Emergency Treatment of Cervical Vertebromedullary Trauma: 10 Years of Experience and Outcome Evaluation.

OBJECTIVE: The aim of the study is to identify and validate, through the recording of clinical and radiological data, the different surgical approaches and treatments valid for most subaxial cervical dislocation fractures and whether there is an advantage from using an anterior approach rather than a posterior approach and conversely.. MATERIAL AND METHODS: A retrospective study was carried out analyzing the case history of the last 10 years of vertebromedullary traumas treated at the spine surgery unit of the Policlinico Gemelli in Rome. Data on surgical timing, American Spinal Injury Association (ASIA) scores for neurological damage, and subsequent assessments on recovery, survival, and mortality were also examined. RESULTS: A total of 80 patients were treated: 50 by the posterior approach, 24 by the anterior approach, and six by the double approach. Our average follow-up time was 4.2 years. A prevalence of surgery with the posterior approach was noted. We observed the worsening of cervical kyphosis about 15 months after the trauma in two cases treated with the posterior approach alone. A second surgical treatment was performed in these patients. One of these patients underwent an anterior fusion; the other case underwent a posterior revision because the patient had ankylosing spondylitis. Although we found no statistically significant difference in outcomes between the various surgical treatments, in this retrospective study, we analyzed the characteristics and outcomes of cervical spine injuries that required surgical treatment. CONCLUSION: The aim of surgery in unstable cervical spine injuries should be to reduce and stabilize the damaged segment, maintain lordosis, and decompress when indicated. The optimal choice of surgical approach and treatment, or its superiority in terms of outcomes, remains a debated issue.

Revealing NOTCH-dependencies in synaptic targets associated with Alzheimer's disease.

Recent studies have identified NOTCH signaling as a contributor of neurodegeneration including Alzheimer's disease' (AD) pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in neurodegenerative dementia, we employed transgenic mouse models with Notch1 and Rbpjk loss of function (LOF) mutation in pyramidal neurons of the CA fields. Using RNA-seq, we have investigated the differential expression of NOTCH-dependent genes either upon environmental enrichment (EE) or upon kainic acid (KA) injury. We found a substantial genetic diversity in absence of both NOTCH1 receptor or RBPJK transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for NOTCH signaling in the modulation of E/I balance. Upon excitotoxic stimulation, loss of RBPJK results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct NOTCH1/RBPJK targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from AD patients performing targeted transcripts analysis. We observe an increased trend for RBPJK and the ligand DNER starting in the mild-moderate stage of the disease with no change of NOTCH1 expression. Alongside, expression of the Notch targets Hes5 and Hey1 tend to rise in the intermediate stage of the disease and drop in severe AD. Similarly the newly discovered NOTCH targets, NPTX2, NPY, BDNF show an up-warding tendency during the mild-moderate stage, and decline in the severe phase of the disease. This study identifies NOTCH as a central signaling cascade capable of modulating synaptic transmission in response to excitatory insult through the activation of neuroprotective genes that have been associated to AD.

DOES AN EARLY POST-OPERATIVE PAIN RELIEVE INFLUENCE THE FUNCTIONAL OUTCOME OF PATIENTS WITH COLLES FRACTURES TREATED WITH EG-BLOCK SYSTEM?

Distal Radius Fractures (DRFs) represent one of the most common elderly patient's fractures. Often DRFs required surgical treatment based on instability of the fragments and due to the high functional demand from patients. A general agreement on the best pharmacological treatment in the post-operative is still missing. The present study describes the clinical outcome in patients who underwent surgery for Colles fracture using ES fixation osteosynthesis. ; The present investigation represents a one center retrospective analysis. In this study, two different medical treatments were recognized, and groups consequently set (Group A: Ketoprofene 100 mg twice a day for 5 days, 59 patients; Group B: Tramadol 75 mg and Dexketoprofen 25 mg, 62 patients). Outcomes were the functionality of the affected wrist through AROM assessment and the evaluation of painkillers intake, pain itself and Quick-DASH.; 121 patients were included in the present study. The pharma blending of Tramadol 75 mg and Dexketoprofen 25 mg resulted effective for the rapid recovery of the treated wrist motion. In fact, in the group B motion was better compared to group A (p<0.05) for any movement examined (flexion, extension, pronation, supination) until the last follow-up (70 days).; Associations of different painkillers are common, even if a general agreement on the most effective combination is still missing. Tramadol and Dexketoprofen provide a good clinical result, less side effects and a better functional recovery of the wrist motion. This guarantees a fewer social cost and a best management of post-operative physiotherapy.

