The optimal diagnostic cut-off of WBC and PMN counts for joint aspiration in periprosthetic joint infection is 2479/µL and 67%, respectively: ICM criteria thresholds are too high.

BACKGROUND: Various organizations have published definitions for periprosthetic joint infection (PJI) with significant differences in the cut-offs of white blood cell (WBC) count and polymorphonuclear (PMN) leukocyte cells. Herein, we aim to analyze optimal cut-offs in patients which are planned to undergo a prosthesis revision and compare them with the actual published thresholds of the International Consensus Meeting (ICM) and European Bone and Joint Infection Society (EBJIS). METHODS: A test kit was compiled in a monocentric prospective study, according to the ICM criteria (2018) and 2021 EBJIS criteria. The kit was implemented using: blood samples (including leukocyte count and C-reactive protein); samples for examining the synovial fluid (WBC count, PMN cell differentiation, microbiological culture for incubation over 14 days, alpha-defensin ELISA laboratory test, and leukocyte-esterase test). The cut-offs for WBC and PMN counts were investigated using ROC analyses and Youden index. The ICM 2018 criteria were applied, using alpha-defensin in all cases. Patients which have to undergo a prosthesis revision were included, a pre-operative joint aspiration had been performed, and the patients had been followed up prospectively. RESULTS: 405 patients were examined with the compiled test kit; 100% had a complete dataset with respect to alpha-defensin; 383 patients, according to WBC count; and 256, according to PMN cell differentiation The cut-off of 2478.89 cells/µl in the WBC count (sensitivity: 87.70%; specificity: 88.10%) and the cut-off of 66.99% in PMN differentiation showed the best accuracy (sensitivity: 86.00%; specificity: 88.80%). Other published cut-offs for WBC were tested in this cohort and showed the following accuracy: 3000/µl (EBJIS/ICM; sensitivity: 82.10%; specificity: 91.00%), 2000/µl (sensitivity: 89.60%; specificity: 83.40%), and 1500/µl (sensitivity: 91.50%; specificity: 75.00%). The published cut-offs for PMN had the following accuracy in this cohort: 80% (ICM; sensitivity: 66.3%; specificity: 96.50%), 70% (sensitivity: 82.6%; specificity: 90%), and 65% (EBJIS, sensitivity: 86%; specificity: 88.8%). CONCLUSIONS: This study aims to improve current cut-offs for PMN- and WB-Count, even though PJI diagnosis is based on the combination of all defined tests. The optimal diagnostic cut-off of WBC and PMN counts was found to be 2479/µL and 67%, respectively, whereas ICM cut-offs in this cohort seem too high, as they provide high specificity but very low sensitivity. On the other hand, a cut-off for WBC count of 1500/µl alone would be very low, leading to low specificity and very high suspicion of PJI. The current consensus guidelines could be actualized considering these results to significantly improve the diagnostic quality. LEVEL OF EVIDENCE: II.

Clinical characteristics, treatment patterns and relapse in patients with clinical stage IS testicular cancer.

PURPOSE: Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. METHODS: Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher's exact and Chi-square test. RESULTS: Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. CONCLUSION: Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

Robot-assisted simple prostatectomy versus open simple prostatectomy: a single-center comparison.

PURPOSE: Open simple prostatectomy (OSP) is a standard surgical technique for patients with benign prostatic hyperplasia with prostate size larger than 80 ml. As a minimally invasive approach, robot-assisted simple prostatectomy (RASP) emerged as a feasible surgical alternative. Currently, there are no definite recommendations for the standard use of RASP. Therefore, we aimed at investigating various clinical outcomes comparing RASP with OSP. METHODS: In this retrospective single-center study, we evaluated clinical data from 103 RASP and 31 OSP patients. Both cohorts were compared regarding different clinical characteristics with and without propensity score matching. To detect independent predictive factors for clinical outcomes, multivariate logistic regression analysis was performed. RESULTS: Robot-assisted simple prostatectomy patients demonstrated a lower estimated blood loss and need for postoperative blood transfusions as well as less postoperative complications. OSP had a shorter operative time (125 min vs. 182 min) longer hospital stay (11 days vs. 9 days) and longer time to catheter removal (8 days vs. 6 days). In the multivariate analysis, RASP was identified as an independent predictor for longer operative time, lower estimated blood loss, shorter length of hospital stay, shorter time to catheter removal, less postoperative complications and blood transfusions. CONCLUSION: Robot-assisted simple prostatectomy is a safe alternative to OSP with less perioperative and postoperative morbidity. Whether OSP (shorter operative time) or RASP (shorter length of hospital stay) has a more favorable economic impact depends on the particular conditions of different health care systems. Further prospective comparative research is warranted to define the value of RASP in the current surgical management of benign prostatic hyperplasia.

Slow cortical potentials neurofeedback in children with ADHD: comorbidity, self-regulation and clinical outcomes 6 months after treatment in a multicenter randomized controlled trial.

Despite sizeable short-term effects of neurofeedback (NF) therapy on attention-deficit and hyperactivity disorder (ADHD), longer-term clinical, comorbidity and self-regulation outcomes are less systematically studied. The aim of this largest NF follow-up to date was to evaluate these outcomes 6 months after NF compared to a semi-active control to disentangle specific from unspecific sustained effects. We performed a multicenter, randomized, parallel, controlled, clinical, superiority trial in five German university outpatient departments. Participants were eligible if they fulfilled DSM-IV-TR criteria for ADHD and were aged from 7 to 9 years. Participants were randomly assigned (1:1-ratio) to 25 sessions of slow cortical potential (SCP)-NF or electromyogram biofeedback (EMG-BF). Participants were not blinded, since they received instructions according to each treatment setting. Primary outcomes were parent ratings of ADHD. The trial was registered, number ISRCTN761871859. Both groups showed improvement of ADHD symptoms compared to baseline at 6-months follow-up with large effect sizes for SCP-NF (d = 1.04) and EMG-BF (d = 0.85), but without group differences. When analyzing all assessments (pre-test, post-test-1, post-test-2 and follow-up), a group-by-time interaction emerged (p = 0.0062), with SCP-NF showing stable improvement following treatment but EMG-BF showing a relapse from post-test-1 to post-test-2, and subsequent remission at follow-up. Six months after the end of treatment, improvement after SCP-NF remained large and stable. However, the lack of group differences at follow-up suggests shared specific and unspecific effects contributing to this clinical outcome. Our correlational results indicate specificity of SCP-NF for selected subscales after training, but not at follow-up.

Efficacy of short-term psychodynamic psychotherapy (STPP) with depressed breast cancer patients: results of a randomized controlled multicenter trial.

BACKGROUND: There is a lack of trials of psychodynamic treatments of depression in breast cancer patients. The purpose of this trial was to determine the efficacy of short-term psychodynamic psychotherapy (STPP) in non-metastatic breast cancer patients diagnosed with depression, one of the most frequent mental comorbidities of breast cancer. PATIENTS AND METHODS: In a multicenter prospective trial, 157 breast cancer patients with comorbid depression were randomized to either individual STPP (intervention group, N=78) or 'treatment as usual' (control group, TAU, N=79). As our primary outcome measure, we hypothesized a higher rate of remission defined as no diagnosis of depression (Structured Clinical Interview for DSM-IV) and reduction in depression score by at least 2 points (Hospital Anxiety and Depression Scale, HADS-D) in STPP versus TAU at treatment termination. Secondary outcomes mainly refer to quality of life (QoL). RESULTS: In the intention to treat (ITT) analysis, 44% of the STPP group achieved highly significantly more remission than TAU (23%). STPP treatment (OR=7.64; P<0.001) was the strongest predictor for remission post-treatment; time was also significant (OR=0.96; P<0.05). A high effect favoring STPP (d=0.82) was observed for the HADS-D score post-treatment (secondary outcome). Regarding further secondary outcomes (QoL), analyses of covariance yielded main effects for group (favoring STPP with an effect size of at least d=0.5) for global QoL, role, emotional and social functioning, pain, treatment side-effects, breast symptoms and upset by hair loss. CONCLUSIONS: STPP is an effective treatment of a broad range of depressive conditions in breast cancer patients improving depression and functional QoL. Findings are limited by the drop-out rate (∼1/3) and delayed post-treatment assessments. Future trials may consider stepped-care approaches, tailored to patients' needs and requirements in the acute treatment phase.

Cognitive-behavioral screening in elderly patients with new-onset epilepsy before treatment.

OBJECTIVES: Cognitive comorbidity at epilepsy onset reflects disease severity and provides a baseline estimate of reserve capacities with regard to the effects of epilepsy and its treatment. Given the high incidence of epilepsy at an older age, this study analyzed objective and subjective cognition as well as quality of life in elderly patients with new-onset focal epilepsy before initiation of anti-epileptic treatment. MATERIALS AND METHODS: A total of 257 untreated patients (60-95 years of age) with new-onset epilepsy underwent objective assessment of executive function (EpiTrack) and performed subjective ratings of cognition (Portland Neurotoxicity Scale) and quality of life (QoL; QOLIE-31). RESULTS: According to age-corrected norms, 58% of patients (N=257) demonstrated deficits in executive function; major determinants were cerebrovascular etiology, neurological comorbidity, and higher body mass index. Subjective ratings indicated deficits in up to 27% of patients. Self-perceived deficits were associated with neurological, cardiovascular, and/or psychiatric comorbidity, whereas poorer QoL was related to neurological comorbidity and female gender. Objectively assessed executive functions correlated with subjective social functioning, energy, motor function, and vigilance. CONCLUSIONS: We found a relatively high QoL, a low rate of subjective impairment, but a high incidence of objective executive deficits in untreated elderly patients with new-onset epilepsy. Neurological status and body mass index, rather than seizure frequency or severity, were risk factors for cognitive impairment. Given the relevance of cognition in the course of epilepsy and its treatment, routine screening before treatment initiation is highly recommended.

The PerPAIN trial: a pilot randomized controlled trial of personalized treatment allocation for chronic musculoskeletal pain-a protocol.

BACKGROUND: The therapy of chronic musculoskeletal pain (CMSP) is complex and the treatment results are often insufficient despite numerous therapeutic options. While individual patients respond very well to specific interventions, other patients show no improvement. Personalized treatment assignment offers a promising approach to improve response rates; however, there are no validated cross-disease allocation algorithms available for the treatment of chronic pain in validated personalized pain interventions. This trial aims to test the feasibility and safety of a personalized pain psychotherapy allocation with three different treatment modules and estimate initial signals of efficacy and utility of such an approach compared to non-personalized allocation. METHODS: This is a randomized, controlled assessor-blinded pilot trial with a multifactorial parallel arm design. CMSP patients (n = 105) will be randomly assigned 1:1 to personalized or non-personalized treatment based on a cluster assignment of the West Haven-Yale Multidimensional Pain Inventory (MPI). In the personalized assignment condition, patients with high levels of distress receive an emotional distress-tailored intervention, patients with pain-related interference receive an exposure/extinction-tailored treatment intervention and patients who adapt relatively well to the pain receive a low-level smartphone-based activity diary intervention. In the control arm, patients receive one of the two non-matching interventions. Effect sizes will be calculated for change in core pain outcome domains (pain intensity, physical and emotional functioning, stress experience, participant ratings of improvement and satisfaction) after intervention and at follow-up. Feasibility and safety outcomes will assess rates of recruitment, retention, adherence and adverse events. Additional data on neurobiological and psychological characteristics of the patients are collected to improve treatment allocation in future studies. CONCLUSION: Although the call for personalized treatment approaches is widely discussed, randomized controlled trials are lacking. As the personalization of treatment approaches is challenging, both allocation and intervention need to be dynamically coordinated. This study will test the feasibility and safety of a novel study design in order to provide a methodological framework for future multicentre RCTs for personalized pain psychotherapy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022792 ( https://www.drks.de ). Prospectively registered on 04/06/2021.

Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain.

BACKGROUND AND OBJECTIVES: Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised clinical trial evaluated patient assessment of the efficacy and tolerability of oral prolonged-release (PR) oxycodone when co-administered with oral naloxone PR. METHODS: Two hundred and two patients with chronic cancer- or non-cancer-related pain undergoing stable oxycodone PR therapy (40, 60 or 80 mg/day) were randomised to one of four intervention groups: 10, 20 or 40 mg/day naloxone PR or placebo. Following a 4-week maintenance phase, patients were followed-up for 2 weeks in which time they received oxycodone PR only. At the end of the maintenance phase, patients and investigators were asked to assess treatment efficacy and tolerability, as well as preference for the titration or maintenance phase. RESULTS: Patient and investigator global assessment of efficacy and tolerability improved with increasing naloxone dose. Efficacy was ranked as 'good' or 'very good' by 50.0%, 67.4% and 72.5% of patients in the 10, 20 and 40 mg naloxone PR dose groups, respectively, compared with 43.5% of patients in the placebo group. Patient assessment of tolerability was similar between treatment groups and placebo, being ranked as 'good' or 'very good' by 83.3%, 79.1% and 82.5% of patients in the 10, 20 and 40 mg/day naloxone PR dose groups, respectively, compared with 71.7% of patients in the placebo group. The maintenance treatment phase was preferred by patients in the naloxone groups. A 2 : 1 dose ratio of oxycodone to naloxone was also assessed. Efficacy was ranked as 'good' or 'very good' by 70.4% of patients treated with the 2 : 1 dose ratio compared with 43.5% of patients receiving placebo. Tolerability of the 2 : 1 dose ratio was ranked as being 'good' or 'very good' by 81.5% of patients compared with 71.1% for the placebo group and patients preferred the maintenance phase. CONCLUSIONS: The co-administration of oral naloxone PR with oxycodone PR improves patient assessment of analgesic opioid therapy for severe chronic pain, in terms of both efficacy and tolerability.

Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma.

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Cough, diarrhea, pyrexia and rash were observed in five patients (33%) each. Grade 3/4 events included leukopenia in 6 (40%), neutropenia in 4 (27%) and thrombocytopenia in 2 patients (13%). An objective response was observed in 14/15 patients (93%), including 5 complete response (33%; all MCL). After a median follow-up of 19 months, 67% of patients are without signs of progression. Temsirolimus can be safely added to BR with promising preliminary activity. Recruitment in phase II is ongoing.

Effects of nicotine on human nasal epithelium: evidence for nicotinic receptors in non-excitable cells.

We investigated the effects of nicotine and its derivate nicotine di-d-tartrate on primary cultured human nasal epithelial cells. Both substances evoked an increase in the intracellular free calcium concentration. In the presence of extracellular Ca2+ the cytosolic Ca2+ ([Ca2+]i) increase was long lasting, whereas in the absence of external Ca2+ there was a transient increase of [Ca2+]i indicating that nicotine has an influence on Ca2+ conductances across the membranes and on intracellular Ca2+ stores. Both effects could be blocked by the nicotinic receptor antagonist methyllycaconitine (MLA). Apical or basolateral application of nicotine during transepithelial transport measurements with confluent monolayers of cultured human nasal cells resulted in a significant, reversible decrease of amiloride-sensitive sodium absorption with an apparent half-maximal blocker concentration of about 950 microM. To exclude the possibility that remnant neuronal components were responsible for the observed effects we used tetrodotoxin and verapamil to block putative neuronal channels and 4-(4-diethylamino)styryl-N-methylpyridinium iodide (4-di-2-Asp) to stain neuronal tissue. Both experimental approaches demonstrated that there were no neuronal-mediated effects. These results indicate the direct effects of nicotine on human nasal epithelium, giving the first evidence of the existence of nicotinic receptors in non-excitable cells.

Cystic fibrosis and non-cystic-fibrosis human nasal epithelium show analogous Na+ absorption and reversible block by phenamil.

Transepithelial short-circuit current (ISC), potential (VT) and resistance (RT) of confluent monolayers of human nasal epithelium cultured from patients with and without cystic fibrosis (CF) were measured. In our Ussing chamber experiments with monolayers derived from non-CF and CF patients neither ISC (non-CF: 14.1 +/- 1.0 microA/cm2, n = 77; CF: 16.7 +/- 1.5 microA/cm2, n = 42), nor RT (non-CF: 288 +/- 15 Omega . cm2; CF: 325 +/- 20 Omega . cm2) showed any significant differences, only VT showed moderate but significant different values (non-CF: -3.6 +/- 0.4 mV; CF: -5.6 +/- 0.7 mV, respectively). Total ISC in CF cells was nearly completely inhibited by amiloride (92 +/- 9.6%), while in non-CF tissue amiloride-insensitive conductances mediated a considerable amount of the ISC (36.3 +/- 6.1%), indicating a lower activity of amiloride-sensitive Na+ conductances in non-CF cells. In both tissues the amiloride-sensitive ISC could also be blocked by the amiloride analogues benzamil, phenamil and 5-(N-ethyl-N-isopropyl)2', 4'-amiloride (EIPA) with different affinities. However, amiloride had a significant lower affinity in CF tissue (half-maximal blocker concentration, K1/2 = 586 +/- 59 nM) compared with non-CF tissue (K1/2 = 294 +/- 22 nM). Astonishingly, phenamil, a blocker which irreversibly blocks all epithelial Na+ channels hitherto described, inhibited the Na+ conductances of human nasal epithelium in a completely reversible way, but nevertheless with high affinity (non-CF: K1/2 = 12.5 +/- 1.2 nM; CF: K1/2 = 17.1 +/- 1.1 nM). Even in high doses none of these blockers had any effect on intracellular Ca2+ concentration as measured with Fura-2. From these findings, we conclude that the epithelial Na+ conductances of human CF nasal epithelium show modified regulation or are functionally different from those of other tissues.

Amiloride-sensitive Na+ channels in human nasal epithelium are different from classical epithelial Na+ channels.

We characterized Na+ absorption in confluent monolayers of primary cultured epithelia derived from human nasal cystic fibrosis (CF) and non-CF epithelium in modified Ussing chambers. Amiloride-sensitive Na+ channels in cells obtained from CF as well as from non-CF patients showed properties different from all previously described epithelial Na+ channels (ENaC). DPC, a potent Cl- channel blocker, which has never been described to block ENaC, inhibited a considerable portion of the amiloride-sensitive Na+ absorption. In contrast to classical ENaC, cAMP induced no activation of amiloride-sensitive short-circuit current. Aldosterone failed to induce any functional stimulation of Na+ absorption in vitro when applied to the cell culture medium prior to measurements. Together with the reportedly reversible inhibition by phenamil we propose that Na+ absorption in human nasal epithelia is either regulated differently or is mediated by a yet still unknown member of the ENaC superfamily.

Effects of topically delivered benzamil and amiloride on nasal potential difference in cystic fibrosis.

The raised nasal transepithelial potential difference (PD) in cystic fibrosis (CF) reflects accelerated active transport of Na+, and is inhibited by topical administration of the Na+ channel blocker, amiloride. The aim of this study was to investigate the dose-effect and time course of topically administered Na+ conductance inhibitors to inhibit nasal PD, including benzamil, an analog of amiloride. We measured the magnitude of drug inhibition of Na+ transport [percent inhibition of baseline PD (DeltaPD%)] and duration of inhibition of PD, defined as the time when drug inhibition of PD had recovered by 50% (effective time = ET50). Amiloride [10(-)3 M (n = 16), 3 x 10(-)3 M (n = 9), 6 x 10(-)3 M (n = 7), 10(-)2 M (n = 3)] or benzamil [1.7 x 10(-)3 M (n = 7), and 7 x 10(-)3 M (n = 5)] were administered to the nasal surface via an aerosol generated by a jet nebulizer and a nasal mask. The concentration-dependent magnitude (DeltaPD%) of inhibition was similar for amiloride and benzamil ( approximately 67- 77%), whereas the duration of inhibition (ET50) was about two-and-a-half times longer after benzamil administration as compared with equivalent concentrations of amiloride [1.6 +/- 0. 06 versus 4.5 +/- 0.6 h (ET50 +/- SEM), at 6-7 x 10(-)3 M]. In vitro studies of cultured normal nasal epithelia demonstrated directly that benzamil induced an approximately 2-fold more prolonged inhibition of active Na+ transport than amiloride. These data suggest aerosolized benzamil is a candidate long-duration Na+ channel blocker for CF.