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Competing Interests: The authors declare no conflicts of interest.

Background: Ischemia/reperfusion injury (IRI) is a complex pathological process, triggered by the restoration of blood flow following an interrupted blood supply. While restoring the blood flow is the only option to salvage the ischemic tissue, reperfusion after a prolonged period of ischemia initiates IRI, triggering a cascade of inflammatory responses ultimately leading to neutrophil recruitment to the inflamed tissue, where they release neutrophil extracellular traps (NETs). NETs are web-like structures of decondensed chromatin and neutrophilic proteins, including peptidyl-arginine deiminase 2 and 4 (PAD2, PAD4), that, once outside, can citrullinate plasma proteins, irreversibly changing their conformation and potentially their function. While the involvement of NETs in IRI is known mainly from rodent models, we aimed to determine the effect of NET formation and especially PADs-mediated extracellular protein citrullination in a porcine model of limb IRI., Methods: We conducted our study on amputated pig forelimbs exposed to 1 h or 9 h of ischemia and then reperfused in vivo for 12 h. Limb weight, edema formation, compartmental pressure were measured, and skeletal muscle was analyzed by immunofluorescence (TUNEL assay and dystrophin staining) to evaluate tissue damage. Fibrin tissue deposition, complement deposition and NETs were investigated by immunofluorescence. Citrullinated plasma proteins were immunoprecipitated and citrullinated fibrinogen was identified in the plasma by Western blot and in the tissue by immunofluorescence and Western blot., Results: Our data consolidate the involvement of NETs in a porcine model of limb IRI, correlating their contribution to damage extension with the duration of the ischemic time. We found a massive infiltration of NETs in the group subjected to 9 h ischemia compared to the 1 h and citrullinated fibrinogen levels, in plasma and tissue, were higher in 9 h ischemia group. We propose fibrinogen citrullination as one of the mechanisms contributing to the worsening of IRI. NETs and protein citrullination represent a potential therapeutic target, but approaches are still a matter of debate. Here we introduce the idea of therapeutic approaches against citrullination to specifically inhibit PADs extracellularly, avoiding the downstream effects of hypercitrullination and keeping PADs' and NETs' intracellular regulatory functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zollet, Arenas Hoyos, Hirsiger, Brahim, Petrucci, Casoni, Wang, Spirig, Nettelbeck, Garcia, Fuest, Vögelin, Constantinescu and Rieben.)

Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection., Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus., Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus., Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Arenas Hoyos, Helmer, Yerly, Lese, Hirsiger, Zhang, Casoni, Garcia, Petrucci, Hammer, Duckova, Banz, Montani, Constantinescu, Vögelin, Bordon, Aleandri, Prost, Taddeo, Luciani, Rieben, Sorvillo and Olariu.)

Background: Vascularized composite allotransplantation (VCA) offers the potential for a biological, functional reconstruction in individuals with limb loss or facial disfigurement. Yet, it faces substantial challenges due to heightened immune rejection rates compared to solid organ transplants. A deep understanding of the genetic and immunological drivers of VCA rejection is essential to improve VCA outcomes., Methods: Heterotopic porcine hindlimb VCA models were established and followed until reaching the endpoint. Skin and muscle samples were obtained from VCA transplant recipient pigs for histological assessments and RNA sequencing analysis. The rejection groups included recipients with moderate pathological rejection, treated locally with tacrolimus encapsulated in triglycerol-monostearate gel (TGMS-TAC), as well as recipients with severe end-stage rejection presenting evident necrosis. Healthy donor tissue served as controls. Bioinformatics analysis, immunofluorescence, and electron microscopy were utilized to examine gene expression patterns and the expression of immune response markers., Results: Our comprehensive analyses encompassed differentially expressed genes, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways, spanning various composite tissues including skin and muscle, in comparison to the healthy control group. The analysis revealed a consistency and reproducibility in alignment with the pathological rejection grading. Genes and pathways associated with innate immunity, notably pattern recognition receptors (PRRs), damage-associated molecular patterns (DAMPs), and antigen processing and presentation pathways, exhibited upregulation in the VCA rejection groups compared to the healthy controls. Our investigation identified significant shifts in gene expression related to cytokines, chemokines, complement pathways, and diverse immune cell types, with CD8 T cells and macrophages notably enriched in the VCA rejection tissues. Mechanisms of cell death, such as apoptosis, necroptosis and ferroptosis were observed and coexisted in rejected tissues., Conclusion: Our study provides insights into the genetic profile of tissue rejection in the porcine VCA model. We comprehensively analyze the molecular landscape of immune rejection mechanisms, from innate immunity activation to critical stages such as antigen recognition, cytotoxic rejection, and cell death. This research advances our understanding of graft rejection mechanisms and offers potential for improving diagnostic and therapeutic strategies to enhance the long-term success of VCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Arenas Hoyos, Helmer, Banz, Zubler, Lese, Hirsiger, Constantinescu, Rieben, Gultom and Olariu.)

