Management of non-compressible torso hemorrhage of the abdomen in civilian and military austere environments: a scoping review.

Background: Non-compressible abdominal hemorrhage (NCAH) is the leading cause of potentially preventable deaths in both civilian and military austere environments, and an improvement in mortality due to this problem has not been demonstrated during the past quarter century. Several innovations have been developed to control hemorrhage closer to the point of injury. Objective: This review assessed NCAH interventions in civilian and military settings, focusing on austere environments. It identified innovations, effectiveness, and knowledge gaps for future research. Methodology: The Joanna Briggs Institute for Evidence Synthesis methodology guided this scoping review to completion. Studies evaluating NCAH with human participants in civilian and military austere environments that were eligible for inclusion were limited to English language studies published between December 1990 and January 2023. The PCC (Participant, Concept, Context) framework was used for data synthesis. Deductive and inductive thematic analyses were used to assess the literature that met inclusion criteria, identify patterns/themes to address the research questions and identify common themes within the literature. A stakeholder consultation was conducted to review and provide expert perspectives and opinions on the results of the deductive and inductive thematic analyses. Results: The literature search identified 868 articles; 26 articles met the inclusion criteria. Textual narrative analysis of the 26 articles resulted in the literature addressing four main categories: NCAH, penetrating abdominal trauma, resuscitative endovascular balloon occlusion of the aorta (REBOA), and ResQFoam. The deductive thematic analysis aimed to answer three research questions. Research question 1 addressed the effectiveness of REBOA, damage control resuscitation, and damage control surgery in managing NCAH in austere environments. No effectiveness studies were found on this topic. Research question 2 identified three knowledge gaps in NCAH management in austere environments. The analysis identified early hemorrhage control, prehospital provider decision-making ability, and REBOA implementation as knowledge gaps in NCAH. Research question 3 identified five innovations that may affect the management of NCAH in the future: transport of patients, advanced resuscitative care, expert consultation, REBOA implementation, and self-expanding foam implementation. The inductive thematic analysis resulted in four recurrent themes from the literature: prehospital care, decision-making, hemorrhage control, and mortality in NCAH. During the stakeholders' consultation, the results of the deductive and inductive thematic analyses were reviewed and agreed on by the stakeholders. Special emphasis and discussion were given to prehospital management, expert opinions in the prehospital environment, decision-making in the prehospital environment, transport and resuscitation in the prehospital setting, REBOA, alternative discussion for research, and research gaps. Conclusion: NCAH is still a significant cause of preventable death in both military and civilian austere environments, even with ongoing research and interventions aimed at extending survival in such conditions. This scoping review has identified several potential concepts that could reduce the mortality associated with a preventable cause of death due to hemorrhage in austere environments.

Microglial activating transcription factor 3 upregulation: An indirect target to attenuate inflammation in the nervous system.

Activating Transcription Factor 3 (ATF3) is upregulated in reaction to several cellular stressors found in a wide range of pathological conditions to coordinate a transcriptional response. ATF3 was first implicated in the transcriptional reaction to axotomy when its massive upregulation was measured in sensory and motor neuron cell bodies following peripheral nerve injury. It has since been shown to be critical for successful axon regeneration in the peripheral nervous system and a promising target to mitigate regenerative failure in the central nervous system. However, much of the research to date has focused on ATF3's function in neurons, leaving the expression, function, and therapeutic potential of ATF3 in glia largely unexplored. In the immunology literature ATF3 is seen as a master regulator of the innate immune system. Specifically, in macrophages following pathogen or damage associated molecular pattern receptor activation and subsequent cytokine release, ATF3 upregulation abrogates the inflammatory response. Importantly, ATF3 upregulation is not exclusively due to cellular stress exposure but has been achieved by the administration of several small molecules. In the central nervous system, microglia represent the resident macrophage population and are therefore of immediate interest with respect to ATF3 induction. It is our perspective that the potential of inducing ATF3 expression to dampen inflammatory microglial phenotype represents an unexplored therapeutic target and may have synergistic benefits when paired with concomitant neuronal ATF3 upregulation. This would be of particular benefit in pathologies that involve both detrimental inflammation and neuronal damage including spinal cord injury, multiple sclerosis, and stroke.

