Tau, Glial Fibrillary Acidic Protein, and Neurofilament Light Chain as Brain Protein Biomarkers in Cerebrospinal Fluid and Blood for Diagnosis of Neurobiological Diseases.

Neurological damage is the pathological substrate of permanent disability in various neurodegenerative disorders. Early detection of this damage, including its identification and quantification, is critical to preventing the disease's progression in the brain. Tau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), as brain protein biomarkers, have the potential to improve diagnostic accuracy, disease monitoring, prognostic assessment, and treatment efficacy. These biomarkers are released into the cerebrospinal fluid (CSF) and blood proportionally to the degree of neuron and astrocyte damage in different neurological disorders, including stroke, traumatic brain injury, multiple sclerosis, neurodegenerative dementia, and Parkinson's disease. Here, we review how Tau, GFAP, and NfL biomarkers are detected in CSF and blood as crucial diagnostic tools, as well as the levels of these biomarkers used for differentiating a range of neurological diseases and monitoring disease progression. We also discuss a biosensor approach that allows for the real-time detection of multiple biomarkers in various neurodegenerative diseases. This combined detection system of brain protein biomarkers holds significant promise for developing more specific and accurate clinical tools that can identify the type and stage of human neurological diseases with greater precision.

The Scapular Skiver Screw: A Useful Fixation Technique for Inferior Glenoid and Scapular Neck Fractures.

SUMMARY: The inferior glenoid and scapular neck are common locations for scapular fractures. Operative exposures for reduction and fixation can be challenging, and frequently, the proximal fracture planes are not conducive to optimal fixation with a plate alone. The purpose of this article was to describe a new technique for enhancing fixation in specific inferior glenoid fractures using a single cortical lag screw.

Exposure-Response and Subgroup Analyses to Support Body Weight-Based Dosing of Brentuximab Vedotin in Children and Young Adults with Newly Diagnosed High-Risk Classical Hodgkin Lymphoma.

PURPOSE: To evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma (cHL) in the phase 3 AHOD1331 study. PATIENTS AND METHODS: Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation. RESULTS: There were no visible trends in disease characteristics across pediatric age subgroups, while BW increased with age. Observed antibody-drug conjugate exposures in patients aged <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks (Q3W), as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival (EFS) was seen in younger subgroups: 3-year EFS was 96.2% (2-<12-years) and 92.0% (12-<18-years), with no events observed in those aged <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children. CONCLUSIONS: No further adjustments based on age or BW are required for the BV dose (1.8 mg/kg Q3W) approved in children.

Does Transparency of Ankle Implant Costs Influence Surgeon Behavior?

Background: Ankle fractures are a common injury treated by orthopaedic surgeons. Unstable, displaced ankle fractures are often fixed with open reduction internal fixation (ORIF) using different implant constructs at various cost. No study to date has looked at transparency in ankle implant costs to surgeon behavior. Our surgeons self-identified that the biggest barrier for lowering implant cost was the lack of cost transparency. This was a surgeon-led-study to evaluate whether increased transparency in implant costs affected surgeon behavior. Methods: Monthly operative logs from December 2021 to September 2022 were reviewed at our level 1 trauma center for operative fixation of ankle fractures. The cost data of each fixation construct was reported to trauma-trained surgeons at the end of each month from March 2022 to June 2022. Average costs of implants were compared before and after education. A linear mixed model was used to explore what factors were associated with changes in costs. Surgeons also participated in a poststudy survey. Results: The implant costs of 110 ankle fracture fixations were reviewed over the period before education (n = 60), during education (n = 30), and after education (n = 20). The mean implant cost difference for unimalleolar fractures was -$204.80 (P = .68), whereas the mean cost difference for bimalleolar fractures was -$9.82 (P = .98). Trimalleolar fractures had a mean cost difference of +$94.47 (P = .84). Linear mixed model demonstrated fracture pattern as the only factor significantly associated with implant costs (P < .01). Post-education surgeon survey revealed that 6 of 7 surgeons felt that monthly updates affected their implant selection. However, only 2 surgeons demonstrated a change in practice with decreased implant costs during the study. Conclusion: The majority of surgeons self-reported being influenced by the implant cost education, but the detected change in implant cost was only observed in less than one-third of surgeons. Our results suggest implant selection and related costs are not influenced by increased cost transparency education alone. Level of Evidence: Level III, case control study.

