Clinical and Radiographic Results After Treatment of Traumatic Syndesmotic Instability Using a Novel Screw-Suture Syndesmotic Fixation Device.

OBJECTIVES: The objective of this study was to report early outcomes of a novel screw-suture syndesmotic device compared with suture button fixation devices when treating traumatic syndesmotic instability. DESIGN: Retrospective chart review. SETTING: Single academic Level 1 Trauma Center. PATIENT SELECTION CRITERIA: All adult patients who had syndesmotic fixation with the novel device [novel syndesmotic repair implant (NSRI) group] compared with a suture button device (SB group) between January 2018 and December 2022. OUTCOME MEASURES AND COMPARISONS: Medial clear space and tibiofibular overlap measurements were compared immediately postoperatively and at the final follow-up. Patients were followed for a minimum of 1 year or skeletal healing. RESULTS: Fifty-nine patients (25 female) with an average age of 47 years (range 19-78 years) were in the NSRI group compared with 52 patients (20 female) with an average age of 41 years (range 18-73 years) in the SB group. There were no significant differences when comparing body mass index, diabetes, or smoking status between groups (P > 0.05). There was no difference when comparing the postoperative and final medial clear space measurements in the NSRI group compared with the SB group (P = 0.86; 95% confidence interval, -0.32 to 0.27). There was no difference when comparing the postoperative and final tibiofibular overlap measurements in the NSRI group compared with the SB group (P = 0.79; 95% confidence interval, -0.072 to 0.09). There were 3 cases of implant removal in the NSRI group compared with 2 in the SB group (P = 0.77). There was 1 failure in the NSRI group and none in the SB group. The remaining patients were all fully ambulatory at the final follow-up (P = 0.35). CONCLUSIONS: A novel screw-suture syndesmotic implant provides the fixation of a screw, and the flexibility of a suture had similar radiographic outcomes compared with suture button fixation devices in treating ankle syndesmotic instability. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Dynamics of Trypanosoma cruzi infection in hamsters and novel association with progressive motor dysfunction.

Chagas disease is a zoonosis caused by the protozoan parasite Trypanosoma cruzi. Clinical outcomes range from long-term asymptomatic carriage to cardiac, digestive, neurological and composite presentations that can be fatal in both acute and chronic stages of the disease. Studies of T. cruzi in animal models, principally mice, have informed our understanding of the biological basis of this variability and its relationship to infection and host response dynamics. Hamsters have higher translational value for many human infectious diseases, but they have not been well developed as models of Chagas disease. We transposed a real-time bioluminescence imaging system for T. cruzi infection from mice into female Syrian hamsters (Mesocricetus auratus). This enabled us to study chronic tissue pathology in the context of spatiotemporal infection dynamics. Acute infections were widely disseminated, whereas chronic infections were almost entirely restricted to the skin and subcutaneous adipose tissue. Neither cardiac nor digestive tract disease were reproducible features of the model. Skeletal muscle had only sporadic parasitism in the chronic phase, but nevertheless displayed significant inflammation and fibrosis, features also seen in mouse models. Whereas mice had normal locomotion, all chronically infected hamsters developed hindlimb muscle hypertonia and a gait dysfunction resembling spastic diplegia. With further development, this model may therefore prove valuable in studies of peripheral nervous system involvement in Chagas disease.

Dialumene-Mediated Production of Phosphines through P4 Reduction.

The formation of phosphorus-rich alanes featuring butterfly-like geometries is achieved. The two-electron reduction products feature a unique P4 2- structure and can act as a source of P3-. The treatment of these phosphorus containing products with electrophiles under mild conditions results in the formation of different phosphines. This approach eliminates the need for high temperatures and/or high pressures, which are commonly required in industrial processes for the preparation of useful phosphines.The activation and further functionalization of white phosphorus (P4) by main group complexes has become an increasingly studied topic in recent times. Herein, we report the controlled formation of phosphorus-rich alanes featuring butterfly-like geometries from the selective reaction of P4 with dialumenes, ([L(IiPr)Al]2) (1: L=Tripp=2,4,6-iPr3C6H2; 2: L=tBu2MeSi; IiPr=[MeCN(iPr)]2C)). The two-electron-reduction product of P4 features a P4 2- structure and is shown to be able to act as a source of P3-. Treatments of different electrophiles (e.g., chlorotrimethylsilane (Me3SiCl), iodotrimethylsilane (Me3SiI), HCl, or acetyl chloride (CH3COCl)) with these alanes under mild conditions gave the corresponding phosphines (e.g., P(SiMe3)3, PH3, or P(COCH3)3).

