Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD-GRN, namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders.

DSM-5 criterion-a-based trauma types in service members and veterans seeking treatment for posttraumatic stress disorder.

OBJECTIVE: In posttraumatic stress disorder (PTSD), the assumption of the equipotentiality of traumas ignores potentially unique contexts and consequences of different traumas. Accordingly, Stein et al. (2012) developed a reliable typing scheme in which assessors categorized descriptions of traumatic events into six "types": life threat to self (LTS), life threat to other, aftermath of violence (AV), traumatic loss, moral injury by self (MIS), and moral injury by other (MIO). We extended this research by validating the typing scheme using participant endorsements of type, rather than assesor-based types. We examined the concordance of participant and assesor types, frequency, and validity of participant-based trauma types by examining associations with baseline mental and behavioral health problems. METHOD: Interviewers enrolled military personnel and veterans (N = 1,443) in clinical trials of PTSD and helped them select the most currently distressing Criterion-A trauma. Participants and, archivally, assessors typed the distressing aspect(s) of this experience. RESULTS: AV was the most frequently participant-endorsed type, but LTS was the most frequently rated worst part of an event. Although participants endorsed MIS and MIO the least frequently, these were associated with worse mental and behavioral health problems. The agreement between participants and assessors regarding the worst part of the event was poor. CONCLUSION: Because of discrepancies between participant and assessor typologies, clinical researchers should use participants' ratings, and these should trump assessor judgment. Differences in pretreatment behavioral and mental health problems across some participant-endorsed trauma types partially support the validity of the participant ratings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clinical and functional outcome after partial or total claviculectomy without reconstruction for oncologic causes.

BACKGROUND: To achieve clear margins in rare malignant clavicular neoplasms, claviculectomy may become necessary. This study aimed to review clinical, functional, and oncologic outcomes following partial or total claviculectomy without reconstruction. METHODS: This study retrospectively included 15 patients from 2 tertiary sarcoma centers (mean age, 42.6 ± 20.3 years; 66.7% male patients). The median length of clinical and oncologic follow-up was 48.0 months (interquartile range [IQR], 24.0-83.5 months). Functional follow-up (Musculoskeletal Tumor Society score and QuickDASH score [short version of the Disabilities of the Arm, Shoulder and Hand questionnaire]) was available in 9 patients at a median of 36.0 months (IQR, 20.0-100.0 months). RESULTS: Of the 15 patients, 7 underwent total claviculectomy; 5, partial lateral claviculectomy; and 3, partial medial claviculectomy. No postoperative complications emerged. The median Musculoskeletal Tumor Society and QuickDASH scores at latest follow-up amounted to 26.0 points (IQR, 24.0-29.0 points) and 18.0 points (IQR, 11.0-22.0 points), respectively. Notably, scores tended to be lower in patients who underwent total claviculectomy (n = 2) in comparison to partial claviculectomy (n = 7). CONCLUSION: Satisfactory clinical and functional results can be achieved following partial or total claviculectomy without reconstruction, with a low complication rate and acceptable mid- to long-term function.

Psychometric Properties of the Self-Injurious Thoughts and Behaviors Interview-Short Form Among U.S. Active Duty Military Service Members and Veterans.

We assessed the interrater reliability, convergent validity, and discriminant validity of the Self-Injurious Thoughts and Behaviors Interview-Short Form (SITBI-SF) in a sample of 1,944 active duty service members and veterans seeking services for posttraumatic stress disorder (PTSD) and related conditions. The SITBI-SF demonstrated high interrater reliability and good convergent and discriminant validity. The measurement properties of the SITBI-SF were comparable across service members and veterans. Approximately 8% of participants who denied a history of suicidal ideation on the SITBI-SF reported suicidal ideation on a separate self-report questionnaire (i.e., discordant responders). Discordant responders reported significantly higher levels of PTSD symptoms than those who denied suicidal ideation on both response formats. Findings suggest that the SITBI-SF is a reliable and valid interview-based measure of suicide-related thoughts and behaviors for use with military service members and veterans. Suicide risk assessment might be optimized if the SITBI-SF interview is combined with a self-report measure of related constructs.