Systemic hypoxia mimicry enhances axonal regeneration and functional recovery following peripheral nerve injury.

Despite the ability of peripheral nerves to regenerate after injury, failure occurs due to an inability of supporting cells to maintain growth, resulting in long-term consequences such as sensorimotor dysfunction and neuropathic pain. Here, we investigate the potential of engaging the cellular adaptive response to hypoxia, via inhibiting its negative regulators, to enhance the regenerative process. Under normoxic conditions, prolyl hydroxylase domain (PHD) proteins 1, 2, and 3 hydroxylate the key metabolic regulator hypoxia inducible factor 1α (HIF1α), marking it for subsequent proteasomal degradation. We inhibited PHD protein function systemically via either individual genetic deletion or pharmacological pan-PHD inhibition using dimethyloxalylglycine (DMOG). We show enhanced axonal regeneration after sciatic nerve crush injury in PHD1-/- mice, PHD3-/- mice, and in DMOG-treated mice, and in PHD1-/- and DMOG-treated mice a reduction in hypersensitivity to cooling after permanent sciatic ligation. Electromyographically, PHD1-/- and PHD3-/- mice showed an increased CMAP amplitude one-month post-injury, probably due to protection against denervation induced muscle atrophy, while DMOG-treated and PHD2+/- mice showed reduced latencies, indicating improved motor axon function. DMOG treatment did not affect the growth of dorsal root ganglion neurites in vitro, suggesting a lack of direct effects of DMOG on axonal regrowth. Enhanced regeneration in vivo was concurrent with an increase in macrophage density, and a shift in macrophage polarization state ratios (from M1-like toward M2-like) in DMOG-treated animals. These results indicate PHD proteins as a novel therapeutic target to improve regenerative and functional outcomes after peripheral nerve injury without manipulating molecular O2.

TXA (Tranexamic Acid) Risk Evaluation in Combat Casualties (TRECC).

BACKGROUND: The use of tranexamic acid (TXA) has become increasingly prevalent for hemorrhage prevention in military trauma patients due to its known survival benefits. There is concern of increased venous thromboembolism (VTE) subsequent to receiving TXA. The purpose of this retrospective study was to determine the rate of VTE in severely injured military personnel during Operation Enduring Freedom (2009-2014). METHODS: An analysis of 859 military trauma patients from the 2009-2014 Department of Defense Trauma Registry included subjects with an injury severity score (ISS) >10 and a massive transfusion (MT) (>10 units of blood products in the first 24 hours). Outcomes included a documented VTE (eg, deep vein thrombosis (DVT) or pulmonary embolism (PE)) during the patient's hospital course. Comparison between those who did/did not receive TXA was analyzed using three separate multiple regression analyses using listwise deletion, systematic replacement and multiple imputation. RESULTS: Subjects (n=620) met inclusion criteria with 27% (n=169) having a documented VTE. A total of 30% that received TXA had a documented VTE, 26% that did not receive TXA had a documented VTE and 43% (n=264, n=620) of the sample did not have TXA documented as either given or not given. Multiple regression analyses using listwise deletion and systematic replacement of the TXA variable demonstrated no difference in odds of VTE, whereas the multiple imputation analysis demonstrated a 3% increased odds of VTE, a9.4% increased odds of PE and 8.1% decreased odds of DVT with TXA administration. DISCUSSION: TXA use with an ISS >10 and MT resuscitation had a 3% increased odds of VTE and an increased odds of PE, whereas the odds of DVT were found to be decreased after multiple imputation analysis. Further research on the long-term risks and benefits of TXA usage in the military population is recommended. LEVEL OF EVIDENCE: IV-therapeutic.

