favor of the iTClamp in 27.5% (n=22) of cases. CONCLUSIONS: CMF injuries are common in both civilian and military settings. Current options like direct manual pressure (DMP) often do not work well, are formidable to maintain on long transports and Raney clips are a historical suggestion. The iTClamp offers a new option for control of external hemorrhage from open wounds within compressible zones.

Worldwide Case Reports Using the iTClamp for External Hemorrhage Control.

BACKGROUND: Historically, hemorrhage control strategies consisted of manual pressure, pressure dressings, gauze with or without hemostatic ingredients for wound packing, or the use of tourniquets. The iTClamp is a relatively new alternative to stop external bleeding. METHODS: An anonymous survey was used to evaluate the outcomes of the iTClamp in worldwide cases of external bleeding. RESULTS: A total of 245 evaluable applications were reported. The iTClamp stopped the bleeding in 81% (n = 198) of the cases. Inadequate bleeding control was documented in 8% (n = 20) and in the remaining 11% (n = 27), bleeding control was not reported. The top three anatomic body regions for iTClamp application were the scalp, 37% (n = 91); arm, 20% (n = 49); and leg, 19% (n = 46). In 26% of the reported cases (direct pressure [23% (n = 63)] and tourniquets [3% (n = 8]), other techniques were abandoned in favor of the iTClamp. Conversely, the iTClamp was abandoned in favor of direct pressure 11 times (4.4%) and abandoned in favor of a tourniquet three times (1%). CONCLUSION: The iTClamp appears to be a fast and reliable device to stop external bleeding. Because of its function and possible applications, it has potential to lessen the gap between and add to the present selection of devices for treatment of external bleeding.

Awake Cricothyrotomy: A Novel Approach to the Surgical Airway in the Tactical Setting.

Airway obstruction on the battlefield is most often due to maxillofacial trauma, which may include bleeding and disrupted airway anatomy. In many of these cases, surgical cricothyrotomy (SC) is the preferred airway management procedure. SC is an emergency airway procedure performed when attempts to open an airway using nasal devices, oral devices, or tracheal intubation have failed, or when the risks from intubation are unacceptably high. The aim of this overview is to describe a novel approach to the inevitably surgical airway in which SC is the first and best procedure to manage the difficult or failed airway. The awake SC technique and supporting algorithm are presented along with the limitations and future directions. Awake SC, using local anesthetic with or without ketamine, will allow the knowledgeable provider to manage patients with a compromised airway across the continuum of emergency care ranging from remote/en route care, austere settings, and prehospital to the emergency department.

Battlefield Trauma-Induced Hypothermia: Transitioning the Preferred Method of Casualty Rewarming.

For centuries, cold and wet weather has affected military combat operations leading to tremendous loss of manpower caused by cold-weather-related injuries including trench foot, frostbite, and hypothermia. The initial battlefield management of hypothermia in military personnel had not advanced significantly following many wars and conflicts until 2006. The aim of this review is to: 1) provide an overview of trauma-induced hypothermia (TIH); 2) highlight the Department of Defense strategy for the implementation of a hypothermia clinical management program for battlefield (prehospital) casualties; 3) highlight the research and development of the Hypothermia Prevention and Management Kit (HPMK) as the preferred field rewarming system for battlefield TIH; and 4) emphasize how the HPMK can be easily transitioned to the civilian sector for active rewarming of both accidental and TIH patients. The HPMK is ideal for those working in civilian Emergency Medical Services and austere prehospital care environments. This kit is a low cost, lightweight, small dimension commercial product that can provide effective passive management or active rewarming for both accidental (primary) and trauma-induced (secondary) hypothermia patients.

Tactical Combat Casualty Care and Wilderness Medicine: Advancing Trauma Care in Austere Environments.

Tactical Combat Casualty Care (TCCC) is a set of evidence-based, best-practice prehospital trauma care guidelines customized for use on the battlefield. Military units that have trained all of their unit members in TCCC have now documented the lowest incidence of preventable deaths in the history of modern warfare and TCCC is now the standard for battlefield trauma care in the US Military. TCCC and wilderness medicine share the goal of optimizing care for patients with trauma in austere environments that impose significant challenges in both equipment and evacuation capability. This article reviews the current battlefield trauma care recommendations in TCCC and discusses their applicability to the wilderness setting.