Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

County-level neonatal opioid withdrawal syndrome rates and real-world access to buprenorphine during pregnancy: An audit ("secret shopper") study in Missouri.

Background: Amid rising rates of neonatal opioid withdrawal syndrome (NOWS) worldwide and in many regions of the USA, we conducted an audit study ("secret shopper study") to evaluate the influence of county-level buprenorphine capacity and rurality on county-level NOWS rates. Methods: In 2019, up to three phone calls were made to buprenorphine prescribers in the state of Missouri (USA). County-level buprenorphine capacity was defined as the number of clinicians (across all specialties) accepting pregnant people divided by the number of births. Multivariable negative binomial regression models estimated associations between buprenorphine capacity, rurality, and county-level NOWS rates, controlling for potential confounders (i.e., poverty, unemployment, and physician shortages) that may correspond to higher rates of NOWS and lower rates of buprenorphine prescribing. Analyses were stratified using tertiles of county-level overdose rates (top, middle, and lowest 1/3 of overdose rates). Results: Of 115 Missouri counties, 81(70 %) had no buprenorphine capacity, 17(15 %) were low-capacity (<0.5-clinicians/1,000 births), and 17(15 %) were high-capacity (≥0.5/1,000 births). The mean NOWS rate was 6.5/1,000 births. In Missouri counties with both the highest and lowest opioid overdose rates, higher buprenorphine capacity did not correspond to decreases in NOWS rates (incidence rate ratio[IRR]=1.23[95 %-confidence-interval[CI]=0.65-2.32] and IRR=1.57[1.21-2.03] respectively). Rurality did not correspond to greater NOWS burden in both Missouri counties with highest and lowest opioid overdose rates. Conclusions: The vast majority of counties in Missouri have no capacity for buprenorphine prescribing during pregnancy. Rurality and lower buprenorphine capacity did not significantly predict elevated rates of NOWS.

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Are Neighborhood Characteristics Associated With Outcomes After THA and TKA? Findings From a Large Healthcare System Database.

