Longitudinal evaluation of polyneuropathy in Parkinson's disease.

BACKGROUND: Increasing evidence indicates a higher prevalence of polyneuropathy (PNP) in Parkinson's disease (PD). However, the involvement of large fiber neuropathy in PD still remains poorly understood. Given the lack of longitudinal data, we investigated the course of PNP associated with PD. METHODS: In total, 41 PD patients underwent comprehensive clinical evaluation including motor and non-motor assessments as well as nerve conduction studies at baseline and at 2 years of follow-up. The definition of PNP was based on electrophysiological standard criteria. Common causes of PNP were excluded. RESULTS: At baseline, PNP was diagnosed in 65.85% of PD patients via electroneurography. Patients with PNP presented with higher age (p = 0.019) and PD motor symptom severity (UPDRS III; p < 0.001). Over the course of 2 years, PNP deteriorated in 21.95% of cases, and 26.83% remained without PNP. Deterioration of nerve amplitude was most prevalent in the median sensory nerve affecting 57.58% of all PD cases with an overall reduction of median sensory nerve amplitude of 45.0%. With regard to PD phenotype, PNP progression was observed in 33.33% of the tremor dominant and 23.81% of the postural instability/gait difficulties subtype. Decrease of sural nerve amplitude correlated with lower quality of life (PDQ-39, p = 0.037) and worse cognitive status at baseline (MoCA, p = 0.042). CONCLUSION: The study confirms the high PNP rate in PD, and demonstrates a significant electrophysiological progression also involving nerves of the upper extremities. Longitudinal studies with larger cohorts are urgently needed and should elucidate the link between PD and PNP with the underlying pathomechanisms.

Concurrent validity of countermovement and squat jump height assessed with a contact mat and force platform in professional soccer players.

Purpose: The aim of this study was to assess the concurrent validity of a contact mat against force plates to measure jump height in countermovement jump (CMJ) and squat jump (SJ) in professional soccer players. Methods: 23 male professional soccer players performed the CMJ and SJ, which were concurrently recorded using a portable contact mat (SmartJump) and a portable dual force plate system (ForceDecks). Equivalence testing between both systems (contact mat vs. force plate) and the two methods (impulse-momentum vs. flight-time and flight-time vs. flight-time) was performed compared to equivalence bounds of ±1.1 cm for the CMJ and ±1.6 cm for the SJ. Additionally, 95% Limits of Agreement (LoA) and intraclass correlation coefficients (ICC) were computed. Results: Mean differences for the impulse-momentum vs. flight-time comparison for CMJ [3.2 cm, 95% CI (2.3-4.1)] and SJ [2.7 cm, (1.8-3.6)] were non-equivalent between both systems. LoA were larger than the equivalence bunds for CMJ and SJ, while ICCs were good [CMJ, 0.89, (0.76-0.95)] and excellent [SJ, 0.91, (0.79-0.96)]. As for the flight-time vs. flight-time comparison, mean differences were non-equivalent for the CMJ [1.0 cm (0.8 to 1.2 cm)] and equivalent for the SJ [0.9 cm (0.7-1.1 cm)]. LoA were narrower than the equivalence bounds for CMJ and SJ, while ICCs were excellent [CMJ, 0.995, 95% CI (0.989-0.998); SJ, 0.997, 95% CI (0.993-0.997)]. Conclusion: Our findings indicate that the SmartJump contact mat cannot be used interchangeably with the ForceDecks force platform to measure jump height for the CMJ and SJ.

Utilization and related harms of systemic glucocorticosteroids for atopic dermatitis: claims data analysis.