Purpose: The objective of this systematic review was to perform epidemiological as well as clinical, radiological and patient-reported outcome analysis of surgically treated perilunate dislocations and fracture dislocations (PLDs and PLFDs) based on the so far largest pooled patient population to date., Material and Methods: This systematic review was written according to the updated guideline for reporting systematic reviews by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. A comprehensive literature search of Pubmed, Embase, CENTRAL, and CINAHL databases was performed. All studies reporting on complications, radiological, functional and/or patient-reported outcomes of surgically treated acute PLDs and PLFDs with a minimum follow-up of 12 months were included., Results: Twenty-six studies encompassing 550 patients with 553 operatively treated acute perilunate injuries (106 PLDs and 447 PLFDs) were included. The overall postoperative complication rate was 15.0% with secondary reduction loss representing the main contributing factor (10.1%). The overall reoperation rate was 10.4% and the incidence of salvage procedures was 2.8%. The risk for secondary reduction loss was higher for PLD than for PLFD injuries (24.2% vs. 7.0%, relative risk [RR] 3.5, 95% confidence interval [CI] 1.6-7.5). There was a higher overall complication rate for the combined dorsopalmar approach when compared to the isolated dorsal approach (17.4% vs. 8.4%, RR 0.5, 95% CI 0.2-1.0, number needed to treat [NNT] 11.2) and for open surgery versus arthroscopic surgery (17.4% vs. 4.8%, RR 0.3, 95% CI 0.1-0.9, NNT 8.0). A significant correlation was found between radiological osteoarthritis (rOA) and follow-up duration of the individual studies, while functional and patient-rated outcomes were comparable., Conclusions: Regardless of surgical technique, PLFDs appear to be less susceptible to secondary reduction loss than PLDs. Whenever possible, less invasive (e.g. arthroscopic) surgery should be performed to minimize postoperative complications. The rate of rOA is high and increases significantly with follow-up duration. Interestingly, rOA does not seem to correlate with reduced wrist function nor patient dissatisfaction and the need for salvage surgery is surprisingly rare., Level of Evidence: Systematic review of level IV studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: This study hypothesized that ratios of sonographic cross-sectional areas (CSAs) throughout the median nerve provide a more reliable tool for diagnosing carpal tunnel syndrome (CTS) than a single CSA value. We first tested this hypothesis in a retrospective cohort and subsequently confirmed it in a prospective blinded case-control series., Methods: Seventy patients were included in the retrospective study, and 50 patients and matched controls were included for the prospective study. We evaluated 4 CSAs, at the forearm, inlet, tunnel, outlet, and their ratios (R forearm , R inlet , R outlet , R outlet forearm ) to evaluate compression of the median nerve. All patients underwent nerve conduction studies. For the prospective cohort, Disabilities of the Arm, Shoulder, and Hand scores and Boston Carpal Tunnel Questionnaire scores were evaluated, and ultrasound was performed by 2 examiners for each participant., Results: The Boston and Disabilities of the Arm, Shoulder, and Hand scores showed worse subjective function in patients with CTS than in controls. Three ultrasonography parameters (CSAs at the inlet, R inlet , and R outlet ) correlated significantly with subjective function. Age and R inlet were significantly correlated with severity of CTS in the nerve conduction studies. In both the retrospective and prospective patient groups, the numbers of CSAs at the inlet and outlet were significantly higher than that of CSAs at the tunnel, whereas in the control group, no such compression was found. Of the single measurements, CSAs at the inlet had the best diagnostic performance with an optimized cutoff of 11.75 mm 2 . The R inlet and R outlet ratios performed even better and showed the highest adjusted odds ratios for predicting CTS of all parameters (cutoff R inlet , 1.25; R outlet , 1.45). Inter-observer correlation was generally high, with better values for single CSAs than for ratios., Conclusions: The 3 CSA measurements of the median nerve and the associated ratios improved diagnostic power for ultrasonography in CTS in our study., Type of Study/level of Evidence: Diagnostic I., (© 2023 The Authors.)