A rare case of post-traumatic infected pilomatricoma of the finger of the hand diagnosed after performing radioiodine therapy.

We present the clinical case of a young woman with pilomatricoma of the finger, a very rare location. The patient got infected after receiving radioiodine therapy to treat a thyroid carcinoma. Given the patient's high functional requirements we choose a minimal treatment which allowed her to maintain a sufficient functionality.

A thoracic pain of difficult diagnosis. Unusual localization of osteoid osteoma.

Osteoid Osteoma (OO) is a benign tumor that can affect any age, but it occurs mostly in adolescents. Only few cases are reported in early infancy but very rare in advanced age. From our series of OO of the spine, we selected a rare case that combines many unusual features that makes diagnosis very difficult. A case of a painful thoracic syndrome in an old female patient due to an OO localized in the inferior edge of the left pedicle of T11 with engagement of the foramen was reported. The age of the patient, the absence of any typical clinical and diagnostic signs, such as nocturnal pain or side effects to NSAIDs administration, are unusual at presentation of OO. She presented instead, a type of pain to the chest that was stabbing, fulminating and radiating. The interest of the case is due to the association of a variety of clinical aspects that stimulate discussion as well as to the role of the modern investigative diagnostic process.

Residual mobility after removal of instrumentation in patient, with type a2-a3 vertebral fractures, treated with percutaneous pedicle screw fixation.

Percutaneous techniques for treatment of thoraco-lumbar fractures type A2 and A3 are widely used. These techniques are considered temporary fixations and instrumentation must be removed with fracture healing. The aim of the study is to analyze clinical results, motility of treated segments and any loss of correction after the removal of instrumentation. We evaluated 36 patients who underwent surgery for removal of the instrumentation. Standard and dynamics x-ray before surgery and at 1 and 12 months after surgery were obtained. Radiographic evaluation was performed by comparing loss of correction after removal of the instrumentation, residual mobility of fractured vertebra, upper and lower level with values defined by Dvorak. For clinical assessment were used SF-12, Oswestry Disability Index (ODI) and Visual Analog Scale (VAS), administered before surgery and at 1 and 12 months after the removal. We analyzed a total of 108 levels in 36 patients. After removal of the instrumentation a normal range of motion was restored in the proximal and distal segment of the fracture, while at level of fractured segment we noticed a decrease in motility. Clinically, patients had a significant decrease in VAS and ODI at 1 month after removal. Our study shows that percutaneous fixation for treatment of thoraco-lumbar fractures type A2 and A3, allows to preserve motility of the treated segments after the removal of the instrumentation until 12 months. The removal of instrumentation is associated with good clinical results without of loss of correction in treated segment.

Severe 5,10-methylenetetrahydrofolate reductase deficiency: a rare, treatable cause of complicated hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Juvenile- or adult-onset forms of severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described. METHODS: Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies. RESULTS: Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 µmol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by MTHFR direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features. CONCLUSIONS: Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders.

Medical management of acute non-specific low back pain: comparison of different medical treatments, one center's retrospective analysis.

Within the developed countries, low back pain and related ailments represent one of the most relevant conditions, affecting both health and socio-economic systems. Non-specific acute low back pain (nsALBP) could represent either an isolated event or the presenting symptom of an underlying condition. Its management is usually medical and radiological investigations should be avoided. However, a general agreement on the best pharmacological treatment is still missing. In the present study, we retrospectively collected patients' data from the institutional database. Two different medical treatments were recognized and groups consequently set. Outcomes were the clinical status, measured using the visual analogue scale (VAS) score for back pain, the use rate of rescue drugs, side effects related to medical treatment, compliance to the treatment, and global satisfaction. The pharma blending of Tramadol 75 mg and Dexketoprofen 25 mg (available blended in a single tablet), resulted effective in the nsALBP management, with less side effects and rescue-drug use along with a higher compliance. Furthermore, patient satisfaction in this treatment group was significatively higher. Many different medical treatments have been investigated and reported in nsALBP management during the last decades. Associations of different drugs are the most common protocols, even though there is no general agreement. Tramadol and Dexketoprofen provide a good clinical result, fewer side effects and a long-lasting and more effective painkiller action, reducing the use of rescue drugs. Moreover, our results suggest that a single tab may provide a higher compliance rate.