Brentuximab vedotin and chemotherapy in relapsed/refractory Hodgkin lymphoma: a propensity score-matched analysis.

ABSTRACT: Several single-arm studies have explored the inclusion of brentuximab vedotin (BV) in salvage chemotherapy followed by autologous stem cell transplantation (ASCT) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, no head-to-head comparisons with standard salvage chemotherapy have been performed. This study presents a propensity score-matched analysis encompassing individual patient data from 10 clinical trials to evaluate the impact of BV in transplant-eligible patients with R/R cHL. We included 768 patients, of whom 386 were treated with BV with or without chemotherapy (BV cohort), whereas 382 received chemotherapy alone (chemotherapy cohort). Propensity score matching resulted in balanced cohorts of 240 patients each. No significant differences were observed in pre-ASCT complete metabolic response (CMR) rates (P = .69) or progression free survival (PFS; P = .14) between the BV and chemotherapy cohorts. However, in the BV vs chemotherapy cohort, patients with relapsed disease had a significantly better 3-year PFS of 80% vs 70%, respectively (P = .02), whereas there was no difference for patients with primary refractory disease (56% vs 62%, respectively; P = .67). Patients with stage IV disease achieved a significantly better 3-year PFS in the BV cohort (P = .015). Post-ASCT PFS was comparable for patients achieving a CMR after BV monotherapy and those receiving BV followed by sequential chemotherapy (P = .24). Although 3-year overall survival was higher in the BV cohort (92% vs 80%, respectively; P < .001), this is likely attributed to the use of other novel therapies in later lines for patients experiencing progression, given that studies in the BV cohort were conducted more recently. In conclusion, BV with or without salvage chemotherapy appears to enhance PFS in patients with relapsed disease but not in those with primary refractory cHL.

The True-Blue technique: Enhanced chondral assessment of the chest wall.

There is a growing understanding and identification of costal cartilage injuries, however, diagnosis of these injuries remains difficult. We present a novel radiodensity based coloring technique, termed the True-Blue technique, to manipulate 3D CT imaging and more accurately diagnose costochondral injuries.

Three-Dimensional Mapping of Scapular Body, Neck, and Glenoid Fractures.

OBJECTIVES: The purpose of this study was to report patterns of scapular fractures and define them with a contemporary methodology. METHODS: . DESIGN: Retrospective study, 2015-2021. SETTING: Single, academic, Level 1 trauma center. PATIENT SELECTION CRITERIA: Consecutive patients ≥18 years, presenting with unilateral scapula fracture, with thin-slice (≤0.5-mm) bilateral computed tomography (CT) scans of the entirety of both the injured and uninjured scapulae. OUTCOME MEASURES AND COMPARISONS: Thin-slice (0.5-mm) CT scans of injured and normal scapulae were obtained to create three-dimensional (3D) virtual models. 3D modeling software (Stryker Orthopedics Modeling and Analytics, Stryker Trauma GmbH, Kiel, Germany aka SOMA) was used to create a 3D map of fracture location and frequency. Fracture zones were delineated using anatomic landmarks to characterize fracture patterns. RESULTS: Eighty-seven patients were identified with 75 (86%) extra-articular and 12 (14%) intra-articular fractures. The dominant fracture pattern emanated from the superior lateral border (zone E) to an area inferior to the spinomedial angle (zone B) and was present in 80% of extra-articular fractures. A second-most common fracture line propagated from the primary (most-common) line toward the inferior medial scapular border with a frequency of 36%. Bare zones (with 1 or no fractures present) were identified in 4 unique areas. Furthermore, intra-articular fractures were found to be heterogenous. CONCLUSIONS: The 3D fracture map created in this study confirmed that extra-articular scapular fractures occur in certain patterns with a relatively high frequency. Results provide greater insight into scapular fracture locations and may help to study prognosis of injury and improve treatment strategy including operative approaches and surgical tactics.