Visualizing the Influence of Social Networks on Recovery: A Mixed-Methods Social Identity Mapping Study with Recovering Adolescents.

Background: Social recovery capital (SRC) refers to resources and supports gained through relationships and is vital to adolescent addiction recovery. Much is known about how substance use relates to social networks, but little is known about how other dimensions of social networks influence recovery (e.g., network size/exposure, degree of conflict). Methods: This mixed-methods study sampled 28 adolescents who received treatment for alcohol and other drug (AOD) use disorder (14-19 yrs.: 71% male; M = 17.32 yrs., SD = 1.33; White 82%): 20 were recovery high school (RHS) students. Adolescents completed a social identity map for addiction recovery (SIM-AR), survey, and interview. Qualitative data were content analyzed and the data from the SIM-AR were quantified. Results: On average, participants reported belonging to five distinct groups within their network (Range, 2-9; SD = 1.63; M = 27.89 people, SD = 20.09). Of their social network connections, 51% drank alcohol and 46% used other substances, on average. Larger networks involved more conflict (r = 0.57). Participants were more likely to spend more time with groups that had greater proportions of non-substance-using members. These linkages were stronger for RHS than for non-RHS students. Qualitative analyses revealed that youth reported their recovery-oriented groups as supportive, but some reported that their substance-using friends also supported their recovery. Discussion: SIM-AR was a useful measurement tool, and, through qualitative interviews, we identified unique aspects of youths' social networks important for further examination. Research with recovering youth should examine SRC-related elements within their networks including relationship quality, belonging, and conflict, alongside the substance use behaviors of network members.

A panel of phenotypically and genotypically diverse bioluminescent:fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research.

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that displays considerable genetic diversity. Infections result in a range of pathological outcomes, and different strains can exhibit a wide spectrum of anti-parasitic drug tolerance. The genetic determinants of infectivity, virulence and therapeutic susceptibility remain largely unknown. As experimental tools to address these issues, we have generated a panel of bioluminescent:fluorescent parasite strains that cover the diversity of the T. cruzi species. These reporters allow spatio-temporal infection dynamics in murine models to be monitored in a non-invasive manner by in vivo imaging, provide a capability to detect rare infection foci at single-cell resolution, and represent a valuable resource for investigating virulence and host:parasite interactions at a mechanistic level. Importantly, these parasite reporter strains can also contribute to the Chagas disease drug screening cascade by ensuring that candidate compounds have pan-species in vivo activity prior to being advanced into clinical testing. The parasite strains described in this paper are available on request.

Outcomes and quality of life in patients receiving mitral surgery for asymptomatic disease.

Objectives: We sought to characterize the demographics, outcomes, and quality of life of asymptomatic patients undergoing mitral valve surgery at our center over a 10-year period. Methods: Adults undergoing mitral surgery were retrospectively reviewed between 2010 and 2019. Patients were included if deemed asymptomatic by review of referring cardiologist and surgeon consultation. Patients were administered a telephone survey consisting of the Kansas City Cardiomyopathy Questionnaire as well as free-response regarding satisfaction surrounding their operation. Outcomes included survival, Kansas City Cardiomyopathy Questionnaire metrics, and thematic analysis of free response questions. Results: A total of 145 patients were identified who were deemed asymptomatic. Their average age was 60.3 ± 12.1 years, and 71% were male. No patients had endocarditis, and 34% had decreased ejection fraction (<60%). Repair was achieved in 95% of patients. Median length of stay was 6 (5-8) days. Ten-year survival was 91%, with no differences noted by ejection fraction. Composite Kansas City Cardiomyopathy Questionnaire score was 100 (96-100). The lowest component score was "Quality of Life," with 22% of patients reporting being "mostly satisfied" with present cardiac status. Most common themes expressed were gratitude with surgery results (58%), satisfaction with being able to stay active (23%), and happiness with early disease treatment (21%). Only 1 patient (0.7%) expressed regret with surgery choice. Conclusions: Mitral surgery for asymptomatic disease can be performed with good long-term outcomes in select patients, and the majority experience excellent quality of life and satisfaction with current health. Continued assessments of quality of life are important in evaluating outcomes of mitral surgery as indications grow.

Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.

How to edit a surgical case video.

A video can help highlight the real-time steps, anatomy and the technical aspects of a case that may be difficult to convey with text or static images alone. Editing with a regimented workflow allows for the transmission of only essential information to the viewer while maximizing efficiency by going through the editing process. This video tutorial breaks down the fundamentals of surgical video editing with tips and pointers to simplify the workflow.

Disentangling Acid-Base Chemistry through Blue Shifting Hydrogen Bond Contributions.