Massed vs Intensive Outpatient Prolonged Exposure for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Improved, efficient, and acceptable treatments are needed for combat-related posttraumatic stress disorder (PTSD). Objective: To determine the efficacy of 2 compressed prolonged exposure (PE) therapy outpatient treatments for combat-related PTSD. Design, Setting, and Participants: This randomized clinical trial was conducted among military personnel and veterans at 4 sites in Texas from 2017 to 2019. Assessors were blinded to conditions. Data were analyzed from November 2020 to October 2022. Interventions: The interventions were massed-PE, which included 15 therapy sessions of 90 minutes each over 3 weeks, vs intensive outpatient program PE (IOP-PE), which included 15 full-day therapy sessions over 3 weeks with 8 treatment augmentations. The IOP-PE intervention was hypothesized to be superior to massed-PE. Main Outcomes and Measures: Coprimary outcomes included the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) (CAPS-5) and the PTSD Checklist for DSM-5 (PCL-5) administered at baseline and posttreatment follow-ups. Measures ranged from 0 to 80, with higher scores indicating greater severity. Diagnostic remission and reliable change were secondary outcomes. Results: Among 319 military personnel and veterans screened, 234 were randomized (mean [SD] age, 39.20 [7.72] years; 182 [78%] male participants), with 117 participants randomized to IOP-PE and 117 participants randomized to massed-PE. A total of 61 participants (26%) were African American, 58 participants (25%) were Hispanic, and 102 participants (44%) were White; 151 participants (65%) were married. Linear mixed-effects models found that CAPS-5 scores decreased in both treatment groups at the 1-month follow-up (IOP-PE: mean difference, -13.85 [95% CI, -16.47 to -11.23]; P < .001; massed-PE: mean difference, -14.13 [95% CI, -16.63 to -11.62]; P < .001). CAPS-5 change scores differed from 1- to 6-month follow-ups (mean difference, 4.44 [95% CI, 0.89 to 8.01]; P = .02). PTSD symptoms increased in massed-PE participants during follow-up (mean difference, 3.21 [95% CI, 0.65 to 5.77]; P = .01), whereas IOP-PE participants maintained treatment gains (mean difference, 1.23 [95% CI, -3.72 to 1.27]; P = .33). PCL-5 scores decreased in both groups from baseline to 1-month follow-up (IOP-PE: mean difference, -21.81 [95% CI, -25.57 to -18.04]; P < .001; massed-PE: mean difference, -19.96 [95% CI, -23.56 to -16.35]; P < .001) and were maintained at 6 months (IOP-PE: mean change, -0.21 [95% CI, -3.47 to 3.06]; P = .90; massed-PE: mean change, 3.02 [95% CI, -0.36 to 6.40]; P = .08). Both groups had notable PTSD diagnostic remission at posttreatment (IOP-PE: 48% [95% CI, 36% to 61%] of participants; massed-PE: 62% [95% CI, 51% to 73%] of participants), which was maintained at 6 months (IOP-PE: 53% [95% CI, 40% to 66%] of participants; massed-PE: 52% [95% CI, 38% to 66%] of participants). Most participants demonstrated reliable change on the CAPS-5 (61% [95% CI, 52% to 69%] of participants) and the PCL-5 (74% [95% CI, 66% to 81%] of participants) at the 1-month follow-up. Conclusions and Relevance: These findings suggest that PE can be adapted into compressed treatment formats that effectively reduce PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT03529435.

A Review of PTSD and Current Treatment Strategies.

Current treatment strategies for control of trauma-associated symptoms of Post Traumatic Stress Disorder (PTSD) have recently been updated by the Veterans Affairs (VA) and the Department of Defense (DoD, after over a decade of dedicated research. The most recent evidence is compelling that its use of trauma-focused therapies such as Cognitive Processing Therapy (CPT), Prolonged Exposure Therapy (PE), Eye Movement, Desensitization, and Restructuring (EMDR), and others with significant trauma focus are the current gold standard for treatment. Additional medication use may be of assistance in treatment of symptomology, with special avoidance of benzodiazepines or other sedative hypnotic medications which are causal of increased intrusive and dissociative symptoms over time.

Written exposure therapy for posttraumatic stress symptoms and suicide risk: Design and methodology of a randomized controlled trial with patients on a military psychiatric inpatient unit.