BACKGROUND AND OBJECTIVES: Systemic glucocorticosteroids (SGCs) are used in the short-term treatment of atopic dermatitis (AD), but are not recommended for long-term use since associated with severe side effects. This study aimed to characterize the utilization and potentially negative effects of SGC use for AD in German statutory health insurance (SHI) claims data. PATIENTS AND METHODS: Cross-sectional and longitudinal analysis of a large nationwide SHI dataset. SGC drug prescriptions and incidences of predefined comorbidities after drug initiation known as potentially harmful side effects were analysed. The SGC use was quantified by 1) the number of quarters with at least one SGC prescription and 2) the defined daily doses (DDD). Adjustments in comparisons were made for age, gender and morbidity. RESULTS: The AD prevalence was 4.07% in 2020 (4.12% women, 3.71% men). During this period 9.91% of persons with AD were prescribed SGCs compared with 5.54% in persons without AD (p < 0.01). Prescribing of SGCs was significantly higher in women (10.20% vs.9.42% in men, p=<0.01) and the elderly. AD and sGC prevalence varied regionally. In a three-year follow-up period, 51% of persons with AD receiving a SGC were prescribed SGCs in > 1 quarter and 15% in > 6 quarters. The odds of developing osteoporosis (odds ratio 3.95 [approach 1] and 1.80 [approach 2]) and diabetes (odds ratio 1.90 [approach 1] and 1.38 [approach 2]) were significantly higher in people with AD on sGCS, especially in the frequently prescribed group compared with the rarely prescribed group, regardless of quantified use. CONCLUSION: A considerable number of persons with AD in Germany are prescribed longterm SGCs. The onset of medical conditions known to be harmful effects from steroids was significantly more frequent in SGC "frequently prescribers", indicating the need for optimized health care.

Comparative Analysis of Vaccine-Induced Neutralizing Antibodies against the Alpha, Beta, Delta, and Omicron Variants of SARS-CoV-2.

The SARS-CoV-2 virus has infected more than 660 million people and caused nearly seven million deaths worldwide. During the pandemic, a number of SARS-CoV-2 vaccines were rapidly developed, and several are currently licensed for use in Europe. However, the optimization of vaccination regimens is still ongoing, particularly with regard to booster vaccinations. At the same time, the emergence of new virus variants poses an ongoing challenge to vaccine efficacy. In this study, we focused on a comparative analysis of the neutralization capacity of vaccine-induced antibodies against four different variants of concern (i.e., Alpha, Beta, Delta, and Omicron) after two and three doses of COVID-19 vaccine. We were able to show that both two (prime/boost) and three (prime/boost/boost) vaccinations elicit highly variable levels of neutralizing antibodies. In addition, we did not observe a significant difference in antibody levels after two and three vaccinations. We also observed a significant decrease in the neutralization susceptibility of all but one SARS-CoV-2 variants to vaccine-induced antibodies. In contrast, a SARS-CoV-2 breakthrough infection between the second and third vaccination results in overall higher levels of neutralizing antibodies with a concomitant improved neutralization of all virus variants. Titer levels remained highly variable across the cohort but a common trend was observed. This may be due to the fact that at the time of this study, all licensed vaccines were still based exclusively on wild-type SARS-CoV-2, whereas infections were caused by virus variants. Overall, our data demonstrate the importance of (booster) vaccinations, but at the same time emphasize the need for the continued adaptation of vaccines to induce a protective immune response against virus variants in order to be prepared for future (seasonal) SARS-CoV-2 outbreaks.

Ticks and tick-borne diseases from Mallorca Island, Spain.

Ixodid ticks are obligate blood-feeding arthropods and important vectors of pathogens. In Mallorca, almost no data on the tick fauna are available. Herein, we investigated ticks and tick-borne pathogens in ticks collected from dogs, a cat and humans in Mallorca as result of a citizen science project. A total of 91 ticks were received from German tourists and residents in Mallorca. Ticks were collected from March to October 2023 from dogs, cat and humans, morphologically and genetically identified and tested for pathogens by PCRs. Six tick species could be identified: Ixodes ricinus (n = 2), Ixodes ventalloi (n = 1), Hyalomma lusitanicum (n = 7), Hyalomma marginatum (n = 1), Rhipicephalus sanguineus s.l. (n = 71) and Rhipicephalus pusillus (n = 9). Rhipicephalus sanguineus s.l. adults were collected from dogs and four females from a cat and the 16S rDNA sequences identified it as Rh. sanguineus s.s. Hyalomma lusitanicum was collected from 1 human, 1 dog and 5 specimens were collected from the ground in the community of Santanyi, together with one H. marginatum male. This is the first report of Hyalomma marginatum in Mallorca. Both I. ricinus were collected from humans and I. ventalloi female was collected from a dog. All ticks tested negative for Anaplasma phagocytophilum, Coxiella spp., Francisella spp., and piroplasms. In 32/71 (45%) specimens of Rh. sanguineus s.s., Rickettsia spp. could be detected and in 18/32 (56.2%) sequenced tick DNAs R. massiliae was identified. Ixodes ventalloi female and both I. ricinus tested positive in the screening PCR, but the sequencing for the identification of the Rickettsia sp. failed.