BACKGROUND: Non-White patients have higher rates of discharge to an extended care facility, hospital readmission, and emergency department use after primary THA and TKA. The reasons for this are unknown. Place of residence, which can vary by race, has been linked to poorer healthcare outcomes for people with many health conditions. However, the potential relationship between place of residence and disparities in these joint arthroplasty outcomes is unclear. QUESTIONS/PURPOSES: (1) Are neighborhood-level characteristics, including racial composition, marital proportions, residential vacancy, educational attainment, employment proportions, overall deprivation, access to medical care, and rurality associated with an increased risk of discharge to a facility, readmission, and emergency department use after elective THA and TKA? (2) Are the associations between neighborhood-level characteristics and discharge to a facility, readmission, and emergency department use the same among White and Black patients undergoing elective THA and TKA? METHODS: Between 2007 and 2018, 34,008 records of elective primary THA or TKA for osteoarthritis, rheumatoid arthritis, or avascular necrosis in a regional healthcare system were identified. After exclusions for unicompartmental arthroplasty, bilateral surgery, concomitant procedures, inability to geocode a residential address, duplicate records, and deaths, 21,689 patients remained. Ninety-seven percent of patients in this cohort self-identified as either White or Black, so the remaining 659 patients were excluded due to small sample size. This left 21,030 total patients for analysis. Discharge destination, readmissions within 90 days of surgery, and emergency department visits within 90 days were identified. Each patient's street address was linked to neighborhood characteristics from the American Community Survey and Area Deprivation Index. A multilevel, multivariable logistic regression analysis was used to model each outcome of interest, controlling for clinical and individual sociodemographic factors and allowing for clustering at the neighborhood level. The models were then duplicated with the addition of neighborhood characteristics to determine the association between neighborhood-level factors and each outcome. The linear predictors from each of these models were used to determine the predicted risk of each outcome, with and without neighborhood characteristics, and divided into tenths. The change in predicted risk tenths based on the model containing neighborhood characteristics was compared to that without neighborhood characteristics.The change in predicted risk tenth for each outcome was stratified by race. RESULTS: After controlling for age, sex, insurance type, surgery type, and comorbidities, we found that an increase of one SD of neighborhood unemployment (odds ratio 1.26 [95% confidence interval 1.17 to 1.36]; p < 0.001) was associated with an increased likelihood of discharge to a facility, whereas an increase of one SD in proportions of residents receiving public assistance (OR 0.92 [95% CI 0.86 to 0.98]; p = 0.008), living below the poverty level (OR 0.82 [95% CI 0.74 to 0.91]; p < 0.001), and being married (OR 0.80 [95% CI 0.71 to 0.89]; p < 0.001) was associated with a decreased likelihood of discharge to a facility. Residence in areas one SD above mean neighborhood unemployment (OR 1.12 [95% CI [1.04 to 1.21]; p = 0.002) was associated with increased rates of readmission. An increase of one SD in residents receiving food stamps (OR 0.83 [95% CI 0.75 to 093]; p = 0.001), being married (OR 0.89 [95% CI 0.80 to 0.99]; p = 0.03), and being older than 65 years (OR 0.93 [95% CI 0.88 to 0.98]; p = 0.01) was associated with a decreased likelihood of readmission. A one SD increase in the percentage of Black residents (OR 1.11 [95% CI 1.00 to 1.22]; p = 0.04) and unemployed residents (OR 1.15 [95% CI 1.05 to 1.26]; p = 0.003) was associated with a higher likelihood of emergency department use. Living in a medically underserved area (OR 0.82 [95% CI 0.68 to 0.97]; p = 0.02), a neighborhood one SD above the mean of individuals using food stamps (OR 0.81 [95% CI 0.70 to 0.93]; p = 0.004), and a neighborhood with an increasing percentage of individuals older than 65 years (OR 0.90 [95% CI 0.83 to 0.96]; p = 0.002) were associated with a lower likelihood of emergency department use. With the addition of neighborhood characteristics, the risk prediction tenths of the overall cohort remained the same in more than 50% of patients for all three outcomes of interest. When stratified by race, neighborhood characteristics increased the predicted risk for 55% of Black patients for readmission compared with 17% of White patients (p < 0.001). The predicted risk tenth increased for 60% of Black patients for emergency department use compared with 21% for White patients (p < 0.001). CONCLUSION: These results can be used to identify high-risk patients who might benefit from preemptive interventions to avoid these particular outcomes and to create more realistic, comprehensive risk adjustment models for value-based care programs. Additionally, this study demonstrates that neighborhood characteristics are associated with greater risk for these outcomes among Black patients compared with White patients. Further studies should consider that race/ethnicity and neighborhood characteristics may not function independently from each other. Understanding this link between race and place of residence is essential for future racial disparities research. LEVEL OF EVIDENCE: Level III, therapeutic study.

White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning.

Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FAT (ß = 0.24, t = 3.05, p = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity (ß = 0.00, t = 2.50, p = 0.027), although an mTBI diagnosis alone did not significantly impact this association (p = 0.088). There was no significant association between PREGNE and FAT (p = 0.380). Importantly, lower FAT is associated with poor psychological functioning (ß = -0.19, t = -2.35, p = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Challenges and Possible Solutions to Adapting to Virtual Recruitment: Lessons Learned from a Survey Study during the Covid-19 Pandemic.

The Covid-19 pandemic required rapid changes to research protocols, including immediate transitions to recruiting research participants and conducting the informed consent process virtually. This case study details the challenges our research team faced adapting an in-person, behavioral-intervention and survey study to virtual recruitment. We reflect on the impact of these rapid changes on recruitment and retention, discuss protocol changes we made to address these challenges and the needs of potential and enrolled participants, and propose recommendations for future work. Using computer technology to display professional return phone numbers, being flexible by contacting potential participants through various means, minimizing email communication due to added regulatory requirements, and partnering with the institutional review board to shorten and improve the consent document and process were critical to study success. This case study can offer insight to other researchers as they navigate similar processes. Virtual recruitment is likely to continue; it is important to ensure that it facilitates, rather than hinders, equitable and just recruitment practices.