Predictive survival factors of the traumatically injured on venovenous extracorporeal membrane oxygenation: A Bayesian model.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (ECMO) has had encouraging evidence suggesting efficacy and acceptable safety in trauma patients with refractory respiratory failure. Given the obstacles of accruing adequate quality prospective data for a resource-intensive modality, it is unclear what is indicative of survival to discharge. We investigate pre-ECMO characteristics (age, Injury Severity Score [ISS], time from admission to cannulation, P:F ratio) in trauma patients to determine correlation with survival. METHODS: To address these challenges, we use Bayesian inference and patients from a level I trauma center and Extracorporeal Life Support Organization-designated Gold Center of Excellence (N = 12), published literature, and Markov chain Monte Carlo simulation to determine if there is strong predictive probability regarding survival to discharge. RESULTS: Bayesian inference probabilities expressed as odds ratios with 95% credible intervals (CrIs) were as follows: age (e = 0.981; CrI, 0.976-0.985), ISS (e = 0.996; CrI, 0.980-1.012), P:F ratio (e = 1.000; CrI, 0.996-1.003), and time from admission to ECMO (e = 0.988; CrI, 0.974-1.004). Bayes factors (BF) were as follows: BFage = 3.151, BFISS = 3.564 × 10, BFpf = 0.463, and BFtime = 913.758. CONCLUSION: Age was the only pre-ECMO factor that demonstrated the most certain effect on hospital mortality for trauma patients placed on venovenous ECMO. The ISS and time to ECMO initiation had some appreciable impact on survival although less certain than age; P:F ratio likely had none. However, the pre-ECMO factors that were found to have any impact on mortality were relatively diminutive. More studies are necessary to update prior distributions and enhance accuracy. LEVEL OF EVIDENCE: Prognostic, Level IV.

An ATF3-CreERT2 Knock-In Mouse for Axotomy-Induced Genetic Editing: Proof of Principle.

Genome editing techniques have facilitated significant advances in our understanding of fundamental biological processes, and the Cre-Lox system has been instrumental in these achievements. Driving Cre expression specifically in injured neurons has not been previously possible: we sought to address this limitation in mice using a Cre-ERT2 construct driven by a reliable indicator of axotomy, activating transcription factor 3 (ATF3). When crossed with reporter mice, a significant amount of recombination was achieved (without tamoxifen treatment) in peripherally-projecting sensory, sympathetic, and motoneurons after peripheral nerve crush in hemizygotes (65-80% by 16 d) and was absent in uninjured neurons. Importantly, injury-induced recombination did not occur in Schwann cells distal to the injury, and with a knock-out-validated antibody we verified an absence of ATF3 expression. Functional recovery following sciatic nerve crush in ATF3-deficient mice (both hemizygotes and homozygotes) was delayed, indicating previously unreported haploinsufficiency. In a proof-of-principle experiment, we crossed the ATF3-CreERT2 line with a floxed phosphatase and tensin homolog (PTEN) line and show significantly improved axonal regeneration, as well as more complete recovery of neuromuscular function. We also demonstrate the utility of the ATF3-CreERT2 hemizygous line by characterizing recombination after lateral spinal hemisection (C8/T1), which identified specific populations of ascending spinal cord neurons (including putative spinothalamic and spinocerebellar) and descending supraspinal neurons (rubrospinal, vestibulospinal, reticulospinal and hypothalamic). We anticipate these mice will be valuable in distinguishing axotomized from uninjured neurons of several different classes (e.g., via reporter expression), and in probing the function of any number of genes as they relate to neuronal injury and regeneration.

Preserved Adrenal Function After Lumbar Spinal Cord Transection Augments Low Pressure Bladder Activity in the Rat.