Growth hormone treatment in aged patients with comorbidities: A systematic review.

OBJECTIVE: Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects. DESIGN: A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library. INCLUSION CRITERIA: participants aged over 65 years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis. RESULTS: The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3×/week), doses (0.41 mg-2.6 mg; mean 1.3 mg per 60 kg patient) and duration (1-12 months; mean 7 months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life. CONCLUSION: Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.

Epidemiology of alopecia areata and population-wide comorbidities in Germany: analysis of longitudinal claims data.

BACKGROUND: Alopecia areata (AA) is a chronic, immune-mediated disease characterized by acute-onset hair loss. The hair loss can range from small, circumscribed hairless areas on the scalp to complete loss of hair on the head and body hair. However, data on the epidemiology of AA are limited. Current evaluations are lacking in Germany. The aim of this study was to evaluate the epidemiology and comorbidity of AA in Germany based on claims data. METHODS: A representative 40% sample of all adults who were insured with a German statutory health insurance company (DAK-Gesundheit) between 2016 and 2020 was evaluated (n = 2.88 million). Based on at least one relevant outpatient or inpatient diagnosis of International Classification of Diseases (ICD)-10 L63, the annual AA prevalence and incidence (ICD-10 L63) were calculated for 2016 to 2020. Different case definitions were used for diagnosis validation. In addition, the occurrence of comorbidities in patients with AA was investigated. RESULTS: In 2020, AA prevalence was 210 cases per 100 000 and incidence 72 cases per 100 000. Compared with persons without AA, those with AA significantly more often had atopic dermatitis [rate ratio (RR) 2.9], pruritus (RR 2.7), lupus erythematosus (RR 2.4), urticaria (RR 2.3) and psoriasis (RR 2.2). Women were affected slightly more often than men (0.2% vs. 0.1%). On a regional level, higher prevalence and incidence rates were found in Brandenburg (prevalence 332 cases per 100 000; incidence 116 cases per 100 000), Hesse (prevalence 344 cases per 100 000; incidence 124 cases per 100 000) and Mecklenburg-Western Pomerania (prevalence 303 cases per 100 000; incidence 111 per 100 000). CONCLUSIONS: AA is a common immune-mediated skin condition with marked regional variations in Germany. For a complete understanding of epidemiology, complementary population-based studies including clinical characteristics of AA are useful.

Prevalence of psoriasis and psoriatic arthritis in Germany - analysis of claims data.

BACKGROUND AND OBJECTIVES: Few studies are available on the epidemiology of psoriasis and psoriatic arthritis in Germany. The aim of this study was to estimate this prevalence based on different case definitions. METHODS: Statutory health insurance (SHI) data were examined (2017 to 2019). Prevalence was analyzed and validated using three different case definitions: (1) At least one inpatient or outpatient diagnosis within one year, (2) additionally at least two outpatient diagnoses within one year, (3) additionally within three years. RESULTS: The administrative prevalence of psoriasis including psoriatic arthritis ranged from 1.90% to 2.51%. For all case definitions, the prevalence increased with age, decreasing from the age of 70 with psoriasis and from the age of 65 with psoriatic arthritis. Males were more likely to be affected at an older age (p <0.0001), while in the under-20 age group, more girls were affected (p  =  0.04). CONCLUSIONS: Psoriasis is a common skin disease in Germany. The internal diagnoses validation showed that in future studies with claims data, the narrow and broad criteria should be used to identify patients with psoriasis, depending on the research question.

Three-dimensional changes of a porcine collagen matrix and free gingival grafts for soft tissue augmentation to increase the width of keratinized tissue around dental implants: a randomized controlled clinical study.