Community access to primary care is an important geographic disparity among ovarian cancer patients undergoing cytoreductive surgery.

Objective: Given the importance of understanding neighborhood context and geographic access to care on individual health outcomes, we sought to investigate the association of community primary care (PC) access on postoperative outcomes and survival in ovarian cancer patients. Methods: This was a retrospective cohort study of Stage III-IV ovarian cancer patients who underwent surgery at a single academic, tertiary care hospital between 2012 and 2015. PC access was determined using a Health Resources and Services Administration designation. Outcomes included 30-day surgical and medical complications, extended hospital stay, ICU admission, hospital readmission, progression-free and overall survival. Descriptive statistics and chi-squared analyses were used to analyze differences between patients from PC-shortage vs not PC-shortage areas. Results: Among 217 ovarian cancer patients, 54.4 % lived in PC-shortage areas. They were more likely to have Medicaid or no insurance and live in rural areas with higher poverty rates, significantly further from the treating cancer center and its affiliated hospital. Nevertheless, 49.2 % of patients from PC-shortage areas lived in urban communities. Residing in a PC-shortage area was not associated with increased surgical or medical complications, ICU admission, or hospital readmission, but was linked to more frequent prolonged hospitalization (26.3 % vs 14.1 %, p = 0.04). PC-shortage did not impact progression-free or overall survival. Conclusions: Patients from PC-shortage areas may require longer inpatient perioperative care in order to achieve the same 30-day postoperative outcomes as patients who live in non-PC shortage areas. Community access to PC is a critical factor to better understanding and reducing disparities among ovarian cancer patients.

Trends in administrative prevalence of multiple sclerosis and utilization patterns of disease modifying drugs in Germany.

BACKGROUND: This study aimed to describe recent developments of multiple sclerosis (MS) prevalence in Germany and to assess utilization patterns of disease-modifying drugs (DMDs). METHODS: We used nationwide outpatient claims data of the statutory health insurance (SHI) from the years 2012 to 2019, covering 87% of the total German population. In annual cross-sectional analyses, MS prevalence was measured as the percentage of the SHI population affected by MS. Annual agent-specific prescription prevalence of DMDs was calculated by the number of patients receiving the DMD per 1.000 MS patients. RESULTS: From 2012 to 2019, the prevalence of MS increased gradually from 0.27% to 0.34%. The overall DMD prescription prevalence in MS patients rose from 436 per 1,000 MS patients (2012) to 483 (2019). From 2012 to 2019 the prescription prevalence of interferon-beta 1a and interferon-beta 1b decreased sharply from 180.2 to 70.8 (-61%) and 80.2 to 34.1 (-57%), respectively. In contrast, the prescription prevalence of teriflunomide (2012: 8.5; 2019: 54.5) and fingolimod (2012: 28.5; 2019: 63.8) exhibited a pronounced increase by factors of 5.4 and 2.2, respectively. CONCLUSION: MS prevalence in Germany steadily increased in recent years. MS treatment patterns changed markedly indicating a shifting predominance of DMD injectable drugs to oral medications.

Unexpected Outcomes of Measuring Decision Regret: Using a Breast Cancer Decision-Making Case Example.

Shared decision making can help patients feel supported and empowered when deciding between healthcare options. Decision regret can be a meaningful measure of the quality of that encounter. However, in a patient-engaged research study examining shared decision making for breast cancer surgery, decision regret was a difficult construct to assess, and asking questions about decision regret caused the patient to experience that emotion upon reflection. In this article, we consider the complexity of decision regret, and discuss the difficulty of measuring that emotion through existing instruments. We call for clarity in definitions of decision regret and offer suggestions for developing a set of questions that can capture regret in a more meaningful way.

[Fixation of displaced fifth metatarsal shaft and neck fractures]. / Osteosynthese dislozierter Metatarsale-V-Schaft- und -Halsfrakturen.