The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function.

Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI.

Chest Wall Injury Society recommendation for surgical stabilization of nonunited rib fractures to decrease pain, reduce opiate use, and improve patient reported outcomes in patients with rib fracture nonunion after trauma.

BACKGROUND: Rib fractures are common injuries which can be associated with acute pain and chronic disability. While most rib fractures ultimately go on to achieve bony union, a subset of patients may go on to develop non-union. Management of these nonunited rib fractures can be challenging and variability in management exists. METHODS: The Chest Wall Injury Society's Publication Committee convened to develop recommendations for use of surgical stabilization of nonunited rib fractures (SSNURF) to treat traumatic rib fracture nonunions. PubMed, Embase, and the Cochrane database were searched for pertinent studies. Using a process of iterative consensus, all committee members voted to accept or reject the recommendation. RESULTS: No identified studies compared SSNURF to alternative therapy and the overall quality of the body of evidence was rated as low. Risk of bias was identified in all studies. Despite these limitations, there is lower-quality evidence suggesting that SSNURF may be beneficial for decreasing pain, reducing opiate use, and improving patient reported outcomes among patients with symptomatic rib nonunion. However, these benefits should be balanced against risk of symptomatic hardware failure and infection. CONCLUSION: This guideline document summarizes the current CWIS recommendations regarding use of SSNURF for management of rib nonunion. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Chemobrain: An accelerated aging process linking adenosine A2A receptor signaling in cancer survivors.

Chemotherapy has a significant positive impact in cancer treatment outcomes, reducing recurrence and mortality. However, many cancer surviving children and adults suffer from aberrant chemotherapy neurotoxic effects on learning, memory, attention, executive functioning, and processing speed. This chemotherapy-induced cognitive impairment (CICI) is referred to as "chemobrain" or "chemofog". While the underlying mechanisms mediating CICI are still unclear, there is strong evidence that chemotherapy accelerates the biological aging process, manifesting as effects which include telomere shortening, epigenetic dysregulation, oxidative stress, mitochondrial defects, impaired neurogenesis, and neuroinflammation, all of which are known to contribute to increased anxiety and neurocognitive decline. Despite the increased prevalence of CICI, there exists a lack of mechanistic understanding by which chemotherapy detrimentally affects cognition in cancer survivors. Moreover, there are no approved therapeutic interventions for this condition. To address this gap in knowledge, this review attempts to identify how adenosine signaling, particularly through the adenosine A2A receptor, can be an essential tool to attenuate accelerated aging phenotypes. Importantly, the adenosine A2A receptor uniquely stands at the crossroads of cancer treatment and improved cognition, given that it is widely known to control tumor induced immunosuppression in the tumor microenvironment, while also posited to be an essential regulator of cognition in neurodegenerative disease. Consequently, we propose that the adenosine A2A receptor may provide a multifaceted therapeutic strategy to enhance anticancer activity, while combating chemotherapy induced cognitive deficits, both which are essential to provide novel therapeutic interventions against accelerated aging in cancer survivors.

Humerus fractures: selecting fixation for a successful outcome.

Current evidence suggests at least one-third of humeral shaft fractures initially managed nonoperatively will fail closed treatment, and this review highlights surgical considerations in those circumstances. Although operative indications are well-defined, certain fracture patterns and patient cohorts are at greater risk of failure. When operative intervention is necessary, internal fixation through an anterolateral approach is a safe and sensible alternative. Determining which patients will benefit most involves shared decision-making and careful patient selection. The fracture characteristics, bone quality, and adequacy of the reduction need to be carefully evaluated for the specific operative risks for individuals with certain comorbid conditions, inevitably balancing the patient's expectations and demands against the probability of infection, nerve injury, or nonunion. As our understanding of the etiology and risk of nonunion and symptomatic malunion of the humeral diaphysis matures, adhering to the principles of diagnosis and treatment becomes increasingly important. In the event of nonunion, respect for the various contributing biological and mechanical factors enhances the likelihood that all aspects will be addressed successfully through a comprehensive solution. This review further explores specific strategies to definitively restore function of the upper extremity with the ultimate objective of an uninfected, stable union.