BACKGROUND: Emerging clinical data points to the relevance of the presence of keratinized tissue (KT). Although apically positioned flap/vestibuloplasty along with free gingival graft (FGG) is considered as a standard intervention for augmenting KT, substitute materials appear to be a viable treatment alternative. So far, there is a lack of data investigating the dimensional changes at implant sites treated with soft-tissue substitutes or FGG. AIM: The present study aimed at comparing three-dimensional changes of a porcine derived collagen matrix (CM) and FGG for increasing KT at dental implants over a 6-month follow-up period. MATERIALS AND METHODS: The study enrolled 32 patients exhibiting deficient KT width (i.e., < 2 mm) at the vestibular aspect who underwent soft tissue augmentation using either CM (15 patients/23 implants) or FGG (17 patients/31 implants). The primary outcome was defined as tissue thickness change (mm) at treated implant sites between 1- (S0), 3- (S1), and 6-months (S2). Secondary outcomes considered changes of KT width over a 6-month follow-up period, surgical treatment time, and patient-reported outcomes. RESULTS: Dimensional analyses from S0 to S1 and from S0 to S2 revealed a mean decrease in tissue thickness of - 0.14 ± 0.27 mm and - 0.04 ± 0.40 mm in the CM group, and - 0.08 ± 0.29 mm and - 0.13 ± 0.23 mm in the FGG group, with no significant differences noted between the groups (3 months: p = 0.542, 6 months: p = 0.659). Likewise, a comparable tissue thickness decrease was observed from S1 to S2 in both groups (CM: - 0.03 ± 0.22 mm, FGG: - 0.06 ± 0.14 mm; p = 0.467). The FGG group exhibited a significantly greater KT gain after 1, 3 and 6 months compared to the CM group (1 month: CM: 3.66 ± 1.67 mm, FGG: 5.90 ± 1.58 mm; p = 0.002; 3 months: CM: 2.22 ± 1.44; FGG: 4.91 ± 1.55; p = 0.0457; 6 months: CM: 1.45 ± 1.13 mm, FGG: 4.52 ± 1.40 mm; p < 0.1). Surgery time (CM: 23.33 ± 7.04 min.; FGG: 39.25 ± 10.64 min.; p = 0.001) and postoperative intake of analgesics were significantly lower in the CM group (CM: 1.2 ± 1.08 tablets; FGG: 5.64 ± 6.39 tablets; p = 0.001). CONCLUSIONS: CM and FGG were associated with comparable three-dimensional thickness changes between 1 and 6 months. While a wider KT band could be established with FGG, the use of CM significantly reduced surgical time and patients´ intake of analgesics.

Cognitive functioning in postural orthostatic tachycardia syndrome among different body positions: a prospective pilot study (POTSKog study).

PURPOSE: Approximately 96% of patients with postural orthostatic tachycardia syndrome (PoTS) report cognitive complaints. We investigated whether cognitive function is impaired during sitting and active standing in 30 patients with PoTS compared with 30 healthy controls (HCs) and whether it will improve with the counter manoeuvre of leg crossing. METHODS: In this prospective pilot study, patients with PoTS were compared to HCs matched for age, sex, and educational level. Baseline data included norepinephrine plasma levels, autonomic testing and baseline cognitive function in a seated position [the Montreal Cognitive Assessment, the Leistungsprüfsystem (LPS) subtests 1 and 2, and the Test of Attentional Performance (TAP)]. Cognitive functioning was examined in a randomized order in supine, upright and upright legs crossed position. The primary outcomes were the cognitive test scores between HCs and patients with PoTS at baseline testing, and among the different body positions. RESULTS: Patients with PoTS had impaired attention (TAP median reaction time) in the seated position and impaired executive functioning (Stroop) while standing compared with HC. Stroop was influenced by position (supine versus upright versus upright legs crossed) only in the PoTS group. Leg crossing did not result in an improvement in executive function. In patients with PoTS, there was a negative correlation of Stroop with norepinephrine plasma levels while standing. CONCLUSION: Compared with HCs, PoTS participants showed impaired cognitive attention and executive function in the upright position that did not improve in the legs crossed position. Data provide further evidence for orthostatic cognitive deterioration in patients with PoTS. TRIAL REGISTRATION INFORMATION: The study was registered at ClinicalTrials.gov (NCT03681080).

How should patient decision aids for schizophrenia treatment be designed? - A scoping review.