OBJECTIVE: Open reduction and internal fixation of grossly dislocated fifth metatarsal shaft and neck fractures aims at restoration of the anatomical structure of the forefoot. The goal is to restore length, axis, rotation and joint position, while observing the metatarsal index (Maestro curve). INDICATIONS: Grossly dislocated and/or open shaft/neck fractures of the fifth metatarsal; combined fractures of the forefoot involving the fifth metatarsal. CONTRAINDICATIONS: Lack of consent to surgery. Overall critical (life-threatening) general condition preventing surgery to the extremities. Contaminated or infected soft tissues. SURGICAL TECHNIQUE: Depending on the planned method of fixation, open reduction is usually conducted via a lateral approach centrally above the easily palpable metatarsal V shaft. The incision lies above the glabrous skin of the sole. For markedly shortened and multifragment subcapital and shaft fractures of the fifth metatarsal, open reduction and plate fixation is the method of choice. Interlocking plates with a screw diameter of 2.0-2.4 mm are preferred to avoid later soft tissue irritation. Anatomic reconstruction is carried out under longitudinal traction at the fifth toe using small reduction clamps and, if necessary, temporary K­wire fixation. If the fragments are large enough, one or more interfragmentary lag screws can be used for fracture compression. A straight or condylar plate is used for internal fixation. Long spiral fifth metatarsal shaft fractures may alternatively be fixed with screws. In the case of transverse or subcapital fractures, percutaneous antegrade or retrograde medullary wiring with two Kirschner wires should be considered. POSTOPERATIVE MANAGEMENT: Following surgical treatment, rest and elevation of the injured leg, and local cooling are indicated. Subsequently, mobilization with partial weight bearing (20 kg) in foot orthosis or cast shoe for 6 weeks. RESULTS: Even grossly displaced fractures of the fifth metatarsal shaft have a good to excellent prognosis following surgical treatment with high union rates and rare complications. Undisplaced and mildly displaced fractures can be successfully managed nonoperatively with 6 weeks of weight bearing as tolerated in a stable orthosis or cast shoes.

Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder.

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes (UBA7, HLA-F, HSPA1B, and RERE) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD.

[Minimally invasive fixation of distal fibular fractures with intramedullary nailing]. / Minimal-invasive Osteosynthese von distalen Fibulafrakturen mittels Marknagels.

OBJECTIVE: Minimally invasive osteosynthesis of distal fibula fractures serves as a biomechanically stable and soft-tissue-friendly fixation method in the case of an unstable fracture, poor bone quality, and/or critical soft tissue conditions with restoration of the length, axis and rotation of the distal fibula as well as stabilization of the ankle mortise. The goal is to reduce and stabilize the distal fibular fracture in a quick and stable manner that protects the soft tissues in ankle fractures. INDICATIONS: Unstable malleolar fractures and fracture dislocations; fibular fractures in combination with distal tibia fractures; critical soft tissue conditions around the ankle. CONTRAINDICATIONS: No consent to surgery by the patient. Overall critical (life-threatening) general condition preventing surgery to the extremities. Very narrow medullary canal of the fibula (less than 3 mm, depending on the implant). SURGICAL TECHNIQUE: Percutaneous placement of a guidewire into the distal fibular tip, opening the medullary canal and drilling the medullary canal in the distal fragment. Reduction of the axis by introduction of the fibular nail, with additional percutaneous use of reduction clamps for restoration of fibular length and rotation, if necessary. Placement of distal locking screws over the targeting device while maintaining rotation and length, in addition proximal static locking is mandatory to maintain the length of the fibula. In case of residual syndesmotic instability after fracture fixation, syndesmotic screws are inserted through the fibular nail via the aiming device. POSTOPERATIVE MANAGEMENT: Following surgery, rest and elevation of the injured leg, and local cooling are indicated. Subsequently, mobilization with partial weight bearing (15-20 kg) in an ankle foot orthosis or plaster/cast for 6 weeks. RESULTS: Minimally invasive fibular fixation with an intramedullary nail results in a significantly lower rate of wound healing complications compared with lateral plating. Reported union rates range from 97.4 to 100% with current nail designs. The quality of reduction and functional outcome is comparable to that after plate fixation. A certain learning curve has to be respected.