The blue shifting of vibrational frequencies in hydrogen bonded molecules, as observed in aqueous environments, has been attributed to local partial charge transfer from solvation. Here, we extrapolate the blue shift model to the stronger ionic interactions between hydrogen bond acceptors associated with protonation through augmented pH levels and competitive interactions with counter ion pairing. The chemical model we utilize in this work is the aqueous pyridine-pyridinium equilibrium to characterize the blue shifts observed in the pyridinium chloride ionic system. The observed agreement between observed experimental and calculated spectral shifts shows that the blue shifting model can be extrapolated to stronger interactions and accurately describe the nature of the hydrogen bond.

The Variability of MCID, SCB, PASS, and MOI Thresholds for PROMs in the Reverse Total Shoulder Arthroplasty Literature: A Systematic Review.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is a common procedure utilized to address degenerative pathologies of the glenohumeral joint and rotator cuff. Increased reliance on patient-reported outcome measures (PROMs) has placed emphasis on the utilization of the minimum clinically important difference (MCID), substantial clinical benefit (SCB), patient acceptable symptom state (PASS), and maximal outcome improvement (MOI) thresholds to assess the clinical efficacy of RTSA. In this study, we systematically reviewed the MCID, SCB, PASS, and MOI thresholds reported for PROMs following RTSA. METHODS: PubMed, Embase, MEDLINE, Cochrane Library, and Google Scholar were queried for articles from Jan. 1, 2000-Aug. 31, 2023 reporting MCID, SCB, PASS, or MOI values for PROMs following RTSA. Patient demographic data, study characteristics, MCID/SCB/PASS/MOI thresholds, and threshold calculation methods were extracted. RESULTS: 141 articles were screened with 39 ultimately included, comprising 11,984 total patients that underwent RTSA. 34 (87%) studies reported MCID thresholds, 20 (51%) reported SCB, 5 (13%) reported PASS, and 2 (5%) reported MOI. 25/39 (64%) studies referenced a previous study when reporting MCID, SCB, PASS, or MOI values, 11 (28%) used an anchor-based method to calculate threshold values, 1 (3%) used a distribution-based method, and 2 (5%) used both anchor and distribution methods. There were 19 newly calculated MCID (11), SCB (5), PASS (1), and MOI (2) thresholds. For five of the six most utilized PROMs (ASES, SST, Constant, UCLA, SPADI), the range of reported MCID values exceeded 50% of the most common threshold. For three of the six, the range of SCB values exceeded 25% of the most common threshold. CONCLUSION: There is substantial variability in the MCID and SCB threshold values reported in the RTSA literature. Standardizing the methodologic calculation and utilization of MCID, SCB, PASS, and MOI thresholds for RTSA may allow for improved assessment of PROMs.

Enteric nervous system regeneration and functional cure of experimental digestive Chagas disease with trypanocidal chemotherapy.

Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. There is a lack of evidence on the mechanism of pathogenesis and rationales for treatment. We used a female C3H/HeN mouse model that recapitulates key clinical manifestations to study how infection dynamics shape DCD pathology and the impact of treatment with the front-line, anti-parasitic drug benznidazole. Curative treatment 6 weeks post-infection resulted in sustained recovery of gastrointestinal transit function, whereas treatment failure led to infection relapse and gradual return of DCD symptoms. Neuro/immune gene expression patterns shifted from chronic inflammation to a tissue repair profile after cure, accompanied by increased cellular proliferation, glial cell marker expression and recovery of neuronal density in the myenteric plexus. Delaying treatment until 24 weeks post-infection led to partial reversal of DCD, suggesting the accumulation of permanent tissue damage over the course of chronic infection. Our study shows that murine DCD pathogenesis is sustained by chronic T. cruzi infection and is not an inevitable consequence of acute stage denervation. The risk of irreversible enteric neuromuscular tissue damage and dysfunction developing highlights the importance of prompt diagnosis and treatment. These findings support the concept of treating asymptomatic, T. cruzi-infected individuals with benznidazole to prevent DCD development.

Examining the Evidence Regarding Smoking and Patient Outcomes for Isolated Meniscus Pathology: A Comprehensive Systematic Review and Meta-Analysis.