Understanding remission in real-world lupus patients across five European countries.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with increased mortality and significant personal, psychological and socioeconomic consequences. An agreed definition of remission is needed and lacking. We sought to visualize 'remission in SLE' in European patients considered by their physicians to be 'in remission' by comparing the reported symptom burden as reported by treating physicians for patients considered to be 'in remission' and those not considered to be 'in remission'. Data for 1227 patients drawn from a multinational, real-world survey of patients with SLE consulting practising rheumatologists and nephrologists in France, Germany, Italy, Spain, and the UK show that physicians classed their patients as 'in remission' despite a considerable ongoing symptom burden and intensive immunosuppressive medication. Patients considered to be 'in remission' still had a mean of 2.68 current symptoms vs 5.48 for those considered to be not 'in remission' (p < 0.0001). The most common symptoms among those seen to be 'in remission' were joint symptoms, fatigue, pain, mucocutaneous involvement, haematological manifestations and kidney abnormalities. The current analysis highlights important ongoing disease activity, symptom burden and immunosuppressive medication in European patients with SLE considered by their treating physician to be 'in remission'. For a further improvement of outcome, there is an urgent need for an international consensus on the definitions for remission among patients with SLE.

Clinical and financial burden of active lupus in Greece: a nationwide study.

Analyses of the medical and economic burden of chronic disorders such as systemic lupus erythematosus (SLE) are valuable for clinical and health policy decisions. We performed a chart-based review of 215 adult SLE patients with active autoantibody-positive disease at the predefined ratio of 30% severe (involvement of major organs requiring treatment) and 70% non-severe, followed at seven hospital centres in Greece. We reviewed 318 patients consecutively registered over three months (sub-study). Disease activity, organ damage, flares and healthcare resource utilization were recorded. Costs were assessed from the third-party payer perspective. Severe SLE patients had chronic active disease more frequently (22.4% vs 4.7%), higher average SLE disease activity index (SLEDAI) (10.5 vs 6.1) and systemic lupus international collaborating clinics (SLICC) damage index (1.1 vs 0.6) than non-severe patients. The mean annual direct medical cost was €3741 for severe vs €1225 for non-severe patients. Severe flares, active renal disease and organ damage were independent cost predictors. In the sub-study, 19% of unselected patients were classified as severe SLE, and 30% of them had chronic active disease. In conclusion, this is the first study to demonstrate the significant clinical and financial burden of Greek SLE patients with active major organ disease. Among them, 30% display chronic activity, in spite of standard care, which represents a significant unmet medical need.

The cost of care of systemic lupus erythematosus (SLE) in the UK: annual direct costs for adult SLE patients with active autoantibody-positive disease.

OBJECTIVES: The aim of the Systemic LUpus Erythematosus Cost of Care In Europe (LUCIE) study was to evaluate the annual direct medical costs of managing adults with active autoantibody-positive disease on medication for SLE in secondary care. This paper presents the UK analyses only. METHODS: A cost-of-illness study was conducted from the perspective of the National Health Service. Health resource utilization data were retrieved over a two-year period from four centres in England and unit cost data were taken from published sources. RESULTS: At baseline, 86 patients were included, 38 (44.2%) had severe SLE and 48 (55.8%) had non-severe SLE. The mean (SD) SELENA-SLEDAI score was 7.7 (5.7). The mean (SD) annual direct medical cost of was estimated at £3231 (£2333) per patient and was 2.2 times higher in patients with severe SLE compared with patients with non-severe SLE (p < 0.001). Multivariate model analyses showed that renal disease involvement (p = 0.0016) and severe flares (p = 0.0001) were associated with higher annual direct costs. CONCLUSIONS: Improvement of the overall stability of SLE and early intervention to minimize the impact of renal disease may be two approaches to mitigate the long-term direct cost of managing SLE patients in the UK.

Effects of genetic type, stage of lactation, and ripening time on Caciocavallo cheese proteolysis.