The incidence of skin cancer and especially cutaneous malignant melanoma is rising, as are indications for staging examinations to detect metastasis. Schwannomas are common benign nerve tumors, which can be mistaken for metastasis even in highly specialized imaging. Risk of nerve lesion is high in inadvertent biopsy., Competing Interests: All authors hereby declare that they have no potential conflicts of interest to disclose., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

We present the case of a 31-year-old woman who was referred with a 12-month history of a tumor on the ulnar side of her dominant right hand. The eventual histopathologic diagnosis was an atypical pleomorphous lipomatous tumor, an entity that has only been recently classified in the World Health Organization Classification of Soft Tissue and Bone Tumors., (Copyright © 2022 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Previous brain imaging studies with chronic cocaine users (CU) using diffusion tensor imaging (DTI) mostly focused on fractional anisotropy to investigate white matter (WM) integrity. However, a quantitative interpretation of fractional anisotropy (FA) alterations is often impeded by the inherent limitations of the underlying tensor model. A more fine-grained measure of WM alterations could be achieved by measuring fibre density (FD). This study investigates this novel DTI metric comparing 23 chronic CU and 32 healthy subjects. Quantitative hair analysis was used to determine intensity of cocaine and levamisole exposure-a cocaine adulterant with putative WM neurotoxicity. We first assessed the impact of cocaine use, levamisole exposure and alcohol use on group differences in WM integrity. Compared with healthy controls, all models revealed cortical reductions of FA and FD in CU. At the within-patient group level, we found that alcohol use and levamisole exposure exhibited regionally different FA and FD alterations than cocaine use. We found mostly negative correlations of tract-based WM associated with levamisole and weekly alcohol use. Specifically, levamisole exposure was linked with stronger WM reductions in the corpus callosum than alcohol use. Cocaine use duration correlated negatively with FA and FD in some regions. Yet, most of these correlations did not survive a correction for multiple testing. Our results suggest that chronic cocaine use, levamisole exposure and alcohol use were all linked to significant WM impairments in CU. We conclude that FD could be a sensitive marker to detect the impact of the use of multiple substances on WM integrity in cocaine but also other substance use disorders., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

In this study we investigated the association between age-related brain atrophy and behavioural as well as electrophysiological markers of vowel perception in a sample of healthy younger and older adults with normal pure-tone hearing. Twenty-three older adults and 27 younger controls discriminated a set of vowels with altered second formants embedded in consonant-vowel syllables. Additionally, mismatch negativity (MMN) responses were recorded in a separate oddball paradigm with the same set of stimuli. A structural magnet resonance scan was obtained for each participant to determine cortical architecture of the left and right planum temporale (PT). The PT was chosen for its function as a major processor of auditory cues and speech. Results suggested that older adults performed worse in vowel discrimination despite normal-for-age pure-tone hearing. In the older group, we found evidence that those with greater age-related cortical atrophy (i.e., lower cortical surface area and cortical volume) in the left and right PT also showed weaker vowel discrimination. In comparison, we found a lateralized correlation in the younger group suggesting that those with greater cortical thickness in only the left PT performed weaker in the vowel discrimination task. We did not find any associations between macroanatomical traits of the PT and MMN responses. We conclude that deficient vowel processing is not only caused by pure-tone hearing loss but is also influenced by atrophy-related changes in the ageing auditory-related cortices. Furthermore, our results suggest that auditory processing might become more bilateral across the lifespan., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cocaine use has been associated with vascular pathologies, including cerebral white matter hyperintensities. Street cocaine is most often adulterated with levamisole, an anthelminthic drug that may also be associated with vascular toxicity. However, whether levamisole exposure from cocaine consumption further accelerates the development of white matter lesions remains unknown., Methods: We investigated the association of cocaine and levamisole exposure with white matter hyperintensities in 35 chronic cocaine users and 34 healthy controls. We measured cocaine and levamisole concentrations in hair samples, which reflected exposure up to 6 months previously. We assessed the number and total surface area of the white matter hyperintensities using structural MRI (FLAIR sequence). Using generalized linear models, we analyzed the contributions of cocaine and levamisole to the number and area of white matter hyperintensities, accounting for several confounding factors., Results: Analysis using generalized linear models revealed that cocaine users had more white matter hyperintensities in terms of total surface area, but not in terms of number. Further generalized linear models that included cocaine and levamisole hair concentrations (instead of group) as predictors indicated that levamisole exposure was strongly associated with more and larger white matter hyperintensities, suggesting that the elevated white matter hyperintensities in cocaine users were driven mainly by levamisole exposure. Finally, white matter hyperintensities in levamisole-exposed cocaine users were located primarily in the periventricular and juxtacortical white matter., Limitations: The sample size was moderate, and blood pressure was not systematically assessed., Conclusion: As an adulterant of cocaine, levamisole appears to increase the risk of white matter injury., Competing Interests: None declared., (© 2021 Joule Inc. or its licensors.)