Spinal cord injury (SCI) disconnects supraspinal micturition centers from the lower urinary tract resulting in immediate and long-term changes in bladder structure and function. While cervical and high thoracic SCI have a greater range of systemic effects, clinical data suggest that those with lower (suprasacral) injuries develop poorer bladder outcomes. Here we assess the impact of SCI level on acute changes in bladder activity. We used two SCI models, T3 and L2 complete transections in male Wistar rats, and compared bladder pressure fluctuations to those of naïve and bladder-denervated animals. By 2 days after L2 transection, but not T3 transection or bladder denervation, small amplitude rhythmic contractions (1 mmHg, 0.06 Hz) were present at low intravesical pressures (<6 mmHg); these were still present 1 month following injury, and at 3 months, bladders from L2 SCI animals were significantly larger than those from T3 SCI or naïve animals. Low-pressure contractions were unaffected by blocking ganglionic signaling or bladder denervation at the time of measurements. L2 (and sham surgery) but not T3 transection preserves supraspinal adrenal control, and by ELISA we show lower plasma adrenal catecholamine concentration in the latter. When an adrenalectomy preceded the L2 transection, the aberrant low-pressure contractions more closely resembled those after T3 transection, indicating that the increased bladder activity after lumbar SCI is mediated by preserved adrenal function. Since ongoing low-pressure contractions may condition the detrusor and exacerbate detrusor-sphincter dyssynergia, moderating bladder catecholamine signaling may be a clinically viable intervention strategy.

Preinjury statin use and thromboembolic events in trauma: a 10-year retrospective evaluation.

BACKGROUND: Traumatic injury is well known to increase the risk of venous thromboembolic events (VTEs), occurring in up to 58% of trauma patients. Statin medications have significant anti-inflammatory properties and have been shown to reduce the risk of VTE. We hypothesized that trauma patients who received statin medication before injury would have a lower incidence of VTE after injury. METHODS: A 10-y retrospective review identified all patients admitted to our trauma service with an injury severity score >9 and an intensive care unit stay of >3 d. This population was categorized as either "statin recipient" (SR) or "statin naïve," with subsequent categorical division by occurrence of VTE. Our primary outcome measure was the occurrence of documented VTE in both statin naïve and SR subjects. RESULTS: A total of 2519 trauma patients were included with 97 (3.8%) developing VTE. Pretrauma statin use in males remained as an independent predictor of VTE (odds ratio = 2.25, 95% confidence interval = 1.25-4.04, P < 0.01). The median time to VTE onset was 3 d longer in SRs (10.0 d; confidence interval = 7.3-12.7, P < 0.05). CONCLUSIONS: Pretrauma statin use does not appear to have a protective benefit of VTE prevention in trauma patients, as we have shown pretrauma SR male trauma patients to have a twofold increased incidence of VTE. However, when considering the 3 d longer median time to VTE onset found in SRs, we consider the protective benefit of statin use reported in the current literature as likely attributable to this observed delayed onset.

Platelet transfusion does not improve outcomes in patients with brain injury on antiplatelet therapy.

INTRODUCTION: Platelet dysfunction following traumatic brain injury (TBI) is associated with worse outcomes. The efficacy of platelet transfusion to reverse antiplatelet medication (APM) remains unknown. Thrombelastography platelet mapping (TEG-PM) assesses platelet function. We hypothesize that platelet transfusion can reverse the effects of APM but does not improve outcomes following TBI. METHODS: An observational study at six US trauma centres was performed. Adult patients on APM with CT evident TBI after blunt injury were enrolled. Demographics, brain CT and TEG-PM results before/after platelet transfusion, length of stay (LOS), and injury severity score (ISS) were abstracted. RESULTS: Sixty six patients were enrolled (89% aspirin, 50% clopidogrel, 23% dual APM) with 23 patients undergoing platelet transfusion. Transfused patients had significantly higher ISS and admission CT scores. Platelet transfusion significantly reduced platelet inhibition due to aspirin (76.0 ± 30.2% to 52.7 ± 31.5%, p < 0.01), but had a non-significant impact on clopidogrel-associated inhibition (p = 0.07). Platelet transfusion was associated with longer length of stay (7.8 vs. 3.5 days, p < 0.01), but there were no differences in mortality. CONCLUSION: Platelet transfusion significantly decreases platelet inhibition due to aspirin but is not associated with change in outcomes in patients on APM following TBI.

Multicenter evaluation of temporary intravascular shunt use in vascular trauma.