Studies of active duty service members have shown that military personnel who screen positive for posttraumatic stress disorder (PTSD) are more than twice as likely to make a suicide attempt. Evidence-based PTSD treatments can reduce suicidal ideation; however, it can be challenging to provide evidence-based, trauma-focused, PTSD treatment to high-risk patients on an acute psychiatric inpatient unit because the priority of care is stabilization. Treatment for PTSD requires more time and resources than are typically afforded during inpatient hospitalizations. Written Exposure Therapy is an evidence-based, five-session, trauma-focused treatment for PTSD that may overcome the implementation challenges of providing PTSD treatment in an acute inpatient psychiatric treatment setting. This paper describes the design, methodology, and protocol of a randomized clinical trial. The goal of the study is to determine if five 60-min sessions of Written Exposure Therapy enhanced with Crisis Response Planning for suicide risk reduces the presence, frequency, and severity of suicidal ideation, suicidal behavior, rehospitalization, and non-suicidal, self-injurious behaviors. The study also will determine if Written Exposure Therapy for Suicide reduces posttraumatic stress symptom severity among military service members, veterans, and other adult military beneficiaries admitted to an acute psychiatric inpatient unit for comorbid suicide ideation or attempt and PTSD symptoms compared with Treatment as Usual. The study is designed to enhance the delivery of care for those in acute suicidal crisis with comorbid PTSD symptoms.

Bactericidal and Biocompatible Properties of Plasma Chemical Oxidized Titanium (TiOB®) with Antimicrobial Surface Functionalization.

Coating of plasma chemical oxidized titanium (TiOB®) with gentamicin-tannic acid (TiOB® gta) has proven to be efficient in preventing bacterial colonization of implants. However, in times of increasing antibiotic resistance, the development of alternative antimicrobial functionalization strategies is of major interest. Therefore, the aim of the present study is to evaluate the antibacterial and biocompatible properties of TiOB® functionalized with silver nanoparticles (TiOB® SiOx Ag) and ionic zinc (TiOB® Zn). Antibacterial efficiency was determined by agar diffusion and proliferation test on Staphylocuccus aureus. Cytocompatibility was analyzed by direct cultivation of MC3T3-E1 cells on top of the functionalized surfaces for 2 and 4 d. All functionalized surfaces showed significant bactericidal effects expressed by extended lag phases (TiOB® gta for 5 h, TiOB® SiOx Ag for 8 h, TiOB® Zn for 10 h). While TiOB® gta (positive control) and TiOB® Zn remained bactericidal for 48 h, TiOB® SiOx Ag was active for only 4 h. After direct cultivation for 4 d, viable MC3T3-E1 cells were found on all surfaces tested with the highest biocompatibility recorded for TiOB® SiOx Ag. The present study revealed that functionalization of TiOB® with ionic zinc shows bactericidal properties that are comparable to those of a gentamicin-containing coating.

Redeveloping Substance Abuse Treatment for Military Personnel.

PURPOSE OF REVIEW: We review the prevailing evidence surrounding treatment of substance use disorder (SUD), with specific focus on alcohol, tobacco, and prescription opiates, and how it informs guidelines for treating active duty military. We survey the evidence regarding preventive screening, treatment, and relapse prevention in substance misuse as it pertains to patient-centered care of the service member. RECENT FINDINGS: Holistic, patient-centered care with an emphasis on identifying maladaptive use or dependence prior to progression to chronic disease is now recognized as the evidenced approach to treating substance use disorders. Early patient-guided intervention with combined behavioral and pharmacologic therapies leads to better outcomes, including greater functional status, lower relapse rates, and decreased rate of psychiatric and other comorbidities. The military has prioritized a patient-centered approach to screening, assessing, and treating SUD. Recent guideline updates represent a progressive, patient-centered approach in delivering unprecedented access to care, serving as a positive example in treating what is widely accepted as one of the country's most pressing public health concerns.

The effect of polyelectrolyte multilayer coated titanium alloy surfaces on implant anchorage in rats.

