Background and objectiveGrowing evidence supports the use of neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC). However, the implications of residual UTUC at radical nephroureterectomy (RNU) after NAC are not well characterized. Our objective was to compare oncologic outcomes for pathologic risk–matched patients who underwent RNU for UTUC who either received NAC or were chemotherapy-naïve. MethodsWe retrospectively identified 1993 patients (including 112 NAC recipients) who underwent RNU for nonmetastatic, high-grade UTUC between 1985 and 2022in a large, international, multicenter cohort. We divided the cohort into low-risk and high-risk groups defined according to pathologic findings of muscle invasion and lymph node involvement at RNU. Recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) estimates were calculated using the Kaplan-Meier method. Multivariable analyses were performed to determine clinical and demographic factors associated with these outcomes. Key findings and limitationsAmong patients with low-risk pathology at RNU, RFS, OS, and CSS were similar between the NAC and chemotherapy-naïve groups. Among patients with high-risk pathology at RNU, the NAC group had poorer RFS (hazard ratio [HR] 3.07, 95% confidence interval [CI] 2.10–4.48), OS (HR 2.06, 95% CI 1.33–3.20), and CSS (subdistribution HR 2.54, 95% CI 1.37–4.69) in comparison to the pathologic risk-matched, chemotherapy-naïve group. Limitations include the lack of centralized pathologic review. Conclusions and clinical implicationsPatients with residual invasive disease at RNU after NAC represent a uniquely high-risk population with respect to oncologic outcomes. There is a critical need to determine an optimal adjuvant approach for these patients. Patient summaryWe studied a large, international group of patients with cancer of the upper urinary tract who underwent surgery either with or without receiving chemotherapy beforehand. We identified a high-risk subgroup of patients with residual aggressive cancer after chemotherapy and surgery who should be prioritized for clinical trials and drug development.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

BackgroundThe Neqstent coil-assisted flow diverter (NQS) is a neck bridging device to facilitate coil occlusion of intracranial aneurysms. CAFI is a prospective, single-arm, multicenter study on the safety and performance of the NQS adjunctive therapy device together with platinum coils for treatment of unruptured intracranial aneurysms.MethodsThirty-eight patients were enrolled. Primary endpoints were occlusion at 6 months for efficacy, and any major stroke or non-accidental death up to 30 days or major disabling stroke within 6 months for safety. Secondary endpoints were re-treatment rate, procedure time, and procedure/device-related adverse events. Procedural and follow-up imaging was reviewed by an independent core laboratory. Adverse events were reviewed and adjudicated by a clinical events committee.ResultsThe NQS was successfully implanted in 36/38 aneurysms, 2/38 in the intention-to-treat group did not receive a NQS and were excluded from follow-up after 30 days. In the per protocol group (PP), 33/36 patients were available for angiographic follow-up. Device related adverse events were recorded in 4/38 (10.5%) patients, one hemorrhagic and three thromboembolic. In the PP group, immediate post-treatment adequate occlusion (RR1 and RR2) was seen in 9/36 (25%) and progressed to 28/36 (77.8%) at 6 months. Complete occlusion (RR1) was achieved in 29/36 (80.6%) at the last available angiogram (3/36 were post procedure). The mean procedure time was 129 min (50–300 min, median 120 min).ConclusionThe NQS in conjunction with coils appears to be effective in the treatment of intracranial wide-neck bifurcation aneurysms, but its safety remains to be proved in larger series.Trial registration numberNCT04187573.

BackgroundThe aim of this study was to evaluate potential synergistic effects of a single, local application of human umbilical cord MSC-derived sEVs in combination with a low dose of recombinant human rhBMP-2 to promote the regeneration of a metaphyseal femoral defect in an osteoporotic rat model.Methods6 weeks after induction of osteoporosis by bilateral ventral ovariectomy and administration of a special diet, a total of 64 rats underwent a distal femoral metaphyseal osteotomy using a manual Gigli wire saw. Defects were stabilized with an adapted Y-shaped mini-locking plate and were subsequently treated with alginate only, or alginate loaded with hUC-MSC-sEVs (2 × 109), rhBMP-2 (1.5 µg), or a combination of sEVs and rhBMP-2 (n = 16 for each group). 6 weeks post-surgery, femora were evaluated by µCT, descriptive histology, and biomechanical testing.ResultsNative radiographs and µCT analysis confirmed superior bony union with callus formation after treatment with hUC-MSC-sEVs in combination with a low dose of rhBMP-2. This finding was further substantiated by histology, showing robust defect consolidation 6 weeks after treatment. Torsion testing of the explanted femora revealed increased stiffness after application of both, rhBMP-2 alone, or in combination with sEVs, whereas torque was only significantly increased after treatment with rhBMP-2 together with sEVs.ConclusionThe present study demonstrates that the co-application of hUC-MSC-sEVs can improve the efficacy of rhBMP-2 to promote the regeneration of osteoporotic bone defects.

The incidence of geriatric acetabular fractures has shown a sharp increase in the last decades. The majority of patients are male, which is different to other osteoporotic fractures. The typical pathomechanism generally differs from acetabular fractures in young patients regarding both the direction and the amount of force transmission to the acetabulum via the femoral head. Geriatric fractures very frequently involve anterior structures of the acetabulum, while the posterior wall is less frequently involved. The anterior column and posterior hemitransverse (ACPHT) fracture is the most common fracture type. Superomedial dome impactions (gull sign) are a frequent feature in geriatric acetabular fractures as well. Treatment options include nonoperative treatment, internal fixation and arthoplasty. Nonoperative treatment includes rapid mobilisation and full weighbearing under analgesia and is advisable in non- or minimally displaced fractures without subluxation of the hip joint and without positive gull sign. Open reduction and internal fixation of geriatric acetabular fractures leads to good or excellent results, if anatomic reduction is achieved intraoperatively and loss of reduction does not occur postoperatively. Primary arthroplasty of geriatric acetabular fractures is a treatment option, which does not require anatomic reduction, allows for immediate postoperative full weightbearing and obviates several complications, which are associated with internal fixation. The major issue is the fixation of the acetabular cup in the fractured bone. Primary cups, reinforcement rings or a combination of arthroplasty and internal fixation may be applied depending on the acetabular fracture type.