Osteoarthritis of the trapeziometarcarpal joint, also called rhizarthrosis, is a common finding in the second half of life. It has a higher prevalence in females and is of growing importance in ageing societies. A variety of conservative and surgical treatment options are known, including conservative treatment up to joint replacement. Without treatment, rhizarthrosis can lead to disabling pain and loss of hand function. The goal of this overview of treatment options is to present a stepwise approach that can be initiated by any physician. Treatment of trapeziometacarpal osteoarthritis should be started early with conservative measures such as splinting and physical therapy, which can be supplemented by oral and topical analgesics and local infiltrations subsequently. If all of these interventions do not provide sufficient relief, referral to a hand surgeon should be considered. Surgical strategies vary from arthroscopic debridement over trapeziectomy, with or without tendon interposition and ligament reconstruction, to interposition implants and total joint replacements. The planned intervention should be based on clinical and subjective functional limitations and associated degenerative changes, as well as the patient’s expectations and needs. The goal of this paper is to develop a treatment algorithm, leading to higher levels of patient functionality and satisfaction. Below we discuss the current literature and point out key treatment options used in our department. &nbsp.

Objective: The optimal duration of postsurgical antibiotic therapy for adult native joint bacterial arthritis remains unknown., Methods: We conducted a prospective, unblinded, randomised, non-inferiority study comparing either 2 or 4 weeks of antibiotic therapy after surgical drainage of native joint bacterial arthritis in adults. Excluded were implant-related infections, episodes without surgical lavage and episodes with a follow-up of less than 2 months., Results: We enrolled 154 cases: 77 in the 4-week arm and 77 in the 2-week arm. Median length of intravenous antibiotic treatment was 1 and 2 days, respectively. The median number of surgical lavages was 1 in both arms. Recurrence of infection was noted in three patients (2%): 1 in the 2-week arm (99% cure rate) and 2 in the 4-week arm (97% cure rate). There was no difference in the number of adverse events or sequelae between the study arms. Of the overall 154 arthritis cases, 99 concerned the hand and wrist, for which an additional subgroup analysis was performed. In this per-protocol subanalysis, we noted three recurrences: one in the 2-week arm (97 % cure); two in the 4-week arm (96 % cure) and witnessed sequelae in 50% in the 2-week arm versus 55% in the 4-week arm, of which five (13%) and six (13%) needed further interventions., Conclusions: After initial surgical lavage for septic arthritis, 2 weeks of targeted antibiotic therapy is not inferior to 4 weeks regarding cure rate, adverse events or sequelae and leads to a significantly shorter hospital stay, at least for hand and wrist arthritis., Trial Registration Number: NCT03615781., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Age-related decline in speech perception may result in difficulties partaking in spoken conversation and potentially lead to social isolation and cognitive decline in older adults. It is therefore important to better understand how age-related differences in neurostructural factors such as cortical thickness (CT) and cortical surface area (CSA) are related to neurophysiological sensitivity to speech cues in younger and older adults. Age-related differences in CT and CSA of bilateral auditory-related areas were extracted using FreeSurfer in younger and older adults with normal peripheral hearing. Behavioral and neurophysiological sensitivity to prosodic speech cues (word stress and fundamental frequency of oscillation) was evaluated using discrimination tasks and a passive oddball paradigm, while EEG was recorded, to quantify mismatch negativity responses. Results revealed (a) higher neural sensitivity (i.e., larger mismatch negativity responses) to word stress in older adults compared to younger adults, suggesting a higher importance of prosodic speech cues in the speech processing of older adults, and (b) lower CT in auditory-related regions in older compared to younger individuals, suggesting neuronal loss associated with aging. Within the older age group, less neuronal loss (i.e., higher CT) in a right auditory-related area (i.e., the supratemporal sulcus) was related to better performance in fundamental frequency discrimination, while higher CSA in left auditory-related areas was associated with higher neural sensitivity toward prosodic speech cues as evident in the mismatch negativity patterns. Overall, our results offer evidence for neurostructural changes in aging that are associated with differences in the extent to which left and right auditory-related areas are involved in speech processing in older adults. We argue that exploring age-related differences in brain structure and function associated with decline in speech perception in older adults may help develop much needed rehabilitation strategies for older adults with central age-related hearing loss., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Chronic anterior sternoclavicular (SC) instability is a rare but potentially disabling condition. It can arise in conjunction with trauma or hyperlaxity, or both. Numerous surgical techniques have been described, but no gold standard exists. SC instability is often position-dependent and can be reduced with the arm in a specific position., Methods: To directly address this issue, we used a technique of corrective osteotomy of the clavicle with the goal to reorient the articular portion of the medial end of the clavicle so that it remains stable in all functional positions of the arm. To illustrate the technique and the correction in space, we performed postoperative 3-dimensional computed tomography analyses of the shoulder girdle of 4 patients. Clinical scores were obtained at the final follow-up and compared with preoperative scores., Results: Mean follow-up was 64 months (range, 19-191 months). The mean Constant score improved from 58 (range, 45-68) preoperatively to 73 (range, 69-84) postoperatively and the Subjective Shoulder Value from 42 (range, 15-80) to 79 (range, 50-100). All patients reported good or very good stability of the SC joint at the last follow-up. We recorded no intraoperative or direct postoperative complications. During follow-up, 3 patients underwent removal of the plate, 1 of them for plate breakage. The mean postoperative correction for combined rotations is given as a 3-dimensional angle and averaged 28.0° (range, 8.6°-39.7°)., Conclusion: In this pilot study, medial corrective clavicular osteotomy using the described technique treated anterior SC instability with improvement of clinical shoulder function scores and good patient satisfaction. The technique appears simple and safe and deserves further evaluation., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: The management of prosthetic joint infections (PJI) with debridement and retention of the implant (DAIR) has its rules. Some authors claim that lacking the exchange of mobile prosthetic parts is doomed to failure, while others regard it as optional. Methods: Single-center retrospective cohort in PJIs treated with DAIR. Results: We included 112 PJIs (69 total hip arthroplasties, 9 medullary hip prostheses, 41 total knee arthroplasties, and 1 total shoulder arthroplasty) in 112 patients (median age 75 years, 52 females (46%), 31 (28%) immune-suppressed) and performed a DAIR procedure in all cases-48 (43%) with exchange of mobile parts and 64 without. After a median follow-up of 3.3 years, 94 patients (84%) remained in remission. In multivariate Cox regression analysis, remission was unrelated to PJI localization, pathogens, number of surgical lavages, duration of total antibiotic treatment or intravenous therapy, choice of antibiotic agents, immune-suppression, or age. In contrast, the exchange of mobile parts was protective (hazard ratio 1.9; 95% confidence interval 1.2⁻2.9). Conclusions: In our retrospective single-center cohort, changing mobile parts of PJI during the DAIR approach almost doubled the probability for long-term remission.