Advances have been achieved in the design and biomechanical performance of orthopedic implants in the last decades. These include anatomically shaped and angle-stable implants for fracture fixation or improved biomaterials (e.g. ultra-high-molecular-weight polyethylene) in total joint arthroplasty. Future modifications need to address the biological function of implant surfaces. Functionalized surfaces can promote or reduce osseointegration, avoid implant-related infections or reduce osteoporotic bone loss. To this end, polyelectrolyte multilayer structures have been developed as functional coatings and intensively tested in vitro previously. Nevertheless, only a few studies address the effect of polyelectrolyte multilayer coatings of biomaterials in vivo. The aim of the present work is to evaluate the effect of polyelectrolyte coatings of titanium alloy implants on implant anchorage in an animal model. We test the hypotheses that (1) polyelectrolyte multilayers have an effect on osseointegration in vivo; (2) multilayers of chitosan/hyaluronic acid decrease osteoblast proliferation compared to native titanium alloy, and hence reduce osseointegration; (3) multilayers of chitosan/gelatine increase osteoblast proliferation compared to native titanium alloy, hence enhance osseointegration. Polyelectrolyte multilayers on titanium alloy implants were fabricated by a layer-by-layer self-assembly process. Titanium alloy (Ti) implants were alternately dipped into gelatine (Gel), hyaluronic acid (HA) and chitosan (Chi) solutions, thus assembling a Chi/Gel and a Chi/HA coating with a terminating layer of Gel or HA, respectively. A rat tibial model with bilateral placement of titanium alloy implants was employed to analyze the bones' response to polyelectrolyte surfaces in vivo. 48 rats were randomly assigned to three groups of implants: (1) native titanium alloy (control), (2) Chi/Gel and (3) Chi/HA coating. Mechanical fixation, peri-implant bone area and bone contact were evaluated by pull-out tests and histology at 3 and 8 weeks. Shear strength at 8 weeks was statistically significantly increased (p<0.05) in both Chi/Gel and Chi/HA groups compared to the titanium alloy control. No statistically significant difference (p>0.05) in bone contact or bone area was found between all groups. No decrease of osseointegration of Chi/HA-coated implants compared to non-coated implants was found. The results of polyelectrolyte coatings in a rat model showed that the Chi/Gel and Chi/HA coatings have a positive effect on mechanical implant anchorage in normal bone.

The effect of plasma chemical oxidation of titanium alloy on bone-implant contact in rats.

Many different technologies have been used to enhance osseointegration in orthopaedic and dental implant surgery. Hydroxyapatite coatings, pure or in combination with growth factors or bisphosphonates, showed improved osseointegration of titanium alloy implants. We choose a different approach to enhance osseointegration: plasma chemical oxidation was used to modify the surface of titanium alloy implants. This technique converts the nm-thin natural occurring titanium oxide layer on an implant to a 4 µm thick ceramic coating (TiOB surface). Bioactive TiOB surfaces have a macroporous structure and were loaded with calcium and phosphorus, while bioinert TiOB surfaces are smooth. A rat tibial model with bilateral placement of titanium alloy implants was employed to analyze the bone response to TiOB surfaces in vivo. 64 rats were randomly assigned to four groups of implants: (1) titanium alloy (control), (2) titanium alloy, type III anodization, (3) bioinert TiOB surface and (4) bioactive TiOB surface. Mechanical fixation, peri-implant-bone area and bone contact were evaluated by pull-out tests and histology at three and eight weeks. Shear strength and bone contact at eight weeks were significantly increased in the bioactive TiOB group compared to all other groups. The results of plasma chemical oxidation in a rat model showed that the bioactive TiOB surface has a positive effect on implant anchorage by enhancing the bone-implant contact in normal bone.

Freezing of rat tibiae at -20°c does not affect the mechanical properties of intramedullary bone/implant-interface: brief report.

BACKGROUND: The effects of freezing-thawing cycles on intramedullary bone-implant interfaces have been studied in a rat model in mechanical pull-out tests. IMPLANTS: Twenty TiAl6V4 rods (Ø 0.8 mm, length 10 mm) implanted in rat tibiae METHODS: 10 rats underwent bilateral tibial implantation of titanium rods. At eight weeks, the animals were sacrificed and tibiae harvested for biomechanical testing. Eight tibiae were frozen and stored at -20°C for 14 days, the remaining eight were evaluated immediately post-harvest. Pull-out tests were used to determine maximum force and interfacial shear strength. RESULTS: There were no significant differences between fresh and those of the frozen-thawed group in maximum force or in interfacial shear strength. CONCLUSION: Frozen Storage of rat tibiae containing implants at -20° C has no effects on the biomechanical properties of Bone/ Implant interface.