Population health management in France: specifying population groups through the DRG system.

BACKGROUND: Population health management (PHM) by hospital groups is not yet defined nor implemented in France. However, in 2019, the French Hospitals Federation launched a pilot program to experiment PHM in five territories around five Territorial Hospital Groups (GHT's). In order to implement PHM, it is necessary to firstly define the population which healthcare facilities (hospitals) have responsibility for. In the French healthcare system, mapping of health territories however relies mainly on administrative data criteria which do not fit with the actual implementation of GHT's. Mapping for the creation of territorial hospital groups (GHTs) also did not include medical criteria nor all healthcare offers particularly in private hospitals and primary care services, who are not legally part of GHT's but are major healthcare providers. The objective of this study was to define the French population groups for PHM per hospital group. METHODS: A database study based on DRG (acute care, post-acute and rehabilitation, psychiatry and home care) from the French National Hospitals Database was conducted. Data included all hospital stays from 1 January 2016 to 31 December 2017. The main outcome of this study was to create mutually exclusive territories that would reflect an accurate national healthcare service consumption. A six-step method was implemented using automated analysis reviewed manually by national experts. RESULTS: In total, 2840 healthcare facilities, 5571 geographical zones and 31,441,506 hospital stays were identified and collated from the database. In total, 132 GHTs were included and there were 72 zones (1.3%) allocated to a different GHTs. Furthermore, 200 zones were manually reviewed with 33 zones allocated to another GHT. Only one area did not have a population superior to 50,000 inhabitants. Three were shown to have a population superior to 2 million. CONCLUSIONS: Our study demonstrated a feasible methodology to define the French population under the responsibility of 132 hospital groups validated by a national group of experts.

Seventeen years' follow-up of the tension-free vaginal tape procedure for female stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The minimally invasive tension-free vaginal tape (TVT) operation has become the "gold standard" of incontinence surgery. The aim of the present study was to evaluate the long-term effect of the tape material and to assess the continence status 17 years after surgery METHODS: A cohort of 90 women operated upon with the TVT procedure at three Nordic centers has been prospectively followed for 17 years. All of the women alive according to national registries were contacted and invited to visit the clinics for evaluation. Pelvic examination was performed to reveal any adverse effects of the tape material. Objective and subjective continence status were assessed by a cough stress test and the patients' global impression of improvement as well as by condition-specific quality of life questionnaires. RESULTS: Seventy-eight percent of the potentially assessable women were evaluated either by a clinic visit or by a telephone interview. One case of a minimal, symptom-free tape extrusion was seen. No other tape complications occurred. Over 90 % of the women were objectively continent. Eighty-seven per cent were subjectively cured or significantly improved. CONCLUSION: The TVT operation is durable for 17 years, with a high satisfaction rate and no serious long-term tape-induced adverse effects.

Nitrite and nitrate measurement in human urine by capillary electrophoresis.

Nitrite and nitrate have been widely used as markers for nitric oxide (NO) formation in vivo and represent the major NO oxidation products in biological fluids. In the present study, the use of capillary electrophoresis (CE) in the measurement of nitrite and nitrate in human urine is described. Urine samples were electrophoresed in an extended light path fused-silica capillary (104 cm; 75 microm ID) at an applied negative potential of 30 kV, and UV detection at 214 nm. Using electrokinetic sample injection (-6 kV x 20 s), we found that urine concentration, pH, sodium and chloride interfered with nitrite and nitrate detection. The detection of nitrite and nitrate was decreased when hydrodynamic sample injection was used (30 mbar x 60 s). However, basal levels of urinary nitrite (0.25 +/- 0.05 microM) and nitrate (591 +/- 115 microM) were detected and no interference by variations in urine concentration and pH was noted when hydrodynamic sample injection was used. Thus, hydrodynamic sample injection is convenient for the measurement of urinary nitrite and nitrate and avoids the effect of variations in urine matrices and pH on nitrite and nitrate detection.

Bacillus Calmette-Guerin induces long-term local formation of nitric oxide in the bladder via the induction of nitric oxide synthase activity in urothelial cells.