Despite the clear rationale for applying shared decision-making in the context of the preference sensitive decision for or against antipsychotics and the upswing of patient decision aids (pDAs) to support this process, there is still a lack of knowledge regarding which key features are crucial for pDAs in schizophrenia treatment. A scoping review according to the PRISMA-SRc was conducted to inform on crucial key features and quality indicators. The review focussed on the following seven aspects for investigating pDAs: (1) Types of decision aids, (2) Values, (3) Decision Guidance, (4) Output of the decision aid, (5) Target group, (6) Effectiveness according to publication and (7) Decision aid evaluation. Eleven studies which addressed six unique decision aids met the eligibility criteria. There were major differences in the design as well as in the development of the decision aids. Three aspects emerged that should be given special consideration in the design of such tools for antipsychotics: the evidence used by the decision aid, the algorithm for translating evidence into a decision aid and finally the presentation of the evidence. We recommend the use of data with a high level of evidence and to combine it with individualized treatment by taking into account patient preferences and previous experiences as well as comparing them with clinical assessments. Fully computerized decision aids that use complicated algorithms, for example, by merging treatment effects with patient characteristics to suggest an appropriate treatment at the end, tend to be paternalistic and thus not appropriate for SDM, in our view. In addition, possible cognitive deficits need to be considered when presenting the output of decision aids for antipsychotics.

Informing the development of a decision aid: Expectations and wishes from service users and psychiatrists towards a decision aid for antipsychotics in the inpatient setting.

OBJECTIVES: Decision aids (DAs) are promising tools to foster evidence-based shared decision-making between practitioners and service users. Nevertheless, it is still obscure how an evidence-based DA for people with severe mental illness, especially psychosis, should look in an inpatient treatment setting to be useful and feasible. Therefore, we conducted focus groups with psychiatrists and service users to collect and assess their expectations and wishes regarding an evidence-based DA. From these findings, we derived immediate recommendations for the future development of DAs. METHODS: We held two group interviews with service users (n = 8) and three group interviews with psychiatrists (n = 10). We used an open, large-scale topic guide. First, we presented data from a current meta-analysis on antipsychotics to the interviewees and, in a second step, asked for their expectations and wishes towards a DA that integrates these data. RESULTS: Our thematic analysis revealed six key themes addressed by the respondents: (1) general considerations on the importance and usefulness of such a DA, (2) critical comments on psychiatry and psychopharmacotherapy, (3) communicative prerequisites for the use of a DA, (4) form and content of the DA, (5) data input, data processing and output as well as (6) application of the DA and possible obstacles. CONCLUSIONS: Participants identified several important features for the development of DAs for selecting antipsychotics in inpatient psychiatric treatment. The digital format was met with the greatest approval. Especially the adaptability to different needs, users and psychopathologies and the possibility to outsource information dissemination via app seemed to be a decisive convincing argument. Further research is required to test specific features of DAs to be developed in clinical settings.

Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia.

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development.

Influence of antiresorptive/antiangiogenic therapy on the extension of experimentally induced peri-implantitis lesions.

OBJECTIVES: To investigate the extension of experimentally induced peri-implantitis lesions under various antiresorptive and antiangiogenic medications. MATERIAL AND METHODS: Fourty-eight albino rats had randomly received the following medications (dual application, n = 8 each): (1) amino-bisphosphonate (zoledronate) (Zo), (2) RANKL inhibitor (denosumab) (De), (3) antiangiogenic (bevacizumab) (Be), (4) Zo+Be, (5) De+Be, or (6) no medication (Co). Ligature- and lipopolysaccharide-induced peri-implantitis lesions were established at 2 maxillary implants over a period of 16 weeks. Histological (e.g., apical extension and surface area of the inflammatory cell infiltrate-aICT, ICT; defect length; defect width; CD68 positive cells) and bone micromorphometric (µCT) outcomes were assessed. The animal was defined as a statistical unit. RESULTS: A total of n = 38 animals (Zo = 6, De = 6, Be = 8, Zo + Be = 6, De + Be = 5, Co = 7) were analyzed. ICT's were commonly marked by a positive CD68 antigen reactivity. Comparable median aICT (lowest-Zo: 0.53 mm; highest-Be: 1.22 mm), ICT (lowest-De + Be: 0.00 mm2; highest-Co: 0.49 mm2), defect length (lowest-Zo: 0.90 mm; highest-Co: 1.93 mm) and defect width (lowest-De+Be: 1.27 mm; highest-Be: 1.80 mm) values were noted in all test and control groups. Within an inner (diameter: 0.8 mm) cylindric volume of interest, the bone microstructure did not significantly differ between groups. CONCLUSIONS: The present analysis did not reveal any marked effects of various antiresorptive/ antiangiogenic medications on the extension of experimentally induced peri-implantitis lesions. CLINICAL RELEVANCE: The extension of peri-implantitis lesions may not be facilitated by the antiresorptive and antiangiogenic medications investigated.