BACKGROUND: The indications and outcomes associated with temporary intravascular shunting (TIVS) for vascular trauma in the civilian sector are poorly understood. The objective of this study was to perform a contemporary multicenter review of TIVS use and outcomes. METHODS: Patients sustaining vascular trauma, requiring TIVS insertion (January 2005 to December 2013), were retrospectively identified at seven Level I trauma centers. Clinical demographics, operative details, and outcomes were abstracted. RESULTS: A total of 213 injuries (2.7%; 94.8% arterial) requiring TIVS were identified in 7,385 patients with vascular injuries. Median age was 27.0 years (range, 4-89 years), 91.0% were male, Glasgow Coma Scale (GCS) score was 15.0 (interquartile range, 4.0), Injury Severity Score (ISS) was 16.0 (interquartile range, 15.0), 26.0% had an ISS of 25 or greater, and 71.1% had penetrating injuries. The most common mechanism was gunshot wound (62.7%), followed by auto versus pedestrian (11.4%) and motor vehicle collision (6.5%). Shunts were placed for damage control in 63.4%, staged repair for combined orthopedic and vascular injuries in 36.1%, and for insufficient surgeon skill set in 0.5%. The most common vessel shunted was the superficial femoral artery (23.9%), followed by popliteal artery (18.8%) and brachial artery (13.2%). An argyle shunt (81.2%) was the most common conduit, followed by Pruitt-Inahara (9.4%). Dwell time was less than 6 hours in 61.4%, 24 hours in 86.5%, 48 hours in 95.9%, with only 4.1% remaining in place for more than 48 hours. Of the patients, 81.6% survived to definitive repair, and 79.6% survived overall. Complications included shunt thrombosis (5.6%) and dislodgment (1.4%). There was no association between dwell time and shunt thrombosis. The use of a noncommercial shunt (chest tube/feeding tube) did not impact shunt thrombosis but was an independent risk factor for subsequent graft failure. The limb salvage rate was 96.3%. No deaths could be attributed to a shunt complication. CONCLUSION: In the largest civilian TIVS experience insertion to date, both damage control and staged orthopedic vascular injuries were common indications for shunting. With an acceptable complication burden and no associated mortality attributed to this technique, shunting should be considered a viable treatment option. LEVEL OF EVIDENCE: Therapeutic study, level V.

A multi-institutional analysis of prehospital tourniquet use.

BACKGROUND: Recent military studies demonstrated an association between prehospital tourniquet use and increased survival. The benefits of this prehospital intervention in a civilian population remain unclear. The aims of our study were to evaluate tourniquet use in the civilian population and to compare outcomes to previously published military experience. We hypothesized that incorporation of tourniquet use in the civilian population will result in an overall improvement in mortality. METHODS: This is a preliminary multi-institutional retrospective analysis of prehospital tourniquet (MIA-T) use of patients admitted to nine urban Level 1 trauma centers from January 2010 to December 2013. Patient demographics and mortality from a previous military experience by Kragh et al. (Ann Surg. 2009;249:1-7) were used for comparison. Patients younger than 18 years or with nontraumatic bleeding requiring tourniquet application were excluded. Data were analyzed using a two-tailed unpaired Student's t test with p < 0.05 as significant. RESULTS: A total of 197 patients were included. Tourniquets were applied effectively in 175 (88.8%) of 197 patients. The average Injury Severity Score (ISS) for MIA-T versus military was 11 ± 12.5 versus 14 ± 10.5, respectively (p = 0.02). The overall mortality and limb amputation rates for the MIA-T group were significantly lower than previously seen in the military population at 6 (3.0%) of 197 versus 22 (11.3%) of 194 (p = 0.002) and 37 (18.8%) of 197 versus 97 (41.8%) of 232 (p = 0.0001), respectively. CONCLUSION: Our study is the largest evaluation of prehospital tourniquet use in a civilian population to date. We found that tourniquets were applied safely and effectively in the civilian population. Adaptation of this prehospital intervention may convey a survival benefit in the civilian population. LEVEL OF EVIDENCE: Epidemiologic study, level V.

MEDEVAC: survival and physiological parameters improved with higher level of flight medic training.