Smoking is a well-known cause of impairment in wound healing and postoperative outcomes; however, its effects on treating meniscus issues remain unclear. This study assesses the relationship between smoking and meniscus treatment outcomes. PubMed, Scopus, Cochrane, and CINAHL were searched from inception to 24 December 2023. Inclusion criteria encompassed studies examining smoking's impact on patient outcomes regarding meniscus pathology. A secondary PubMed search targeted randomized controlled trials (RCTs) in the top ten orthopedic journals focusing on meniscus pathology and smoking as a demographic variable. Meta-analysis of six studies (n = 528) assessed meniscus failure rate based on smoking status. Eighteen observational studies (n = 8353 patients; 53.25% male; mean age: 51.35 ± 11.53 years; follow-up: 184.11 ± 117.34 months) were analyzed, covering meniscus repair, meniscectomy, allograft transplant, conservative care, and arthroscopy. Results showed four studies (36.36%) linked smoking with worse meniscus repair outcomes, while seven studies (63.64%) did not find significant associations. Meta-analysis from six studies showed no significant impact of smoking on repair failure (p = 0.118). Regarding meniscectomy, one study (33.33%) identified a significant association with smoking, but two did not. Only one (3.8%) of the RCTs in leading orthopedic journals included smoking as a factor. The evidence on smoking's effect on meniscus treatment is mixed, necessitating further investigation.

Hematuria Cancer Risk Score with Ultrasound Informs Cystoscopy Use in Patients with Hematuria.

BACKGROUND: Hematuria is a cardinal symptom of urinary tract cancer and would require further investigations. OBJECTIVE: To determine the ability of renal bladder ultrasound (RBUS) with the Hematuria Cancer Risk Score (HCRS) to inform cystoscopy use in patients with hematuria. DESIGN, SETTING, AND PARTICIPANTS: The development cohort comprised 1984 patients with hematuria from 40 UK hospitals (DETECT 1; ClinicalTrials.gov: NCT02676180) who received RBUS. An independent validation cohort comprised 500 consecutive patients referred to secondary care for a suspicion of bladder cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity and true negative of the HCRS and RBUS were assessed. RESULTS AND LIMITATIONS: A total of 134 (7%) and 36 (8%) patients in the development and validation cohorts, respectively, had a diagnosis of urinary tract cancer. Validation of the HCRS achieves good discrimination with an area under the receiver operating characteristic curve of 0.727 (95% confidence interval 0.648-0.800) in the validation cohort with sensitivity of 95% for the identification of cancer. Utilizing the cutoff of 4.500 derived from the HCRS in combination with RBUS in the development cohort, 680 (34%) patients would have been spared cystoscopy at the cost of missing a G1 Ta bladder cancer and a urinary tract cancer patient, while 117 (25%) patients would have avoided cystoscopy at the cost of missing a single patient of G1 Ta bladder cancer with sensitivity for the identification of cancer of 97% in the validation cohort. CONCLUSIONS: The HCRS with RBUS offers good discriminatory ability in identifying patients who would benefit from cystoscopy, sparing selected patient cohorts from an invasive procedure. PATIENT SUMMARY: The hematuria cancer risk score with renal bladder ultrasound allows for the triage of patients with hematuria who would benefit from visual examination of the bladder (cystoscopy). This resulted in 25% of patients safely omitting cystoscopy, which is an invasive procedure, and would lead to health care cost savings.

The Delayed Presentation and Diagnosis of Youth Wrestling Injuries: A 20-Year Analysis of National Injury Data.

INTRODUCTION: The nature of wrestling may lead athletes to mask injuries with the delayed presentations of youth wrestling-related injuries not being well characterized. METHODS: This descriptive epidemiological study queried the National Electronic Injury Surveillance System database to characterize delayed presentations of wrestling-related injuries in middle and high-school athletes. Data collection consisted of national estimates, demographics, and injury characteristics of patients with delayed (D) presentations (≥1 day) and same-day (S) presentations to US emergency departments after sustaining a wrestling-related injury during the scholastic wrestling season (December to February, 2000 to 2019). RESULTS: Of middle and high-school wrestlers presenting to US emergency departments, 5.6% (95% confidence interval [CI] 4.3% to 7.1%) reported delayed presentations for a total of 1,110 patients (CI, 591 to 1,630) annually. Most commonly (P < 0.001), injuries were sustained on Saturdays in both cohorts (D, 28.2%; CI, 22.4% to 34.8%; S, 29.6%; CI, 24.3% to 35.5%). Patients reporting delayed presentations were less likely to sustain fractures (D, 11.5%; CI, 8.3% to 15.6%; S, 18.9%; CI, 15.0% to 23.5%; P = 0.019) and injuries of the head/neck (D, 20.0%; CI, 16.5 to 24.1%; S, 26.2%; CI, 21.4% to 31.7%; P = 0.011). DISCUSSION: A substantial proportion of adolescent wrestlers report delayed presentations of injuries. This emphasizes the need for vigilance in detecting subtle signs of injury.