Open Reduction and Internal Fixation of a Chronic Precordial Flail Chest Segment: A Case Report.

CASE: We report on a 35-year-old man presenting with disabling pain secondary to multiple rib nonunions and a costochondral dislocation 5 months after sustaining a chest wall crush injury. He underwent surgical reconstruction of the chest and was followed for 2 years. Surgical exposure to the heart was necessary during open reduction of the flail segment, followed by costochondral joint fixation with plates and screws. Although he was a workers' compensation patient, he returned to full gainful employment. CONCLUSION: Open reduction and internal fixation of a symptomatic, chronically displaced, precordial, flail segment can relieve pain and promote return to baseline function.

Surgical management of traumatic sternal body nonunions: Technical tricks and clinical experience.

BACKGROUND: Rarely, traumatic sternum fractures may result in nonunion, which can have drastic, negative implications. Literature on traumatic sternal nonunion reconstruction outcomes is limited to case reports. We present the surgical principles and report clinical outcomes for seven patients following surgical reconstruction of a traumatic sternal body nonunion. METHODS: Consecutive adult patients with a nonunion after a traumatic sternum fracture who underwent reconstruction using locking plate technology and iliac crest bone graft at a Level I trauma center from 2013 to 2021 were identified. Demographic, injury, and surgery data was collected, and postoperative patient-reported outcome (PRO) scores were obtained. Patient-reported outcome scores included the one-question single assessment numeric evaluation (SANE), and the combined 10-question global physical health and global mental health values. Injuries were classified and all fractures were mapped onto a sternum template. Postoperative radiographs were reviewed for union. RESULTS: Of the study's seven patients, five were female, and the mean age was 58 years. Mechanism of injury included motor vehicle collision (5) and blunt object chest trauma (2). The mean time from initial fracture to nonunion fixation was 9 months. Four of the seven patients achieved in-clinic follow-up at ≥12 months (mean = 14.3 months), while the other three achieved ≥6 months of in-clinic follow-up. Six patients completed outcomes surveys ≥12 months after surgery (mean = 28.9 months). Mean PRO scores at final follow-up included: SANE of 75 (out of 100), and global physical health and global mental health of 44 and 47, respectively (US population mean = 50).Six of seven patients achieved known radiographic union. CONCLUSION: We describe an effective and practical method of achieving stable fixation in traumatic sternal body nonunions as evidenced by the positive clinical outcomes of a seven-patient series. Despite the variation in presentation and fracture morphology of this rare injury, the surgical technique and principles outlined can serve as a useful tool for chest wall surgeons. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Effectiveness of an Orthopaedic Trauma Research Fellowship to Produce Successfully Matching Residents.

OBJECTIVE: Orthopaedics is becoming increasingly competitive. Approximately 25% of applicants to orthopaedic surgery go unmatched each year. The mean US Medical Licensing Examination step scores and average publication numbers have increased markedly in recent years. Reapplicants have a match rate of <60%. This study describes the results of an orthopaedic trauma research fellowship and its effectiveness in obtaining a successful orthopaedic match. METHODS: A 1 to 2-year research fellowship was established at a level 1 academic trauma center. Prefellowship and fellowship metrics of 11 fellows were recorded, including undergraduate and medical schools; step-1 + step-2 scores; Alpha Omega Alpha appointment; and publication, podium, poster, and chapter accomplishments. RESULTS: The average step-1 score of the fellows was 218 (range, 192 to 252) and 232 (range, 212 to 254) for step-2. Seven of 11 fellows were reapplicants. Prefellowship, the average number of journal publications was 1, one podium, two posters, and zero textbook chapters. During fellowship, the average publications was 5, five podiums, six posters, and 1.5 textbook chapters. Ten of 11 fellows successfully matched into an orthopaedic residency, with six of seven being reapplicants. CONCLUSIONS: Six of 7 reapplying fellows (86%) successfully matched highlighting the effectiveness of this fellowship. Research fellowships should be considered as an excellent choice for applicants who may be less than ideal candidates or reapplicants.