PURPOSE: Bladder instillation of bacillus Calmette-Guerin (BCG) is effective therapy for recurrent superficial bladder cancer and carcinoma in situ. BCG induces nitric oxide synthase activity in the bladder. Nitric oxide is formed from L-arginine by nitric oxide synthase. We investigated nitric oxide formation and its localization in bladder cancer patients treated with intravesical BCG instillation. MATERIALS AND METHODS: The L-citrulline conversion assay was done to assess nitric oxide synthase activity in BCG treated T24 human bladder cancer cells and cultured normal human urothelial cells. Nitrite and nitrate in cell culture medium, urine and plasma were measured by capillary electrophoresis. Nitric oxide formation in the bladder was measured by chemiluminescence. RESULTS: A 24-hour treatment with BCG induced calcium independent nitric oxide synthase activity in T24 cells in a dose dependent manner. Nitrite and nitrate production by T24 cells also increased in a dose dependent manner after 24-hour BCG treatment. BCG treatment of cultured normal human urothelial cells resulted in the induction of calcium dependent and independent nitric oxide synthase activity. Nitrite in the urine of patients receiving BCG for the first time was increased 5-fold 24 hours after instillation. Furthermore, BCG increased luminal nitric oxide in the bladder. The increase was noted after a single treatment and sustained for 6 months. No changes in plasma nitrite or nitrate were observed after BCG treatment. CONCLUSIONS: BCG induces the local formation of nitric oxide in the bladder, whereas no evidence for systemic nitric oxide formation was noted. Increased nitric oxide production in the bladder is likely due to the induction of nitric oxide synthase activity in urothelial cells.

Increased intrathecal nitric oxide formation in multiple sclerosis; cerebrospinal fluid nitrite as activity marker.

Nitric oxide is formed from L-arginine by a family of enzymes: nitric oxide synthase (NOS). The inducible nitric oxide synthase is activated by cytokines and it has been suggested that activation of the enzyme gives rise to neurotoxic levels of reactive nitrogen oxides. This enzyme has been shown to be localized in multiple sclerosis (MS) lesions but the role of nitric oxide formation in the pathogenesis of MS is still unclear. Using capillary electrophoresis, we have analysed nitrite and nitrate in cerebrospinal fluid (CSF) and demonstrate increased levels of reactive nitrogen products in 17 patients with MS. The total levels of oxidized nitrogen products were significantly elevated in MS patients when compared with controls. In patients with active MS, nitrite levels were significantly increased when compared with controls and patients in remission. This is supportive of NOS induction in MS. We suggest that capillary electrophoresis analysis of nitrite and nitrate in CSF could provide a clinically useful way to determine disease activity in MS.

Increased nitric oxide in infective gastroenteritis.

Nitric oxide (NO) production is increased in several inflammatory disorders, although the role of this gas is not clear. The purpose of this study was to determine whether luminal NO in the intestine is increased in infective gastroenteritis. Rectal gas was sampled in 17 patients with gastroenteritis and 10 healthy volunteers, with balloon catheters made of 100% silicone and analyzed for NO by chemiluminescence. Plasma nitrate and nitrite levels were determined by capillary electrophoresis. Rectal NO was (mean+/-SEM) 9441+/-3126 parts per billion (ppb) in the patients and 74+/-13 ppb in controls (P<.0001). There was no individual overlap. Plasma nitrite but not nitrate was significantly increased in patients compared with controls. These data indicate that luminal NO is greatly increased in gastroenteritis. The high levels of NO are easily measurable by rectal sampling, and measurement of luminal NO seems to be useful for evaluating local NO production in the gut in health and disease.

Endogenously formed nitric oxide modulates cell growth in bladder cancer cell lines.

OBJECTIVES: Nitric oxide (NO) is formed in many mammalian tissues, and a growing body of evidence suggests that NO is involved in cell growth and cell differentiation. Low concentrations of NO can stimulate cell growth; high concentrations result in cytostatic/cytotoxic effects. It has previously been shown that intravesical treatment with bacille Calmette-Guérin (BCG) for bladder cancer increases NO production in the human urinary bladder and that NO inhibits bladder cancer cell growth in vitro. In this study, we investigated nitric oxide synthase (NOS) activity in different bladder cancer cells and the role of the NO precursor L-arginine in cell proliferation. METHODS: NOS activity was assessed by citrulline assay in cultured normal human urothelial cells and bladder cancer cell lines T24 and MBT-2 before and after treatment with cytokines. We also measured cell growth at various L-arginine concentrations and after addition of the NOS inhibitor N(G)-nitro-L-arginine (L-NNA) in unstimulated and cytokine-stimulated cells. RESULTS: Normal urothelial cells, as well as T24 and MBT-2 cells, showed calcium-dependent NOS activity under basal conditions. The bladder cancer cell lines also showed calcium-independent NOS activity in contrast to the normal cells. After cytokine treatment, both the normal cells and the cancer cell lines showed a marked increase in calcium-independent NOS activity. There was a dose-dependent stimulation of cell growth in the cancer cell lines after L-arginine addition, and this effect could be antagonized by L-NNA. Cytokine treatment inhibited cell growth, and this inhibition was partly reversed by L-NNA. CONCLUSIONS: Normal urothelial cells and bladder cancer cell lines MBT-2 and T24 show NOS activity, and cytokine treatment induces calcium-independent NOS activity. Our results suggest that endogenous activity of the constitutively expressed form of NOS in unstimulated cells promotes cell proliferation, and NO production secondary to increased activity of the inducible form of NOS after cytokine treatment inhibits cell growth.