Recognition, Treatment, and Outcome of Calcaneal Fracture-Dislocation.

BACKGROUND: Calcaneal fracture-dislocations are rare but potentially disabling injuries that are regularly overlooked at first presentation. To date, only about 50 cases have been reported in the literature. METHODS: Over a period of 8 years, 10 patients (average age 61.7 years) with acute fracture-dislocations of the calcaneus were treated at 2 level 1 trauma centers. The calcaneocuboid joint was involved in 9 patients. There was a concomitant fracture of the lateral talar process and of the tip of the distal fibula in 7 patients each. Open reduction and internal fixation was performed in 9 of 10 patients via an oblique lateral dislocation approach. One patient underwent primary subtalar fusion. All patients were seen for clinical and radiographic follow-up at an average of 3 years using patient-reported outcome scores. RESULTS: Anatomic fixation was achieved in all patients as judged by postoperative computed tomographic imaging. In the 9 patients treated with internal fixation, the Foot Function Index averaged 12.8, the EuroQol 5D score averaged 0.89 and the visual analog scale score for patient satisfaction averaged 79.3 at final follow-up. Signs of mild subtalar arthritis were seen in 6 patients. No secondary subtalar fusions were needed. CONCLUSION: When recognized and treated early, prognosis of calcaneal fracture-dislocation was favorable. A dislocation approach starting over the distal fibula, continuing over the sinus tarsi, and extending toward the calcaneocuboid joint allowed for adequate visualization of the subtalar joint and treatment of all components of the injury. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Early Corrections after Failed Ankle Fracture Fixation. / Frühkorrekturen nach fehlgeschlagener Osteosynthese bei Sprunggelenkfrakturen.

Even minor residual fragment malpositioning after internal fixation of ankle fractures is associated with a worse prognosis. Frequent causes for non-anatomical reduction are fibular shortening due to comminuted fractures or poor bone quality, translational or rotational malpositioning of the distal fibula within the tibial incisura with unstable syndesmosis injuries, and inadequately addressed bony avulsions of the tibiofibular syndesmosis. After operative treatment of fracture dislocations with syndesmotic fixation, in case of complex fracture pathoanatomy, and with suspected non-anatomic reduction in postoperative radiographs, computed tomography imaging of both ankles should be performed. Correction of relevant malreductions should be performed as early as possible in order to speed up rehabilitation and to avoid late sequelae due to a load shift or instability in a weight-bearing joint.

What matters most: Randomized controlled trial of breast cancer surgery conversation aids across socioeconomic strata.

BACKGROUND: Women of lower socioeconomic status (SES) with early-stage breast cancer are more likely to report poorer physician-patient communication, lower satisfaction with surgery, lower involvement in decision making, and higher decision regret compared to women of higher SES. The objective of this study was to understand how to support women across socioeconomic strata in making breast cancer surgery choices. METHODS: We conducted a 3-arm (Option Grid, Picture Option Grid, and usual care), multisite, randomized controlled superiority trial with surgeon-level randomization. The Option Grid (text only) and Picture Option Grid (pictures plus text) conversation aids were evidence-based summaries of available breast cancer surgery options on paper. Decision quality (primary outcome), treatment choice, treatment intention, shared decision making (SDM), anxiety, quality of life, decision regret, and coordination of care were measured from T0 (pre-consultation) to T5 (1-year after surgery. RESULTS: Sixteen surgeons saw 571 of 622 consented patients. Patients in the Picture Option Grid arm (n = 248) had higher knowledge (immediately after the visit [T2] and 1 week after surgery or within 2 weeks of the first postoperative visit [T3]), an improved decision process (T2 and T3), lower decision regret (T3), and more SDM (observed and self-reported) compared to usual care (n = 257). Patients in the Option Grid arm (n = 66) had higher decision process scores (T2 and T3), better coordination of care (12 weeks after surgery or within 2 weeks of the second postoperative visit [T4]), and more observed SDM (during the surgical visit [T1]) compared to usual care arm. Subgroup analyses suggested that the Picture Option Grid had more impact among women of lower SES and health literacy. Neither intervention affected concordance, treatment choice, or anxiety. CONCLUSIONS: Paper-based conversation aids improved key outcomes over usual care. The Picture Option Grid had more impact among disadvantaged patients. LAY SUMMARY: The objective of this study was to understand how to help women with lower incomes or less formal education to make breast cancer surgery choices. Compared with usual care, a conversation aid with pictures and text led to higher knowledge. It improved the decision process and shared decision making (SDM) and lowered decision regret. A text-only conversation aid led to an improved decision process, more coordinated care, and higher SDM compared to usual care. The conversation aid with pictures was more helpful for women with lower income or less formal education. Conversation aids with pictures and text helped women make better breast cancer surgery choices.