Disparities in parental distress in a multicenter clinical trial for pediatric acute lymphoblastic leukemia.

BACKGROUND: Parent psychological distress during childhood cancer treatment has short- and long-term implications for parent, child, and family well-being. Identifying targetable predictors of parental distress is essential to inform interventions. We investigated the association between household material hardship (HMH), a modifiable poverty-exposure defined as housing, food, or utility insecurity, and severe psychological distress among parents of children aged 1-17 years with acute lymphoblastic leukemia (ALL) enrolled on the multicenter Dana-Farber ALL Consortium Trial 16-001. METHODS: This was a secondary analysis of parent-reported data. Parents completed an HMH survey within 32 days of clinical trial enrollment (T0) and again at 6 months into therapy (T1). The primary exposure was HMH at T0 and primary outcome was severe parental distress at T0 and T1, defined as a score greater than or equal to 13 on the Kessler-6 Psychological Distress Scale. Multivariable models were adjusted for ALL risk group and single parent status. RESULTS: Among 375 evaluable parents, one-third (32%; n = 120/375) reported HMH at T0. In multivariable analyses, T0 HMH was associated with over twice the odds of severe psychological distress at T0 and T1 HMH was associated with over 5 times the odds of severe distress at T1. CONCLUSIONS: Despite uniform clinical trial treatment of their children at well-resourced pediatric centers, HMH-exposed parents-compared with unexposed parents-experienced statistically significantly increased odds of severe psychological distress at the time of their child's leukemia diagnosis, which worsened 6 months into therapy. These data identify a high-risk parental population who may benefit from early psychosocial and HMH-targeted interventions to mitigate disparities in well-being.

Current Concepts in Sternoclavicular Joint Injuries.

LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.

Prognostic value of chest x-ray- and CT-defined large mediastinal adenopathy in high-risk pediatric Hodgkin lymphoma: A report from the Children's Oncology Group Study AHOD0831.

PURPOSE/OBJECTIVE: We compared the prognostic value of chest radiograph (CXR)- and computed tomography (CT)-derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL). MATERIALS/METHODS: Total 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MRCXR ) > 1/3; (ii) mediastinal mass ratio on CT (MRCT ) > 1/3; (iii) mediastinal mass volume on CT (MVCT ) > 200 mL; (iv) normalized mediastinal mass volume (MVCT /thoracic diameter [TD]) > 1 mL/mm; (v) mediastinal mass diameter on CT (MDCT ) > 10 cm; and (vi) normalized mediastinal mass diameter (MDCT /TD) > 1/3. RESULTS: Median age at diagnosis was 15.8 years (range: 5.2-21.3 years). In patients with a slow early response (SER) to chemotherapy, MVCT  > 200 mL, MDCT  > 10 cm, and MDCT /TD > 1/3 were associated with worse relapse-free survival (RFS) on MVA, while MRCXR  > 1/3, MRCT  > 1/3, and MVCT /TD > 1 mL/mm trended toward worse RFS; MDCT /TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MDCT /TD > 1/3 versus ≤1/3 on MVA (p = .02). CONCLUSION: LMA according to MVCT  > 200 mL, MDCT  > 10 cm, and MDCT /TD > 1/3 is associated with poor prognosis in advanced-stage HL patients with SER. The normalized mediastinal diameter, MDCT /TD > 1/3 appears to be the strongest predictor of inferior RFS.

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm.  DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain.  Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.