Analysis of immune responses in patients with CLL after heterologous COVID-19 vaccination.

Patients with chronic lymphocytic leukemia (CLL) treated with B-cell pathway inhibitors and anti-CD20 antibodies exhibit low humoral response rates following SARS-CoV-2 vaccination. To investigate this observation, a prospective single-institution study was conducted comparing peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates following heterologous BNT162b2/ChAdOx1 vaccination of 15 patients with CLL/small lymphocytic lymphoma (SLL). Two-dose antibody response rate was 40%, increasing to 53% after booster. Patients on Bruton tyrosine kinase inhibitor (BTKi) and venetoclax ± anti-CD20 antibody within 12 months of vaccination responded inferiorly compared with those under BTKi alone. The 2-dose-T-cell response rate was 80%, which increased to 93% after the booster dose. Key transcriptional findings were that interferon-mediated signaling activation including activation of the JAK-STAT pathway generally occurred within days of vaccination, but was independent from the magnitude of the antibody response. Increasing counts of IGHV genes were associated with B-cell reconstitution and improved humoral response rate in the vaccinated patients. T-cell responses in patients with CLL appeared independent of treatment status, whereas higher humoral response rate was associated with BTKi treatment and B-cell reconstitution. Boosting was particularly effective when intrinsic immune status was improved by CLL treatment. Limitations included studying a relatively small cohort, with different treatments and vaccination schedules.

In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer.

Lung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapy for brain metastases. Here, we established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning-microscopy. This approach enabled in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of Lewis lung carcinoma cells (expressing the tumor cell-antigen EpCAM) was performed, and EpCAM-directed CAR T-cells were injected either intravenously or into the adjacent brain parenchyma. In mice receiving EpCAM-directed CAR T-cells intravenously, we neither observed substantial CAR T-cell accumulation within the tumor nor relevant anti-tumor effects. Local CAR T-cell injection, however, resulted in intratumoral CAR T-cell accumulation compared to controls treated with T-cells lacking a CAR. This finding was accompanied by reduced tumorous growth as determined per in vivo-microscopy and immunofluorescence of excised brains and also translated into prolonged survival. However, the intratumoral number of EpCAM-directed CAR T-cells decreased during the observation period, pointing toward insufficient persistence. No CNS-specific or systemic toxicities of EpCAM-directed CAR T-cells were observed in our fully immunocompetent model. Collectively, our findings indicate that locally (but not intravenously) injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the intratumoral CAR T-cell persistence may further boost the therapeutic success.

Do we still need to screen our patients?-Orthopaedic scoring based on motion tracking.

PURPOSE: Orthopaedic scores are essential for the clinical assessment of movement disorders but require an experienced clinician for the manual scoring. Wearable systems are taking root in the medical field and offer a possibility for the convenient collection of motion tracking data. The purpose of this work is to demonstrate the feasibility of automated orthopaedic scorings based on motion tracking data using the Harris Hip Score and the Knee Society Score as examples. METHODS: Seventy-eight patients received a clinical examination and an instrumental gait analysis after hip or knee arthroplasty. Seven hundred forty-four gait features were extracted from each patient's representative gait cycle. For each score, a hierarchical multiple regression analysis was conducted with a subsequent tenfold cross-validation. A data split of 70%/30% was applied for training/testing. RESULTS: Both scores can be reproduced with excellent coefficients of determination R2 for training, testing and cross-validation by applying regression models based on four to six features from instrumental gait analysis as well as the patient-reported parameter 'pain' as an offset factor. CONCLUSION: Computing established orthopaedic scores based on motion tracking data yields an automated evaluation of a joint function at the hip and knee which is suitable for direct clinical interpretation. In combination with novel technologies for wearable data collection, these computations can support healthcare staff with objective and telemedical applicable scorings for a large number of patients without the need for trained clinicians.