Background: Cocaine use has been consistently associated with decreased gray matter volumes in the prefrontal cortex. However, it is unclear if such neuroanatomical abnormalities depict either pre-existing vulnerability markers or drug-induced consequences. Thus, this longitudinal MRI study investigated neuroplasticity and cognitive changes in relation to altered cocaine intake., Methods: Surface-based morphometry, cocaine hair concentration, and cognitive performance were measured in 29 cocaine users (CU) and 38 matched controls at baseline and follow-up. Based on changes in hair cocaine concentration, CU were classified either as Decreasers (n = 15) or Sustained Users (n = 14). Surface-based morphometry measures did not include regional tissue volumes., Results: At baseline, CU displayed reduced cortical thickness (CT) in lateral frontal regions, and smaller cortical surface area (CSA) in the anterior cingulate cortex, compared to controls. In Decreasers, CT of the lateral frontal cortex increased whereas CT within the same regions tended to further decrease in Sustained Users. In contrast, no changes were found for CSA and subcortical structures. Changes in CT were linked to cognitive performance changes and amount of cocaine consumed over the study period., Conclusions: These results suggest that frontal abnormalities in CU are partially drug-induced and can recover with decreased substance use. Moreover, recovery of frontal CT is accompanied by improved cognitive performance confirming that cognitive decline associated with cocaine use is potentially reversible., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Surgical planning of corrective osteotomies is traditionally based on conventional radiographs and clinical findings. In the past 10 years, 3-dimensional (3D) preoperative planning approaches with patient-specific guides have been developed. However, the application of this technology to posttraumatic deformities of the metacarpals and phalangeal bones has not yet been investigated. Our goal was to evaluate the feasibility of the surgical application to the latter and to evaluate the extent and precision of correction., Methods: We present results of 6 patients (8 osteotomies) treated with phalangeal or metacarpal corrective osteotomy. Deformities were located in the third ray in 1, fourth ray in 3, and fifth ray in 4 cases. Six malunited metacarpal bones (1 intra-articular) and 2 deformed proximal phalanges were treated. Computer-based 3D preoperative planning using the contralateral hand as a template allowed the production of 3D-printed patient-specific guides that were used intraoperatively for navigation. The precision of the reduction was assessed using pre- and postoperative computed tomography by comparing the postoperative bone model with the preoperatively simulated osteotomy. Range of motion and grip strength were documented pre- and postoperatively., Results: The mean follow-up time was 6 months (range: 5-11 months). Rotational deformity was reduced from a mean of 10.0° (range: 7.2°-19.3°) preoperatively to 2.3° (range: 0.7°-3.7°) postoperatively, and translational incongruency decreased from a mean of 1.4 mm (range: 0.7-2.8 mm) to 0.4 mm (range: 0.1-0.9 mm)., Conclusion: Preliminary results indicate that a precise reduction for corrective osteotomies of metacarpal and phalangeal bones can be achieved by using 3D planning and patient-specific guides.