Central nervous system nitric oxide formation in cerebral systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory disease in which up to two thirds of the patients present neurological symptoms. The diagnosis of the disease is based on clinical findings and the presence of autoantibodies, and the pathogenesis is unclear. The purpose of this study was to determine if the pathogenesis was partly mediated via nitric oxide (NO) formation. Cerebrospinal fluid (CSF) samples from 15 patients with cerebral SLE were analyzed for the NO metabolites nitrite and nitrate using capillary electrophoresis. The severity of neurological symptoms was scored by dividing the patients into two groups with either mild or moderate/severe CNS involvement. All patients with cerebral SLE showed increased levels of NO metabolites. In CSF, there was a relationship between signs of NO production and clinical results showing that increased levels of nitrite and nitrate were associated with more severe neurological symptoms. These findings may shed new light on the pathogenesis of cerebral SLE, and analysis of nitrate and nitrate may prove to be of value in monitoring the activity of the disease.

The role of nitric oxide in bacillus Calmette-Guérin mediated anti-tumour effects in human bladder cancer.

Bacillus Calmette-Guérin (BCG) has been used for many years to treat cancer of the urinary bladder. It constitutes effective intravesical therapy of carcinoma in situ and recurrent superficial bladder cancer. Although the mechanism of action is unknown, most evidence suggests an immune-mediated mechanism. BCG treatment is known to increase cytokine production in the urinary bladder. As cytokines may induce nitric oxide synthase (NOS) activity and as nitric oxide (NO) exerts cytotoxic effects on tumour cells, we investigated the role of NO in BCG-mediated anti-tumour activity. Here we demonstrate a marked induction of both calcium-dependent and calcium-independent NOS activity in the human urinary bladder after BCG treatment. The presence of NOS in the urothelial cells was also demonstrated by the use of immunohistochemistry. Furthermore, patients treated with BCG showed a 30 times higher production of gaseous NO as measured in the urinary bladder by chemiluminescence. Finally, NO donors exerted cytotoxic effects on bladder cancer cell lines. These findings suggest that NO synthesis may be an important mechanism in BCG-mediated anti-tumour therapy.

Nitric oxide synthase activity in human renal cell carcinoma.

PURPOSE: Nitric oxide (NO) is generated in mammalian tissue by the conversion of L-arginine to L-citrulline. The reaction is catalyzed by nitric oxide synthase (NOS). NO has been suggested to have a dual role in tumor biology with both antitumor and tumor promoter activity. Furthermore, it has been proposed that NO contributes to interleukin-2-induced antitumor activity. Since interleukin-2 is used in the treatment of renal cell carcinoma (RCC) it was of interest to study the NOS activity in the human kidney and in RCC and its correlation to tumor grade. Furthermore, the effect of cytokine treatment on NOS activity and the effect of NO donor application was studied in cultured cells. MATERIALS AND METHODS: The effect of cytokine treatment on NOS activity and the effect of NO donor application on cell proliferation was studied in cultured human proximal tubular cells and in RCC cell lines HN4 and HN51. NOS activity was measured by the L-arginine to L-citrulline conversion assay. RESULTS: Calcium-dependent NOS activity was found in all non-malignant kidney tissues (486+/-63 pmol. min(-1) g(-1) tissue). The activity was significantly lower in RCC (24+/-6 pmol. min(-1) g(-1) tissue) and correlated with tumor grade; thus high grade tumors showed lower activity than low grade tumors. Calcium-independent NOS activity was not detected in non-malignant kidney tissue or in RCC tissue. In cultured proximal tubular cells and RCC cell lines HN4 and HN51, cytokine treatment induced a marked increase in NOS activity and NO exerted cytostatic effects on these cell lines. CONCLUSIONS: The NOS activity was higher in non-malignant kidney tissue than in RCC tissue and was inversely correlated with tumor grade. Furthermore, cytokine treatment induced a marked increase in NOS activity and NO exerted cytostatic effects on cultured proximal tubular cells and RCC cell lines.