Cardiac rehabilitation (CR) patients often do not sustain physical activity (PA) behaviour in the long run, once they progress into a self-management stage of secondary prevention. This study aimed to explore former CR patients' PA preferences, determinants (i.e., influencing factors) and motivation for sustained PA engagement. We conducted a cross-sectional multi-centre survey using an original questionnaire based on prior qualitative interviews with cardiac patients. Five CR centres in Austria posted 500 questionnaires to former CR patients who had completed CR approximately three years prior, and 117 patients (23%) responded. Descriptive analysis was used to analyse closed-ended questions, and self-determination theory (SDT) was applied as a qualitative framework to analyse open-ended questions concerning motivation for PA engagement. Patients were generally physically active, but the majority (75.3%) did not fulfil the World Health Organisation's recommendations for aerobic PA and muscle strengthening. Most patients preferred being physically active outdoors (70%), engaging in aerobic-related (95%), individual and non-competitive exercises, with cycling (52%), walking (32%) and hiking (25%) among the most popular activities. Main determinants of PA were health, pain and motivation for 80%, 68%, 67% of patients, respectively. A subset of patients (77%) expanded on their motivations behind PA. According to SDT, most reasons (90%) were regulated by autonomous motivation (either extrinsically autonomously-regulated or intrinsic motivation) and stemmed mostly from health-related goals (e.g., fitness, general health, weight control), future quality-of-life aspirations (e.g., self-sufficiency in old age, presence for loved ones, preserving mobility) and enjoyment of PA. Patients' responses underscore the importance of promoting not only general PA, but also muscle strengthening training in CR interventions to maximise optimal health benefits. Our data further suggest that interventions which are aligned to patients' health goals and foster autonomous motivation may be particularly beneficial in increasing adherence to PA in the long-term.

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2–9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3′,4′-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

Stroke resulting from occlusion of the middle cerebral artery (MCA) can have devastating consequences, potentially leading to aloss of independence. This study aimed to investigate the relationship between the distance to the thrombus (DT) and both ischemic lesion volume (ILV) and clinical outcomes. We retrospectively evaluated patients with thromboembolic MCA M1 segment occlusion who underwent neurovascular imaging followed by endovascular thrombectomy (EVT) at two comprehensive stroke centers over a3-year period (2018-2020). Preinterventional computed tomography (CT) or magnetic resonance (MR) angiography was used to measure DT, defined as the distance from the carotid‑T bifurcation to the proximal surface of the M1 occlusion. Postinterventional CT or MR imaging was employed to determine the ILV and clinical outcomes were assessed using the modified Rankin scale (mRS) at 3 months. There were 346 patients evaluated. The median DT was 9.4 mm (interquartile range, IQR 6.0-13.7 mm) and the median ILV was 13.9 ml (IQR 2.2-53.1 ml). After adjustment, an increase in DT was associated with adecrease in odds for a larger ILV (odds ratio, OR 0.96, 95% confidence interval, CI 0.92-0.99, p = 0.041). Through this association, more distal thrombi were associated with good clinical outcome (mRS 0-2; clinical outcome available in 282 patients, p = 0.018). The ILV was inversely associated with better clinical outcome OR 0.52 (95% CI 0.40-0.67). Based on the findings, DT was identified as an independent albeit weak predictor for ILV and clinical outcomes in patients with MCA M1 occlusion who underwent EVT.

Traumatic brain injuries cause enormous individual and socioeconomic burdens. Survivors frequently struggle with motor handicaps as well as impaired cognition and emotion. In addition to the primary mechanical brain damage, complex secondary mechanisms are the main drivers of functional impairment. Many of these pathophysiological mechanisms are now well known: excitotoxic amino acids, breakdown of the blood-brain barrier, neuroinflammation with subsequent damage to cell organelles and membranes, cerebral edema, and apoptotic processes triggering neuronal death; however, paracrine resilience factors may counteract these processes. Specific neuroprotective and neuroregenerative intensive care therapies are few. This review highlights medical approaches aimed at mitigating secondary damage and promoting neurotrophic processes in severe traumatic brain injury. Some pharmacologic attempts that appeared very promising in experimental settings have had disappointing clinical results (progesterone, cyclosporineA, ronopterin, erythropoietin, dexanabinol). Thus, the search for drugs that can effectively limit ongoing posttraumatic neurological damage is ongoing. Some medications appear to be beneficial: N‑methyl-D-aspartate receptor (NMDA) antagonists (esketamine, amantadine, Mg++) reduce excitotoxicity and statins and cerebrolysin are known to counteract neuroinflammation. By supporting the impaired mitochondrial energy supply, oxidative processes are inhibited and neuroregenerative processes, such as neurogenesis, angiogenesis and synaptogenesis are promoted by citicoline and cerebrolysin. First clinical evidence shows an improvement in cognitive and thymopsychic outcomes, underlined by own clinical experience combining different therapeutic approaches. Accordingly, adjuvant treatment with neuroprotective substances appears to be apromising option, although more randomized prospective studies are still needed.