Currently, levamisole is the most common cocaine adulterant worldwide and it is known to induce a variety of adverse side effects. Animal studies and human case reports suggest potential neurotoxicity of the compound but neither neuroanatomical nor cognitive effects of levamisole have been systematically investigated in cocaine users so far. We examined cognitive performance and cortical structural differences between chronic cocaine users with low and high recent exposure to levamisole objectively determined by quantitative toxicological hair analyses. In Study 1, we compared 26 chronic cocaine users with low levamisole exposure (lowLevCU), 49 matched cocaine users with high levamisole exposure (highLevCU), and 78 matched stimulant-naive controls regarding cognitive functioning employing a comprehensive neuropsychological test battery. In Study 2, we investigated cortical thickness by use of T1-weighted MRI in a subgroup of 12 lowLevCU, 17 highLevCU, and 38 stimulant-naive controls. In Study 1, both cocaine user groups showed significant impairments in the cognitive domains of attention and working memory as well as in the global cognitive index. However, highLevCU showed significantly worse executive functions compared to lowLevCU although both groups did not differ in severity of cocaine consumption and other clinical dimensions. Study 2 revealed that highLevCU, displayed reduced cortical thickness specifically in the middle frontal gyrus compared to both controls and lowLevCU. Our results suggest that levamisole exposure during the last months in cocaine users is associated with increased executive function impairments and pronounced thinning of the lateral prefrontal cortex. Consequently, prevention and drug policy-making should aim to reduce levamisole contamination of street cocaine.

To gain more insight into central hearing loss, we investigated the relationship between cortical thickness and surface area, speech-relevant resting state EEG power, and above-threshold auditory measures in older adults and younger controls. Twenty-three older adults and 13 younger controls were tested with an adaptive auditory test battery to measure not only traditional pure-tone thresholds, but also above individual thresholds of temporal and spectral processing. The participants' speech recognition in noise (SiN) was evaluated, and a T1-weighted MRI image obtained for each participant. We then determined the cortical thickness (CT) and mean cortical surface area (CSA) of auditory and higher speech-relevant regions of interest (ROIs) with FreeSurfer. Further, we obtained resting state EEG from all participants as well as data on the intrinsic theta and gamma power lateralization, the latter in accordance with predictions of the Asymmetric Sampling in Time hypothesis regarding speech processing (Poeppel, Speech Commun 41:245-255, 2003). Methodological steps involved the calculation of age-related differences in behavior, anatomy and EEG power lateralization, followed by multiple regressions with anatomical ROIs as predictors for auditory performance. We then determined anatomical regressors for theta and gamma lateralization, and further constructed all regressions to investigate age as a moderator variable. Behavioral results indicated that older adults performed worse in temporal and spectral auditory tasks, and in SiN, despite having normal peripheral hearing as signaled by the audiogram. These behavioral age-related distinctions were accompanied by lower CT in all ROIs, while CSA was not different between the two age groups. Age modulated the regressions specifically in right auditory areas, where a thicker cortex was associated with better auditory performance in older adults. Moreover, a thicker right supratemporal sulcus predicted more rightward theta lateralization, indicating the functional relevance of the right auditory areas in older adults. The question how age-related cortical thinning and intrinsic EEG architecture relates to central hearing loss has so far not been addressed. Here, we provide the first neuroanatomical and neurofunctional evidence that cortical thinning and lateralization of speech-relevant frequency band power relates to the extent of age-related central hearing loss in older adults. The results are discussed within the current frameworks of speech processing and aging.