The objective of this experiment was to evaluate the effects of genetic type, stage of lactation, and ripening time on proteolysis in Caciocavallo cheese. One hundred twenty Caciocavallo cheeses made from the milk of 2 breeds, Italian Brown and Italian Holstein and characterized by different stages of lactation were obtained and ripened for 1, 30, 60, 90, and 150d. Cheese proteolysis was investigated by ripening index (ratio of water-soluble N at pH 4.6 to total protein, %) and by the study of degradation of the protein fractions (αS1-, ß-, and para-κ-casein), which was determined by densitometric analysis of isoelectric focusing results. The statistical analysis showed a significant effect of the studied factors. Ripening index was higher in Italian Brown Caciocavallo cheese and in cheeses made with early lactation milk, whereas casein solubilization was greater in the first 2mo of ripening. Isoelectric focusing analysis of cheese samples during ripening showed extensive hydrolysis of caseins. In particular, the protein fraction that underwent major degradation by proteolytic enzymes was αS1-casein, followed by ß-casein, whereas para-κ-casein was less degraded. Italian Brown cheese showed a lower residual quantity of ß- and para-κ-casein, whereas Italian Holstein cheese showed a lower residual quantity of αS1-casein. In addition, significant interactions of both first and second order were found on both ripening index and degradation of protein fractions. This study demonstrated that the analyzed factors influenced proteolysis of Caciocavallo cheese, which forms the basis of new knowledge that could lead to the production of a pasta filata cheese with specific characteristics.

Effect of genetic type and casein haplotype on antioxidant activity of yogurts during storage.

The aim of this work was to investigate the antioxidant activity of yogurt made from the milk of 2 breeds-Italian Brown and Italian Holstein-characterized by different casein haplotypes (αS1-, ß-, and κ-caseins) during storage up to 15 d. The casein haplotype was determined by isoelectric focusing; antioxidant activity of yogurt was measured using 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid). The statistical analysis showed a significant effect of the studied factors. Antioxidant activity increased during storage of both yogurt types, but yogurt produced with Italian Brown milk showed higher antioxidant activity than those produced with Italian Holstein milk. A high scavenging activity was present in yogurts with the allelic combination of BB-A(2)A(2)-BB. The results of this study suggest that the genetic type and the haplotype make a significant contribution in the production of yogurts with high nutraceutical value.

Postural stability and plantar pressure parameters in healthy subjects: variability, correlation analysis and differences under open and closed eye conditions.

Introduction: The "postural control system" acts through biomechanical strategies and functional neuromuscular adaptations to maintain body balance under static and dynamic conditions. Postural stability and body weight distribution can be affected by external sensory inputs, such as different visual stimuli. Little information is available about the influence of visual receptors on stabilometric and plantar pressure parameters. The aim of this study was to analyze variability, correlations, and changes in these parameters under open- (OE) and closed-eye (CE) conditions. Methods: A total of 31 stabilometric and plantar pressure parameters were acquired in 20 young and healthy adults during baropodometric examination performed in bipedal standing under both visual conditions. Variability of parameters was evaluated via the coefficient of variation, correlation analysis via Pearson's R2, and statistical differences via the Wilcoxon test. Results: High intra-subject repeatability was found for all plantar pressure parameters and CoP-speed (CV < 40%) under OE and CE conditions, while CoP-sway area (CoPsa) and length surface function (LSF) showed larger variability (CV > 50%). Mean and peak pressures at midfoot and total foot loads showed the least number of significant correlations with other parameters under both visual conditions, whereas the arch-index and rearfoot loads showed the largest number of significant correlations. The limb side significantly affected most plantar pressure parameters. A trend of larger LSF and lower CoPsa and mean and peak pressures at the right forefoot was found under the CE condition. Discussion: The present study provides a deeper insight into the associations between postural stability and foot load. Interesting postural adaptations, particularly with respect to different visual stimuli, the effect of the dominant side, and the specific role of the midfoot in balance control were highlighted.

Total parathyroidectomy without autotransplantation in the surgical treatment of secondary hyperparathyroidism of chronic kidney disease.