Increased nitric oxide production in collagenous and lymphocytic colitis.

The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn's disease. We have studied NO production in collagenous colitis (CC) and lymphocytic colitis (LC), both of which are inflammatory bowel disorders of unknown aetiology. NO levels were measured directly in gas sampled from the colon during colonoscopy. Plasma levels of NO metabolites (nitrate/nitrite) were also measured. Luminal NO levels were more than 100 times higher in patients with CC compared with controls. In addition, plasma levels of nitrate/nitrite were increased in the patients as compared with controls. Measurements of NO directly in the colon or its oxidation products in plasma may be a helpful tool in further understanding the role of NO in the pathophysiology of CC and LC. Moreover, it is tempting to speculate that these measurements could be clinically useful in the diagnosis and therapy monitoring of these two inflammatory bowel diseases.

Urinary nitrite: more than a marker of infection.

OBJECTIVES: The bacteriostatic gas nitric oxide (NO) is formed when nitrite is acidified. Infected urine may contain considerable amounts of nitrite as a result of bacterial nitrate reductase activity, and detection of nitrite in urine is routinely used in the diagnosis of bacterial cystitis. We sought to determine whether NO was generated from acidified nitrite-containing urine. Furthermore, we also studied the growth of the urinary pathogen Escherichia coll in acidified nitrite-containing urine. METHODS: Urine, collected from healthy control subjects or from patients with infected nitrite-containing urine, was acidified and incubated in a closed syringe with varying amounts of nitrite added. After 30 minutes, the headspace gas was removed and immediately injected into a chemiluminescence NO analyzer. In addition, NO was measured in urine collected from healthy control subjects after ingestion of vitamin C. Bacterial growth was measured continuously in control urine for 10 hours after incubation for 2 hours in acidic urine with varying concentrations of nitrite added. RESULTS: Large amounts of NO were released from infected nitrite-containing urine after mild acidification. NO was also released from acidified control urine if nitrite was added, and this release was greatly potentiated in the presence of vitamin C. Furthermore, the growth of E. coli was markedly reduced by the addition of nitrite to acidified urine. CONCLUSIONS: We propose that nitrite-producing bacteria induce their own death in acidic urine by supplying substrate for generation of bacteriostatic compounds such as NO. This mechanism might explain why urinary acidification and vitamin C may be effective in the treatment of bacteriuria.

L-arginine enhances functional recovery and Ca(2+)-dependent nitric oxide synthase activity after ischemia and reperfusion in the rat heart.

The effects of L-arginine on ischemia/reperfusion-induced myocardial dysfunction as well as the tissue activity of nitric oxide synthase (NOS) were investigated in rat isolated Langendorff-perfused hearts. Hearts were subjected to nonischemic perfusion or 30 min of global ischemia followed by 30 min of reperfusion. The hearts subjected to ischemia/reperfusion received either vehicle, L-arginine (1 mM), D-arginine (1 mM), the NOS inhibitor NG-nitro-L-arginine (L-NNA, 1 mM), or L-arginine (1 mM) plus L-NNA (1 mM) at the beginning of ischemia. L-Arginine but not D-arginine significantly enhanced the recoveries of left ventricular double product and coronary flow compared with the vehicle group. There was a substantial activity of Ca(2+)-dependent NOS but no significant Ca(2+)-independent NOS activity in the hearts undergoing 60 min of nonischemic perfusion. After ischemia/reperfusion, Ca(2+)-dependent NOS activity significantly decreased (by > 90%) in comparison with that of nonischemic hearts. L-Arginine increased the Ca(2+)-dependent NOS activity compared with the vehicle group to a level that was similar to that observed in nonischemic hearts. There was no difference in Ca(2+)-dependent NOS activity between vehicle- and D-arginine-treated groups. Administration of L-NNA abolished the beneficial effects of L-arginine on functional recovery and on Ca(2+)-dependent NOS activity. There were no significant Ca(2+)-independent NOS activities in any of the ischemic groups. These results suggest that myocardial ischemia/reperfusion reduces Ca(2+)-dependent NOS activity in the heart. Administration of L-arginine enhances myocardial function and preserves Ca(2+)-dependent NOS activity after ischemia/reperfusion through a pathway involving NOS activity.