Aging is associated with microstructural white matter (WM) changes. WM microstructural characteristics, measured with diffusion tensor imaging (DTI), are different in normal appearing white matter (NAWM) and WM hyperintensities (WMH). It is largely unknown how the microstructural properties of WMH are associated with cognition and if there are regional effects for specific cognitive domains. We therefore examined within 200 healthy older participants (a) differences in microstructural characteristics of NAWM and WMH per cerebral lobe; and (b) the association of macrostructural (WMH volume) and microstructural characteristics (within NAWM and WMH separately) of each lobe with measures of executive function and processing speed. Multi-modal imaging (i.e., T1, DTI, and FLAIR) was used to assess WM properties. The Stroop and the Trail Making Test were used to measure inhibition, task-switching (both components of executive function), and processing speed. We observed that age was associated with deterioration of white matter microstructure of the NAWM, most notably in the frontal lobe. Older participants had larger WMH volumes and lowest fractional anisotropy values within WMH were found in the frontal lobe. Task-switching was associated with cerebral NAWM volume and NAWM volume of all lobes. Processing speed was associated with total NAWM volume, and microstructural properties of parietal NAWM, the parietal WMH, and the temporal NAWM. Task-switching was related to microstructural properties of WMH of the frontal lobe and WMH volume of the parietal lobe. Our results confirm that executive functioning and processing speed are uniquely associated with macro- and microstructural properties of NAWM and WMH. We further demonstrate for the first time that these relationships differ by lobar region. This warrants the consideration of these distinct WM indices when investigating cognitive function.

Three-dimensional computer-assisted preoperative planning, combined with patient-specific surgical guides, has become an effective technique for treating complex extra- and intraarticular bone malunions by corrective osteotomy. The feasibility and accuracy of such a technique has not yet been evaluated for ankle deformities. Four surgical cases of varying complexity and location were selected for evaluation. Three-dimensional bone models of the affected and contralateral healthy lower limb were generated from computed tomography scans. The preoperative planning software permitted quantification of the deformity in 3 dimensions and subsequent simulation of reduction, yielding a precise surgical plan. Patient-specific surgical guides were designed, manufactured, and finally applied during surgery to reproduce the preoperative plan. Evaluation of the postoperative computed tomography scans indicated adequate reduction accuracy with residual translational and rotational errors of <3 mm and <6°, respectively. Two patients required revision surgery owing to anterior osseous impingement or delayed union of the osteotomy. All patients were satisfied with the postoperative course and were pain free at a mean follow-up period of 2.5 (range 1 to 4) years. These promising results require confirmation in a clinical study with a larger sample size., (Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Cerebellar volume declines with aging. Few studies have investigated age differences in regional cerebellar volume (RCV) and their association with motor and cognitive function. In 213 healthy older adults, we investigated the association of age with motor skills, cognition and RCV. Subsequently, we studied the association of RCV with motor skills and cognition. RCVs were derived from T1-weighted MRI scans using the automated SUIT segmentation method and clustered using principal component analysis (PCA). Motor skill (manual dexterity, tapping speed, bimanual visuomotor coordination, grip force) and cognition (mental rotation, verbal memory, inhibition, mental flexibility) were assessed. Behavioral measures were clustered into compounds using PCA: left hand motor skill, right hand motor skill, verbal memory and mental flexibility, and mental rotation & inhibition. Volume of the rostral middle frontal gyri (rMFG) and premotor areas (PMA) were related to performance for reference. Analyses were adjusted for age, sex, and education. Volume of the cerebellar anterior lobe and top of the superior posterior lobe were positively associated with motor skill. Volume of the bottom part of the posterior superior lobe and the inferior posterior lobe was positively associated with cognition. PMA volume was associated with cognition and motor skill and rMFG volume with motor skill. Although these results did not survive FDR correction, their effect sizes suggest that regional cerebellar volume selectively contributes to cognitive and motor skill. Effect sizes of cerebellar associations with performance were similar to those of rMFG/PMA and performance suggesting parallel contributions to performance.

Age-related behavioral declines may be the result of deterioration of white matter tracts, affecting brain structural (SC) and functional connectivity (FC) during resting state. To date, it is not clear if the combination of SC and FC data could better predict cognitive/motor performance than each measure separately. We probed these relationships in the cingulum bundle, a major white matter pathway of the default mode network. We aimed to attain deeper knowledge about: (a) the relationship between age and the cingulum's SC and FC strength, (b) the association between SC and FC, and particularly (c) how the cingulum's SC and FC are related to cognitive/motor performance separately and combined. We examined these associations in a healthy and well-educated sample of 165 older participants (aged 64-85). SC and FC were acquired using probabilistic tractography to derive measures to capture white matter integrity within the cingulum bundle (fractional anisotropy, mean, axial and radial diffusivity) and a seed-based resting-state functional MRI correlation approach, respectively. Participants performed cognitive tests measuring processing speed, memory and executive functions, and motor tests measuring motor speed and grip force. Our data revealed that only SC but not resting state FC was significantly associated with age. Further, the cingulum's SC and FC showed no relation. Different relationships between cognitive/motor performance and SC/FC separately were found, but no additive effect of the combined analysis of cingulum's SC and FC for predicting cognitive/motor performance was apparent., (© 2015 Wiley Periodicals, Inc.)

Objectives: Functional neuroimaging and voxel-based morphometry studies have confirmed the important role of the cerebellum in motor behavior. However, little is known about the relationship between cerebellar gray (GMv) and white matter (WMv) volume and manual motor performance in aging individuals. This study aims to quantify the relationship between cerebellar tissue volume and manual motor performance., Experimental Design: To gain more insight into cerebellar function and how it relates to the role of the primary motor cortex (M1), we related cerebellar GMv, WMv, and M1v to manual motor performance in 217 healthy older individuals. Left and right cerebellar GMv and WMv, and M1v were obtained using FreeSurfer. The following motor measures were obtained: grip force, tapping speed, bimanual visuomotor coordination, and manual dexterity., Principal Observations: Significant positive relationships were observed between cerebellar GMv and WMv and grip strength, right cerebellar WMv and right-hand tapping speed, right cerebellar WMv and dexterity, M1v and grip strength, and right M1v and left-hand dexterity, though effect sizes were small., Conclusions: Our results show that cerebellar GMv and WMv are differently associated with manual motor performance. These associations partly overlap with the brain-behavior associations between M1 and manual motor performance. Not all observed associations were lateralized (i.e., ipsilateral cerebellar and contralateral M1v associations with motor performance), which could point to age-related neural dedifferentiation. The current study provides new insights in the role of the cerebellum in manual motor performance. In consideration of the small effect sizes replication studies are needed to validate these results., (© 2015 Wiley Periodicals, Inc.)

Sleep quality markedly declines across the human lifespan. Particularly the amount of slow-wave sleep (SWS) decreases with age and this decrease is paralleled by a loss of cognitive functioning in the elderly. Here we show in healthy elderly females that the amount of SWS can be extended by a hypnotic suggestion "to sleep deeper" before sleep. In a placebo-controlled cross-over design, participants listened to hypnotic suggestions or a control tape before a midday nap while high density electroencephalography was recorded. After the hypnotic suggestion, we observed a 57% increase in SWS in females suggestible to hypnosis as compared to the control condition. Furthermore, left frontal slow-wave activity (SWA), characteristic for SWS, was significantly increased, followed by a significant improvement in prefrontal cognitive functioning after sleep. Our results suggest that hypnotic suggestions might be a successful alternative for widely-used sleep-enhancing medication to extend SWS and improve cognition in the elderly., (Copyright © 2015. Published by Elsevier Ltd.)

Aging is associated with impaired motor performance across a range of tasks. Both primary neural representations of movement and potential compensatory cognitive mechanisms appear to be disrupted in older age. Here we determined how age is associated with resting state sensorimotor functional connectivity, and whether connectivity strength is associated with motor performance. We investigated the association between age and resting state functional connectivity of several sensorimotor networks in 191 healthy older, right-handed individuals. Regions of interest were defined in the left motor cortex, left putamen, and right cerebellar lobules V and VIII. Analyses were adjusted for head motion, gray matter volume, diastolic blood pressure, and smoker status; we then evaluated whether connectivity is associated with participants' manual motor performance. We found both increased and decreased connectivity within portions of the motor cortical and cerebellar networks after adjusting for covariates. We observed that connectivity increased with age for the motor cortex and cerebellar lobule VIII with the putamen, providing evidence of greater interactivity across networks with age. Higher tapping frequency and greater grip force were associated with stronger connectivity between the motor cortex during resting state, putamen, cerebellar lobule VIII and the insular cortex, suggesting that greater network interactivity may protect against age declines in performance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

FreeSurfer is a tool to quantify cortical and subcortical brain anatomy automatically and noninvasively. Previous studies have reported reliability and statistical power analyses in relatively small samples or only selected one aspect of brain anatomy. Here, we investigated reliability and statistical power of cortical thickness, surface area, volume, and the volume of subcortical structures in a large sample (N=189) of healthy elderly subjects (64+ years). Reliability (intraclass correlation coefficient) of cortical and subcortical parameters is generally high (cortical: ICCs>0.87, subcortical: ICCs>0.95). Surface-based smoothing increases reliability of cortical thickness maps, while it decreases reliability of cortical surface area and volume. Nevertheless, statistical power of all measures benefits from smoothing. When aiming to detect a 10% difference between groups, the number of subjects required to test effects with sufficient power over the entire cortex varies between cortical measures (cortical thickness: N=39, surface area: N=21, volume: N=81; 10mm smoothing, power=0.8, α=0.05). For subcortical regions this number is between 16 and 76 subjects, depending on the region. We also demonstrate the advantage of within-subject designs over between-subject designs. Furthermore, we publicly provide a tool that allows researchers to perform a priori power analysis and sensitivity analysis to help evaluate previously published studies and to design future studies with sufficient statistical power., (Copyright © 2014 Elsevier Inc. All rights reserved.)