Quantifying Inferior Vena Cava Compliance and Distensibility in an In Vivo Ovine Model Using 3D Angiography.

Synthetic vascular grafts overcome some challenges of allografts, autografts, and xenografts but are often more rigid and less compliant than the native vessel into which they are implanted. Compliance matching with the native vessel is emerging as a key property for graft success. The current gold standard for assessing vessel compliance involves the vessel's excision and ex vivo biaxial mechanical testing. We developed an in vivo method to assess venous compliance and distensibility that better reflects natural physiology and takes into consideration the impact of a pressure change caused by flowing blood and by any morphologic changes present. This method is designed as a survival procedure, facilitating longitudinal studies while potentially reducing the need for animal use. Our method involves injecting a 20 mL/kg saline bolus into the venous vasculature, followed by the acquisition of pre and post bolus 3D angiograms to observe alterations induced by the bolus, concurrently with intravascular pressure measurements in target regions. We are then able to measure the circumference and the cross-sectional area of the vessel pre and post bolus. With these data and the intravascular pressure, we are able to calculate the compliance and distensibility with specific equations. This method was used to compare the inferior vena cava's compliance and distensibility in native unoperated sheep to the conduit of sheep implanted with a long-term expanded polytetrafluorethylene (PTFE) graft. The native vessel was found to be more compliant and distensible than the PTFE graft at all measured locations. We conclude that this method safely provides in vivo measurements of vein compliance and distensibility.

Prevalence, Patterns, and Predictors of SARS-CoV-2 RNA and Culturable Virus in Tears of a Case-Ascertained Household Cohort.

PURPOSE: To investigate the prevalence, patterns, and predictors of SARS-CoV-2 RNA and culturable virus in tears of a case-ascertained household cohort. DESIGN: Prospective, longitudinal case-ascertained household cohort identified through convenience sampling. METHODS: This analysis was restricted to individuals who were non-hospitalized, symptomatic, and tested positive for SARS-CoV-2 by nasal RT-PCR. Tears and anterior nasal biospecimens were serially collected throughout the acute period. Tears specimens were collected by the study staff using Schirmer test strips, and nasal specimens were self-collected. For both, SARS-CoV-2 RNA was quantified using qRT-PCR, and culturable virus was detected using presence of cytopathic effect (CPE) in tissue culture; positive CPE was confirmed by a qRT-PCR step. A series of cross-sectional unadjusted analyses were performed investigating the relationship between different sociodemographic determinants and biological factors associated with tears RNA positivity. RESULTS: Among the 83 SARS-CoV-2 infected participants, 10 (12%) had at least one RNA-positive tears specimen. Amongst these 10, 5 (50%) had concurrent presence of culturable virus, at a median of 7 days postsymptom onset (IQR: 4-7 days) (absolute range: 4-8 days). CONCLUSIONS: In this longitudinal cohort, we found evidence of culturable virus in the tears of a small proportion of nonhospitalized SARS-CoV-2 infected individuals. Current public health infection precautions do not account for transmission via tears, so these findings may improve our understanding of potential sources of SARS-CoV-2 transmission and contribute to developing future guidelines.

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging.

Chagas disease, or American trypanosomiasis, is a neglected tropical disease which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include (i) the discovery of novel drugs/chemical classes, (ii) filling the pipeline with drug candidates that have new mechanisms of action, and (iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzylmenadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino)benzylmenadione derivatives via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified by high content imaging an anti-amastigote "early lead" 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a).

The quantitative genetics of gene expression in Mimulus guttatus.

Gene expression can be influenced by genetic variants that are closely linked to the expressed gene (cis eQTLs) and variants in other parts of the genome (trans eQTLs). We created a multiparental mapping population by sampling genotypes from a single natural population of Mimulus guttatus and scored gene expression in the leaves of 1,588 plants. We find that nearly every measured gene exhibits cis regulatory variation (91% have FDR < 0.05). cis eQTLs are usually allelic series with three or more functionally distinct alleles. The cis locus explains about two thirds of the standing genetic variance (on average) but varies among genes and tends to be greatest when there is high indel variation in the upstream regulatory region and high nucleotide diversity in the coding sequence. Despite mapping over 10,000 trans eQTL / affected gene pairs, most of the genetic variance generated by trans acting loci remains unexplained. This implies a large reservoir of trans acting genes with subtle or diffuse effects. Mapped trans eQTLs show lower allelic diversity but much higher genetic dominance than cis eQTLs. Several analyses also indicate that trans eQTLs make a substantial contribution to the genetic correlations in expression among different genes. They may thus be essential determinants of "gene expression modules," which has important implications for the evolution of gene expression and how it is studied by geneticists.