Barriers to accessing opioid agonist therapy in pregnancy.

BACKGROUND: The incidence of opioid use disorder during pregnancy has risen dramatically in the last couple of decades. Despite the safety and efficacy of treatment for opioid use during pregnancy, pregnant women often cannot access treatment. OBJECTIVE: This study aimed to determine the availability of opioid agonist therapy to pregnant women in Missouri and Illinois and to compare different markers of treatment accessibility between opioid treatment programs and buprenorphine providers and between rural and urban practices. STUDY DESIGN: Buprenorphine providers and opioid treatment programs in Missouri and Illinois were identified using the Substance Abuse and Mental Health Services Administration website. A phone audit was conducted to evaluate barriers to care, including whether clinics accepted new patients, pregnant patients, and insurance, and the time to the first appointment and appointment cost. Rural-urban commuting area codes and practice ZIP codes were used to determine whether practice location was rural or urban. Provider specialty was determined from state licensing databases. RESULTS: There were 1363 buprenorphine providers and 98 opioid treatment programs listed. Clinics were clustered around metropolitan areas, and only 13% of buprenorphine providers (183 of 1363) and 5% of opioid treatment programs (5 of 98) were in rural areas. Despite 3 contact attempts for each clinic, we were unable to reach 42% of buprenorphine providers (401 of 965) and 14% of opioid treatment programs (14 of 98). Of those reached, 40% of buprenorphine providers (223 of 564) and 80% of opioid treatment programs (67 of 84) were accepting new pregnant patients (P=.01). Buprenorphine providers required more contact attempts (>2 attempts in 34% vs 15%; P<.0001) and had longer wait times for the first appointment (>7 days in 27% vs 4%; P=.002) than opioid treatment programs. Buprenorphine providers in urban areas required more attempts to reach (>2 attempts in 36% vs 24%; P=.03) and were less likely to accept Medicaid than those in rural areas (52% vs 74%; P=.008). More than 23% of buprenorphine provider listings (238 of 1038) contained incorrect information, whereas no opioid treatment program listing had incorrect information. Most buprenorphine providers were in primary care or psychiatry, whereas <5% of buprenorphine providers (43 of 1363) were obstetrician-gynecologists. CONCLUSION: This is the first phone audit to evaluate access to opioid agonist therapy for pregnant women. Only a minority of buprenorphine providers offered care for this patient population, and a large proportion required multiple contact attempts and wait times of >7 days. Opioid treatment programs were more responsive and accepting of new pregnant patients but comprised a minority of clinics and were predominately located in urban areas. There is an urgent need for improved reliability of contact information for opioid agonist providers, timely intake and acceptance for treatment of pregnant patients, and overall improved access to clinics that are challenged by geographic and insurance status barriers.

Urban-Rural Disparities in Access to Low-Dose Computed Tomography Lung Cancer Screening in Missouri and Illinois.