OBJECTIVE: Determine if a higher level of Army flight medic (AFM) training was associated with improved physiological state on arrival to a combat support hospital (CSH). METHODS: A retrospective study comparing casualties who were evacuated by two AFM units with only Emergency Medical Technicians-Basic (EMT-Bs) to an Army National Guard unit with Critical Care Flight Paramedics (CCFPs) in Afghanistan with an injury severity score >16 in different time periods looking at their 48-hour mortality, hematocrit (HCT), base deficit (BD), oxygen saturation (SpO2), and physiological parameters on arrival to the CSH. RESULTS: The CCFP group had better HCT [36.5 (8.8)] than the EMT-B group [33.1 (11.4); p ≤ 0.001]. BD and SpO2 were better in the CCFP group [-3.2 (4.7)]/[97.8 (4.8)] than the EMT-B group [-4.4 (5.5)]/[96.3 (10.9)] [p ≤ 0.014]. The CCFP group had a 72% lower estimated risk ratio of mortality with an associated improvement in 48-hour survivability of 4.9% versus 15.8% for the EMT-B-group. CONCLUSIONS: There is a statistically significant improvement in the HCT, BD, SpO2, and 48-hour survivability at the CSH in the cohort transported by the CCFP group when compared to the cohort transported by the EMT-B group.

Risk factors for hypotension in urgently intubated burn patients.

BACKGROUND: When urgently intubating patient in the burn intensive care unit (BICU), various induction agents, including propofol, are utilized that may induce hemodynamic instability. METHODS: A retrospective review was performed of consecutive critically ill burn patients who underwent urgent endotracheal intubation in BICU. Basic burn-related demographic data, indication for intubation, and induction agents utilized were recorded. The primary outcomes of interest were clinically significant hypotension requiring immediate fluid resuscitation, initiation or escalation of vasopressors immediately after intubation. Secondary outcomes included ventilator days, stay length, and in-hospital mortality. RESULTS: Between January 2003 and August 2010, we identified 279 urgent intubations in 204 patients. Of these, the criteria for presumed sepsis were met in 60% (n=168) of the intubations. After intubation, 117 patients (42%) experienced clinically significant hypotension. Propofol (51%) was the most commonly utilized induction agent followed by etomidate (23%), ketamine (15%), and midazolam (11%). On multiple logistic regression, %TBSA (OR 1.016, 95% CI 1.004-1.027, p<0.001) and presumed sepsis (OR 1.852, 95% CI 1.100-3.117, p=0.02) were the only significant predictors of hypotension. None of the induction agents, including propofol, were significantly associated with hypotension in patients with or without presumed sepsis. CONCLUSIONS: In critically ill burn patients undergoing urgent endotracheal intubation, specific induction agents, including propofol, were not associated with clinically significant hypotension. Presumed sepsis and %TBSA were the most important risk factors.

Male reproductive hormones and thyroid function in pesticide applicators in the Red River Valley of Minnesota.

In the present effort, 144 pesticide applicators and 49 urban control subjects who reported no chronic disease were studied. Applicators provided records of the season's pesticides used by product, volumes, dates, and methods of application. Blood specimens for examination of hormone levels were obtained in summer and fall. In the herbicide-only applicator group, significant increases in testosterone levels in fall compared to summer and also elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the fall were noted. With respect to fungicide use, in an earlier cross-sectional epidemiologic study, data demonstrated that historic fungicide use was associated with a significant alteration of the sex ratio of children borne to applicators. As before, among current study subjects it was noted that historic fungicide use was associated with increased numbers of girls being born. Lower mean total testosterone concentrations by quartile were also correlated with increased numbers of live-born female infants. A downward summer to fall seasonal shift in thyroid-stimulating hormone (TSH) concentrations occurred among applicators but not among controls. Farmers who had aerial application of fungicides to their land in the current season showed a significant shift in TSH values (from 1.75 to 1.11 mU/L). Subclinical hypothyroidism was noted in 5/144 applicators (TSH values >4.5 mU/L), but not in urban control subjects. Based on current and past studies, it was concluded that, in addition to pesticide exposure, individual susceptibility and perhaps economic factors may play a supporting role in the reported results.

Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA.

We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed.