The need for cardiac surgery differential tariffs in Israel at the era of aging population and emerging technology: Importance of procedure type and patient complexity as assessed by EuroSCORE.

BACKGROUND: Reimbursement for cardiac surgical procedures in Israel is uniform and does not account for diversity in costs of various procedures or for diversity in patient mix. In an era of new and costly technology coupled with higher risk patients needing more complex surgery, these tariffs may not adequately reflect the true financial burden on the caregivers. In the present study we attempt to determine whether case mix and complexity of procedures significantly affect cost to justify differential tariffs. METHODS: We included all patients undergoing cardiac surgery at Shaare Zedek Medical Center between the years 1993-2016. Patients were stratified according to (1) type of surgery and (2) clinical profile as reflected by the predicted operative risk according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE). Approximate cost of each group of patients was estimated by the average number of days in the Intensive Care Unit and days in the postoperative ward multiplied by the respective daily costs as determined by the Ministry of Health. We then added the fixed cost of the components used in the operating room (manpower and disposables). The final estimated cost (the outcome variable) was then evaluated as it relates to type of surgery and clinical profile. ANOVA was used to analyze cost variability between groups, and backward regression analysis to determine the respective effect of the abovementioned variables on cost. Because of non-normal distribution, both costs and lengths of stay were Log-transformed. RESULTS: Altogether there were 5496 patients: 3863, 836, 685 and 112 in the isolated CABG, CABG + valve, 1 valve and 2 valves replacement groups. By ANOVA, the costs in all EuroSCORE subgroups were significantly different from each other, increasing with increased EuroSCORE subgroup. Cost was also significantly different among procedure groups, increasing from simple CABG to single valve surgery to CABG + valve surgery to 2-valve surgery. In backward stepwise multiple regression analysis, both type of procedure and EuroSCORE group significantly impacted cost. ICU stay and Ward stay were significantly but weakly related while EuroSCORE subgroup was highly predictive of both ICU stay and ward stay. CONCLUSIONS: The cost of performing heart surgery today is directly influenced by both patient profile as well as type of surgery, both of which can be quantified. Modern day technology is costly yet has become mandatory. Thus reimbursement for heart surgery should be based on differential criteria, namely clinical risk profile as well as type of surgery. Our results suggest an urgent need for design and implementation of a differential tariff model in the Israeli reimbursement system. We suggest that a model using a fixed, average price according to the type of procedure costs, in addition to a variable hospitalization cost (ICU + ward) determined by the patient EuroSCORE or EuroSCORE subgroup should enable an equitable reimbursement to hospitals, based on their case mix.

[Bone-specific therapy with radium-223 dichloride : Castration-resistant prostate cancer with symptomatic bone metastases]. / Knochenspezifische Radium-223-Dichlorid-Therapie : Symptomatisches, ossär metastasiertes, kastrationsresistentes Prostatakarzinom.

Radium-223 dichloride (Xofigo®, Alpharadin) is approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. As a calcium mimetic, it is integrated into osteoplastic bone lesions and emits alpha particles with high energy which leads to local destruction of tumor cells. In the 2013 published ALSYMPCA trial, a significant advantage for overall survival and quality of life in comparison to placebo was found. Recent data suggest an increased potential in combination with next generation hormonal treatment.

[PSMA-targeted radioligand therapy in prostate cancer]. / Radionuklidtherapie des Prostatakarzinoms mittels PSMA-Lutetium.

Radioligand therapy (RLT) directed against prostate-specific membrane antigen (PSMA) enables tumor-specific treatment directed against PSMA-overexpressing prostate cancer cells. Several PSMA ligands such as PSMA-617 or PSMA-I&T have been developed that can be labeled with ß­radiating lutetium-177. These are currently applied in compassionate use programs to treat metastatic castration-resistant prostate cancer (mCRPC). PSMA-directed RLT is currently being offered in several nuclear medicine departments throughout Germany. Several retrospective case series demonstrate its activity with a prostate-specific antigen (PSA) decrease >50% in 30-60% of mCRPC patients. The toxicity seems to be low. Hematologic grade 4 toxicity has not been observed and grade 3 toxicities rarely occur. The main nonhematologic adverse events are intermittent dry mouth because of unspecific PSMA expression in the salivary glands as well as fatigue and nausea. Currently there are no prospective studies available for evaluation of PSMA-targeted RLT and a survival benefit over approved standard therapies such as abiraterone, enzalutamide, radium-223-dichloride, docetaxel or cabazitaxel has not been shown. PSMA-targeted RLT should therefore currently only be offered after critical evaluation in patients who exhausted the approved standard therapies.

[Varicocele and pubertal testicular growth. A prospective study]. / Varikozele und pubertäres Hodenwachstum. Eine prospektive Studie.

BACKGROUND: We prospectively assessed male students in the 4th and 8th forms to see whether varicoceles affect testicular growth. PARTICIPANTS AND METHODS: Ultrasound measurements were done in 778 boys to define testicular size according to the different pubertal stages. Seven hundred boys had a left or bilateral varicocele; 257 children and 287 adolescents with unilateral varicoceles were assessed for testicular size discrepancies in relationship to the varicocele size and the Doppler grades of venous reflux in the upright and supine positions. RESULTS: Rapid testicular growth occurred at puberty. By comparing the frequencies and extent of ipsilateral growth failures in adolescents, we noted significant differences among the varicocele grades. A volume loss of >or=15% was associated with the higher varicocele grades and the reflux grades in the supine position. CONCLUSION: Varicoceles may impair testicular growth at puberty. The severity of volume loss depends on the varicocele size and the related alterations in circulatory flow.

[Diclofenac during prostate needle biopsy. Significant pain reduction]. / Prostatastanzbiopsie unter Diclofenac. Signifikante Schmerzreduktion und Verbesserung der Patientenakzeptanz.

BACKGROUND: The aim of this study was to evaluate the efficacy of diclofenac to reduce pain during prostate biopsy. METHODS: After prospective randomization all patients received an intrarectal lidocaine gel instillation. Group 1 (n=80) functioned as control group, group 2 (n=72) received a placebo, and group 3 (n=76) a 50 mg diclofenac suppository in addition. Patients were asked to identify their pain score (VAS 10) after the biopsy. Two weeks later, the patients were called and asked about the post-biopsy course. RESULTS: Patients in the diclofenac group had significantly lower pain scores than control or placebo group patients. Another biopsy without additional anesthesia was refused by 25% of the control group and 34% of the placebo group, but only by 11% of the diclofenac group (p<0.05). CONCLUSIONS: The preinterventional administration of diclofenac suppositories is a simple but efficient procedure for pain reduction in patients who undergo prostate biopsy.

A Doppler-based study on the prevalence of varicocele in German children and adolescents.

The prevalence of varicocele was estimated among pupils of forms 4 and 8 in the city of Hamburg and the severity of the associated venous reflux was analysed. In the school year of 1998/99, a genital examination was performed on 2756 children (median age 10.2 years) and 2008 adolescents (14.6 years). The varicocele degree was determined according to the WHO. Venous reflux was proven by CW-Doppler sonography, distinguishing between Valsalva-induced reflux (VR) and continuous reflux (CR). As a result, varicoceles were detected in 18.0% of the children (1.2% bilaterally) and 42.7% of the adolescents (7.2%). High-graded forms (palpable/visible) occurred with increasing rate (from 7% to 22.9%) on the left side. Subtle forms (subclinical/during Valsalva) counted for >90% of all right-sided findings, whilst an age-related shift towards higher degrees was noted left-sided. VR occurred bilaterally, CR was almost only established left-sided. VR was mainly associated with subtle varicoceles, CR was predominantly found in the high-graded forms. These results suggest that even in children varicoceles are not a rare phenomenon. However, adolescence is the main period of manifestation. A major venous malfunction is already evident in maturing boys, which seems to be associated with the formation of high-graded varicoceles.

[Bilateral testicular gunshot injuries]. / Doppelseitige Hodenschussverletzung.

Gunshot injuries to the testicles are rare and usually result in testicular atrophy. In the case of severe bilateral testicular injuries, this could cause not only infertility but also the need for lifetime testosterone-substitution. We report an 18-year-old patient with bilateral testicular gunshot injury. During the surgical exploration an orchiectomy of the complete ruptured left testicle was necessary. Debridement of the damaged tissue and a partial orchiectomy was performed on the right side. After the operation, the patient developed an incretory hypogonadism and oligozoospermia. During follow-up, an improvement in the sperm count and of the hormonal status occurred. These finally reached normal levels. After genital traumata, immediate surgical exploration should be performed. Based on the above results, the patient benefits from conservative debridement and primary repair of the injured testicle, if possible. An improvement in hormonal status and sperm parameters after testicular injury and consecutive testicular malfunction can occur. Regeneration of the testicular tissue seems possible.

Randomized, double-blind study of SR142801 (Osanetant). A novel neurokinin-3 (NK3) receptor antagonist in panic disorder with pre- and posttreatment cholecystokinin tetrapeptide (CCK-4) challenges.

OBJECTIVE: The present study was designed to examine the efficacy and tolerability of the non-peptide neurokinin-3 (NK3) receptor antagonist SR142801 in outpatients suffering from panic disorder. METHODS: In a pilot study, 52 patients who were responders to a cholecystokinin tetrapeptide (CCK-4) challenge were randomized to four weeks of treatment with SR142801 (n = 36) or placebo (n = 16). Panic symptoms were assessed on weekly visits and a second CCK-4 challenge was performed at the end of the double-blind placebo controlled treatment period. Tolerability of SR142801 was generally good. RESULTS: The proportion of patients who had at least one adverse event (AE) in the SR142801 group and the placebo group was similar (58.3 and 50 %, respectively). Independent of treatment group, patients' overall panic symptomatology was substantially improved at the end of the treatment. CONCLUSION: With regard to efficacy of outcome, the compound was not significantly different from placebo. However, post-CCK-4 plasma prolactin concentrations showed a significant difference between placebo and SR142801.

[Transurethral resection of bladder tumours in sodium chloride solution]. / Transurethrale Resektion von Blasentumoren in Kochsalzlösung.

BACKGROUND: Electrical transurethral resection is a well established and developed procedure. It is performed using high frequency current in a nonconductive irrigation medium. Due to these features this procedure is compromised by two possible complications: (1) spontaneous contractions of adductors caused by electrical stimulation of the obturator nerve may lead to bladder perforation, and (2) excessive flushing of the irrigation medium into the circulation can cause TUR syndrome. We present our initial experiences with a new system for transurethral resection which has overcome these potential sources of complications. The system, developed by Olympus, works with a modified guided high frequency current in 0.9% saline as irrigant. It is called TURIS (transurethral resection in saline). METHODS: A total of 35 resections of bladder tumors were performed using the TURIS technique. The operations were carried out under intravenous anaesthesia without relaxation or nerve block. During resection high frequency current passes through and active electrode (resection loop) to the sheath electrode. About 90% of the current flows through the saline to the sheath of the resectoscope, only a small amount circulates through the body of the patient. The experiences of the surgeons were documented. The resected specimens were histologically examined for artificial thermal changes and compared with a control group of conventionally resected patients. RESULTS: The handling of the TURIS resectoscope is very similar to that of well known instruments. Therefore, no special training was required for the surgeon or the theatre nurse. The control of the cutting was very efficient. Coagulation of bleeding was very good. The lack of carbonisation at the resection ground led to an excellent assessment of the resected areas. The resected tissue did not stick to the resection loop. Contraction due to nerve stimulation was not observed. No complications occurred. Histology showed no significant differences in the quantity or quality of thermal artifacts due to current. CONCLUSIONS: TURIS can be performed safety without a learning curve. Especially in TUR-B, it seems to be advantageous due to the excellent control of the extent of cutting and the lack of nerve stimulation. Quantity and quality of thermal changes in histology are not different from a conventionally resected control group.

[Antegrade sclerotherapy for varicocele testis--possible and avoidable complications]. / Die antegrade Sklerotherapie der Varicocele testis--Mögliche und vermeidbare Komplikationen.

Antegrade sclerotherapy is an established procedure for the treatment of varicocele. To avoid complications during the dissection of the pampiniform plexus, detailed knowledge of the angioarchitecture of the spermatic cord is recommended. One group of plexus veins is situated ventrolaterally and is surrounded by a yellowish fat which serves as a landmark. This vein group should be chosen for preparation. Phlebography of the internal testicular vein is mandatory. If arteries or major pelvic veins become visible while applying contrast media, sclerotherapy should not be performed. Paravasation of sclerosing agent has to be recognized and treated immediately to prevent deleterious effects.

[Long term outcome after percutaneous sclerotherapy of renal cysts with polidocanol]. / Langzeitergebnisse nach perkutaner Sklerosierung von Nierenzysten mit Polidocanol.

Methodology and long-term results of treatment of uncomplicated kidney cysts by percutaneous sclerotherapy with polidocanol are presented. Between 1991 and 1998, 132 patients with 151 kidney cysts were treated by percutaneous sclerotherapy with polidocanol as the sclerosing agent. The average volume of the cysts was 288 ml. Over a mean period of 25.8 months, 118 patients with 132 cysts were followed up. In 56% of the cysts treated the cystic cavity disappeared completely, and in 30% the remaining volume was less than 10% of the initial volume. The existing symptoms before intervention remained unchanged only in four (3.4%) patients. The morbidity of the method was 9% and surgical reintervention was not necessary. There was no mortality. The mean hospitalization was 1.06 days. Percutaneous sclerotherapy of uncomplicated kidney cysts with polidocanol offers a high rate of success without the costs and invasiveness associated with laparoscopic surgery and also without the need for repeated interventions associated with sclerotherapy performed with ethanol.

Identification of nucleolin as a new L-selectin ligand.

Apart from leucocyte-endothelial interactions, the adhesion molecule L-selectin mediates the homotypic adhesion of leucocytes during recruitment at sites of acute inflammation, as well as intercellular adhesion of haematopoietic progenitor cells during haematopoiesis. There is evidence that, in addition to P-selectin glycoprotein ligand-1, other as-yet-unidentified proteins function as L-selectin ligands on human leucocytes and haematopoietic progenitor cells. In the present study, we show: (i) by affinity chromatography on L-selectin-agarose; (ii) by protein identification using MS; and (iii) by covalent cell-surface labelling with sulphosuccinimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate that the multifunctional nuclear protein nucleolin is partly exposed on the cell surface, and is a ligand of L-selectin in human leucocytes and haematopoietic progenitor cells.

[Repetitive transcranial magnetic stimulation (rTMS) in the acute and long-term therapy of refractory depression--a case report]. / Repetitive transkranielle Magnetstimulation (rTMS) in der Akut- und Langzeittherapie bei therapieresistenter Depression. Eine Falldarstellung.

We report on a patient with therapy-resistant major depression according to DSM-IV criteria who has been hospitalized for 60 months during the last 7 years. Not even five electroconvulsive therapy (ECT) series (61 single applications) brought lasting remission of symptoms. As cognitive deficits developed and prolonged postnarcotic recovery times were observed, further ECT was contraindicated. The left frontal cortex was chosen as the target site for repetitive transcranial magnetic stimulation (rTMS) treatment. For identification, a neuronavigational system was used that allows online monitoring of the position of the magnetic coil in relation to the individual cortex. The therapeutic progress was monitored by standardized psychiatric ratings (HAMD, BDI). In addition, cognitive performance was tested during the course of treatment. Only a few rTMS applications already caused an obvious brightening in mood, remission of depressive delusional symptoms, and an increase in personal interests and activities. After 4 weeks of daily treatment, the patient was discharged from the ward. The rTMS treatments and psychotherapeutic counseling have been continued on an outpatient basis. Thus, pharmaco- and psychotherapeutic interventions combined with rTMS led to persistent symptom remission and social reintegration.

Determination of optimal non-denaturing elution conditions from affinity columns by a solid-phase screen.

The purification of biological macromolecules by affinity chromatography is a widespread technique used to separate a protein from other biological components. However, this method may destroy the protein's physiological activity because elution conditions aimed to dissociate the protein of interest from the high-affinity matrix often irreversibly denature it. In the present work, we have developed a solid-phase assay to determine the optimal elution conditions for any buffer (in two steps) by determining (i) the lowest buffer concentration yielding maximum dissociation from the immobilized component and (ii) the highest buffer concentration that can be used without the loss of the protein's binding activity. Any buffer that can be reasonably used between these defined concentrations is suitable for elution within this interval. The screen is easily performed within a few hours and only requires nanograms to a few micrograms of protein. As an example, we demonstrate that more than 95% of the human transferrin receptor bound to a transferrin-sepharose ligand affinity column can be eluted with full binding activity at KSCN concentrations between 232 and 414 nM, whereas elution with urea is not suitable to purify fully functional protein.

Development of a novel molecular adapter for the optimization of immunotoxins.

Immunotoxins consisting of catalytic domains of natural toxins and tumor-specific ligands were modified by introducing a molecular adapter that is able to transport the toxic domain more efficiently into cells. The adapter is a three-component structure: its core is a membrane transfer sequence (MTS) flanked by two different cleavable sequences. The directed and irreversible cellular uptake of the construct is driven by either enzymatic or chemical cleavage of the two flanking sequences. In our studies, the purified A-chain of diphtheria toxin (DT) was coupled to two different MTSs via disulfide bonds. A cytotoxicity assay revealed that the constructs containing the MTSs were more potent than DT A-chain alone and that the disulfide bond was cleaved.

The fate of desmosomal proteins in apoptotic cells.

Activation of caspases results in the disruption of structural and signaling networks in apoptotic cells. Recent biochemical and cell biological studies have shown that components of the cadherin-catenin adhesion complex in epithelial adherens junctions are targeted by caspases during apoptosis. In epithelial cells, desmosomes represent a second type of anchoring junctions mediating strong cell-cell contacts. Using antibodies directed against a set of desmosomal proteins, we show that desmosomes are proteolytically targeted during apoptosis. Desmogleins and desmocollins, representing desmosome-specific members of the cadherin superfamily of cell adhesion molecules, are specifically cleaved after onset of apoptosis. Similar to E-cadherin, the desmoglein-3 cytoplasmic tail is cleaved by caspases. In addition the extracellular domains of desmoglein-3 and desmocollin-3 are released from the cell surface by a metalloproteinase activity. In the presence of caspase and/or metalloproteinase inhibitors, both cleavage reactions are almost completely inhibited. As reported previously, the desmosomal plaque protein plakoglobin is cleaved by caspase-3 during apoptosis. Our studies now show that plakophilin-1 and two other major plaque proteins, desmoplakin-1 and -2, are also cleaved by caspases. Immunofluorescence analysis confirmed that this cleavage results in the disruption of the desmosome structure and thus contributes to cell rounding and disintegration of the intermediate filament system.

Shed L-selectin (sCD62L) load in trauma patients.

BACKGROUND: Low circulating plasma concentrations of the leukocyte adhesion molecule L-selectin (sCD62L) were found to be associated with an increased risk for subsequent lung failure and case fatality after severe trauma. The objective of this study was to determine the robustness of soluble L-selectin, correcting for a broad spectrum of physiological variables. METHODS: Patients with suspected multiple and/or trunk injuries were enrolled into this study over a 1-year period. Plasma samples were obtained on hospital presentation, and circulating soluble L-selectin was measured with a commercially available ELISA kit. Study records comprised all relevant clinical and laboratory data. Thirty-day survival rate, subsequent acute lung failure, and nosocomial pneumonia were defined as study endpoints. Statistical analysis was performed using multivariate logistic regression models. RESULTS: Seventy patients with a mean age of 35.51 years (range, 10-87 years) and a mean ISS score of 36.61 (95% CI, 31.08-42.14) entered the study. Eleven patients died, leading to an attributable mortality of 15.70%. L-Selectin levels did not differ between survivors and nonsurvivors. Five patients progressed to acute lung injury, whereas 11 patients developed hospital-acquired pneumonia. Lower L-selectin levels indicated patients at risk for lung injury with a relative odds estimated at 4.43 (P = 0.017). Statistical significance diminished in the multivariate model. In contrast, plasma concentrations of circulating sCD62L were significantly decreased in patients developing nosocomial pneumonia (P = 0.023), with a twofold increased relative odds (OR, 1.96; 95% CI, 0.51-7.50). No effect modification was observed by the included covariables. CONCLUSIONS: The results of this study highlight the independent predictive value of initially decreased soluble L-selectin levels for the identification of patients susceptible to subsequent respiratory complications after severe trauma.

LI-cadherin: a marker of gastric metaplasia and neoplasia.

BACKGROUND: Intestinal metaplasia is considered a risk factor for the development of gastric adenocarcinomas of the intestinal type and is found in approximately 20% of gastric biopsies. Conventional histology only detects advanced stages of intestinal metaplasia. AIMS: To study expression of the enterocyte specific adhesion molecule liver-intestinal (LI)-cadherin in intestinal metaplasia as well as in gastric cancer, and to evaluate its use as a diagnostic marker molecule. PATIENTS: Gastric biopsies (n=77) from 30 consecutive patients (n=30; aged 28-90 years) as well as surgically resected tissue samples (n=24) of all types of gastric carcinomas were analysed. METHODS: Single and double label immunofluorescence detection on cryosections of gastric biopsies; alkaline phosphatase antialkaline phosphatase method on paraffin embedded carcinoma tissue sections. RESULTS: Of 77 biopsies (from 30 patients), 12 (from 10 patients) stained positive for LI-cadherin. LI-cadherin staining correlated with the presence of intestinal metaplasia. Conventional histological diagnosis however failed to detect subtle gastric intestinal metaplasia (three of 10 patients). In contrast, only LI-cadherin and villin were positive in these cases whereas sucrase-isomaltase also failed to detect intestinal metaplasia in four of 10 patients. Well differentiated gastric carcinomas showed intense staining for LI-cadherin while undifferentiated carcinomas showed only weak diffuse cytoplasmic staining. CONCLUSIONS: To detect early metaplastic changes in the gastric mucosa, LI-cadherin has a sensitivity superior to sucrase-isomaltase and conventional histology and comparable with that of villin. Its specificity exceeds that of villin. Thus LI-cadherin represents a new, reliable, and powerful marker molecule for early detection of gastric intestinal metaplasia and well differentiated adenocarcinomas.