INTRODUCTION: Low-dose computed tomography (LDCT) lung cancer screening is recommended for current and former smokers who meet eligibility criteria. Few studies have quantitatively examined disparities in access to LDCT screening. The objective of this study was to examine relationships between 1) rurality, sociodemographic characteristics, and access to LDCT lung cancer screening and 2) screening access and lung cancer mortality. METHODS: We used census block group and county-level data from Missouri and Illinois. We defined access to screening as presence of an accredited screening center within 30 miles of residence as of May 2019. We used mixed-effects logistic models for screening access and county-level multiple linear regression models for lung cancer mortality. RESULTS: Approximately 97.6% of metropolitan residents had access to screening, compared with 41.0% of nonmetropolitan residents. After controlling for sociodemographic characteristics, the odds of having access to screening in rural areas were 17% of the odds in metropolitan areas (95% CI, 12%-26%). We observed no association between screening access and lung cancer mortality. Southeastern Missouri, a rural and impoverished area, had low levels of screening access, high smoking prevalence, and high lung cancer mortality. CONCLUSION: Although access to LDCT is lower in rural areas than in urban areas, lung cancer mortality in rural residents is multifactorial and cannot be explained by access alone. Targeted efforts to implement rural LDCT screening could reduce geographic disparities in access, although further research is needed to understand how increased access to screening could affect uptake and rural disparities in lung cancer mortality.

Genetic predictors of hippocampal subfield volume in PTSD cases and trauma-exposed controls.

Behavioural, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in posttraumatic stress disorder (PTSD) pathogenesis. Recent work in a normative, primarily European, sample identified 15 unique genetic loci contributing to structural variability in six hippocampal subfield volumes. We explored the relevance of these loci in two samples (Mental Illness Research Education and Clinical Centre [MIRECC] and Grady; n = 290) of trauma-exposed individuals enriched for PTSD and of diverse ancestry. Four of the previous loci demonstrated nominal evidence of replication in the MIRECC dataset, primarily within non-Hispanic whites (NHW). One locus replicated in the Grady cohort, which was composed exclusively of non-Hispanic blacks (NHB). Our data supported genetic interactions with diagnosis of lifetime PTSD and genetic interactions with childhood trauma in the MIRECC sample, but not the Grady sample. Given the racial, diagnostic, and trauma-exposure differences with the original genome-wide association study (GWAS) report, we conducted a full GWAS in the MIRECC and Grady datasets. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for single nucleotide polymorphisms (SNPs) with evidence of main effects. Genetic associations surpassed false discovery rate (FDR)-correction within hippocampal subfields in fimbria, subiculum, cornu ammonis-1 (CA1), and hippocampal amygdala transition area (HATA). One association was replicated in the Grady cohort (rs12880795 in TUNAR with left (L)-HATA volume). The most significant association in the MIRECC dataset was between rs6906714 in LINC02571 and right (R)-fimbria volume (p = 5.99×10-8, q = 0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with exposure to childhood trauma (gene*environment [G*E] interaction p = 0.022). These preliminary results argue for G*E interactions between genetic loci with PTSD and childhood trauma on hippocampal phenotypes. Our results underscore the need for larger neuroimaging-genetic studies in PTSD, trauma, and ancestrally diverse populations.

Las neuroimagenologia, conductual, estructural y funcional ha implicado que el hipocampo se constituye como una región cerebral critica en la patogénesis del trastorno de estrés postraumático (TEPT). Un trabajo reciente, realizado en una muestra normativa, principalmente europea, identifico 15 loci genéticos únicos que contribuyen a la variabilidad estructural de seis volúmenes de subcampos hipocampales. Exploramos la relevancia de estos loci en dos muestras enriquecidas para TEPT (del Centro de Educación y Clínica Investigación sobre Enfermedades Mentales, MIRECC por sus siglas en inglés y Grady; n=290) de individuos expuestos a trauma y de ascendencia diversa. Cuatro de los loci previos demostraron evidencia nominal de replicación en la base de datos MIRECC, principalmente en personas de raza blanca no hispánicos (NHW). Se replicó un locus en la cohorte Grady, que estaba compuesta exclusivamente por personas de raza negra no hispánicos (NHB). Nuestros datos respaldaron las interacciones genéticas con el diagnostico de TEPT a lo largo de la vida e interacciones genéticas con trauma infantil en la muestra MIRECC, pero no en la de Grady. Debido a las diferencias raciales, diagnósticas y de exposición a trauma con el reporte original del estudio de asociación del genoma completo (GWAS por sus siglas en ingles), realizamos un GWAS completo con la base de datos MIRECC y Grady. Se exploraron polimorfismos de nucleótido único (SNPs por sus siglas en ingles) en las interacciones de variantes genéticas del TEPT a lo largo de la vida y del trauma infantil, con evidencia de un efecto genético principal. Las asociaciones genéticas sobrepasaron a la corrección de tasa de falso descubrimiento (FDR) dentro de los subcampos hipocampales de la fimbria, subículo, asta de Amon-1 (CA1), y el área de transición hipocampo-amigdaliana (HATA). Una asociación se replicó en la cohorte de Grady (rs 12880795 en TUNAR con volumen izquierdo del HATA). La asociación más significativa en la base de datos de MIRECC estuvo entre rs6906714 en LINC02571 y el volumen de la fimbria derecha (p=5.99×10-8, q=0.0056). Interesantemente, el efecto rs6906714 sobre el volumen de la fimbria derecha se incrementaba con la exposición al trauma infantil (interacción gen* ambiente [G*A] p=0.022). Estos resultados preliminares orientarían a la presencia de interacciones G*A de loci genéticos con el TEPT y trauma infantil en fenotipos del hipocampo. Nuestro resultados destacan la necesidad de estudios más grandes que vinculen neuroimagenes y genética en poblaciones con TEPT, trauma, y genealogía diversa.

[External fixator: temporary fixation and soft tissue management of the ankle]. / Fixateur externe: temporäre Fixation und Weichteilmanagement am oberen Sprunggelenk.

OBJECTIVE OF SURGERY: Joint-spanning transfixation of the ankle joint aims at mostly temporary retention of the reduction, i.e. restoring length and axial alignment and stabilization of the ankle mortise in highly unstable fractures around the ankle and under critical soft tissue conditions. In selected cases, external fixation serves as an additional stabilization also following completed internal fixation or the fracture can be treated in the external fixator. The goal of surgery is to allow quick soft tissue recovery, prevention of redislocation and stabilization of the ankle and adjacent structures. INDICATIONS: a) Fractures of the tibial pilon; b) very distal, extra-articular lower leg fractures (without the option for pin positioning in the distal fragment); c) highly unstable malleolar fractures with tendency to subluxation and dislocation fractures; d) critical soft tissue conditions around the ankle; e) dislocation fractures of the talus, Chopart and Lisfranc joints (if necessary with additional transarticular transfixation). CONTRAINDICATIONS: Missing consent to surgery by the conscious patient, life-threatening general condition by other prioritized injuries. SURGICAL TECHNIQUE: Percutaneous pin placement of the appropriate caliber into so-called safe zones of the tibia, metatarsus and calcaneus, as needed. Additional transfixation of the Chopart and Lisfranc joints with K­wires as needed. Fixation of the struts with the foot in a neutral position. Besides consideration of biomechanical principles, pin placement must be done in anticipation of the definitive stabilization and future approaches respecting the anatomical structures while achieving maximum stability and soft tissue protection. POSTOPERATIVE MANAGEMENT: Following initial transfixation, elevation of the injured leg for soft tissue protection, local cooling and bed rest are indicated. In cases of compartment syndrome and open fractures with temporary soft tissue coverage, second look surgery after 24-72 h is mandatory. For exact fracture analysis and optimal planning of the definitive surgical strategy, the indications for CT imaging should be generously considered. The timing of definitive care depends on the local soft tissue status and the overall condition of the patient. RESULTS: The presence of a dislocation at the time of the accident represents a negative prognostic factor for ankle fractures. Higher rates of posttraumatic arthrosis are also found in pilon fractures and trimalleolar fractures, direct cartilage damage and rupture of the syndesmosis. In cases of anatomic reconstruction of the mortice and ankle joint congruence, good to excellent results can be achieved in 75-89%.