BACKGROUND: Subtotal parathyroidectomy (SP) and total parathyroidectomy (TP) with autotransplantation (TPai) are the most commonly adopted operations for the treatment of secondary hyperparathyroidism (2HPT). TP without autotransplantation had previously been confined to patients with advanced dialytic vintage, not eligible for kidney transplantation. Over the years, the procedure has gained more widespread use, but there is no precise knowledge on the immediate and long-term effects. METHODS: The authors analyzed the immediate and long-term results of TP without autotransplantation, that is after the systematic removal of at least four glands in 20 patients operated for 2HPT, which were compared with results from TPai in an equal number of cases. RESULTS: An improvement of the typical clinical symptoms was found in every patient undergoing surgery, and a significant reduction in intact PTH (iPTH) serum levels was achieved. Immediate normalization of iPTH level was observed in 11/20 TP cases, hypoparathyroidism in 4/20 and persistent HPT in 5/20 cases. One year of follow-up showed a slight increase in hypoparathyroidism, with 1/20 (5%) recurrence of the disease. One-year TPai results showed a similar percentage of euparathyroidism, as well as a higher longterm recurrence rate (4/20, 20%), although values do not reach statistical significance. CONCLUSIONS: TP may still be considered the operation of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation, because of its low recurrence rate (5%). Post-operative aparathyroidism is rare, while hypoparathyroidism and hypocalcemia can be well controled by medical treatment.

Long-term outcomes following "presumed" total parathyroidectomy for secondary hyperparathyroidism of chronic kidney disease.

AIM: The most efficacious surgical treatment for renal hyperparathyroidism is still subject of research. Considering its low incidence rate of long-term relapse, "presumed" total parathyroidectomy without autotrasplantation (TP) may be indicated for secondary hyperparathyroidism (2HPT) in patients with chronic kidney disease (CKD), not eligible for kidney transplantation. The aim of this study was to analyse the TP long-term results in 2HPT haemodialysis (HD) patients. METHOD: Between January 2004 and October 2009, 25 2HPT HD patients, not eligible for kidney transplantation, underwent TP of at least four parathyroid glands. Clinical status and intact parathyroid hormone (iPTH) serum levels were assessed intraoperatively and during a 36-month follow-up. RESULTS: TP improved the typical clinical symptoms and a significant reduction of iPTH serum levels was achieved in each patient. Aparathyroidism was never observed; in case of severe postoperative hypocalcemia, hypocalcemic seizures were never reported and the long-term recurrence rate was 8%. Only one patient received a kidney transplantation. Postoperative cardiovascular events (hypertension, peripheral artery disease, arrhythmia, coronary or cerebrovascular disease) were observed in 32% of cases and mortality rate was 16%. CONCLUSIONS: Considering its low long-term relapse rate and the absence of postoperative aparathyroidism, TP may still be considered the treatment of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation. In case of postoperative hypoparathyroidism, hypocalcaemia can be effectively managed by medical treatment.

Decrease of activity of antioxidant enzymes, lysozyme content, and protein degradation in milk contaminated with heavy metals (cadmium and lead).

The aim of this study was to evaluate the effect of added Cd and Pb to milk on its stability by determining antioxidant enzymatic activities, lysozyme content, and protein degradation. Antioxidant enzymatic activities were spectrophotometrically determined by superoxide dismutase, catalase, xanthine oxidase, and glutathione peroxidase assays; lysozyme was identified and quantified by HPLC-UV analysis, and protein degradation was investigated by spectrophotometric analysis of advanced oxidation protein products (AOPP) and dityrosine content. In this study, contaminated milk samples showed a significant reduction in activity of all studied enzymes compared with control milk. The contamination of milk also led to a significant reduction in the lysozyme content; lysozyme content was decreased about 22% and 18% in Pb milk and Cd milk, respectively, compared with control milk. The presence of the contaminants in the milk resulted in a significant increase of both dityrosine concentration and AOPP compared with the control milk. Moreover, between types of contaminated milk, dityrosine and AOPP values were significantly higher in the Pb milk than in the Cd milk. Therefore, it is important to monitor the presence of these toxic elements in milk for the damage they cause to consumer health both directly due to their ingestion and indirectly due to loss of milk stability.

Megaprosthesis in articular fractures of the lower limbs in fragile patients: a proposal for the therapeutic algorithm.

OBJECTIVE: The use of megaprosthetic implants could provide substantial advantages in elderly population affected by complex fractures. The aim of the study was to identify the patients suitable to megaprosthetic implants in the treatment of lower limbs fractures, as well as periprosthetic fractures. PATIENTS AND METHODS: From January 1st, 2015, to December 31st, 2021, all patients affected by femoral fractures with severe bone loss or previous surgery failure were retrospectively reviewed. ADL, IADL, SF-12 values pre- and post-operative were recorded. Hemoglobin value, NLR, PLR were recorded pre- and peri-operatively for all patients. Complications were recorded. All patients underwent a radiological follow-up. Significance was set at p ≤ 0.05. RESULTS: 23 patients were considered eligible, 10 males and 13 females; the mean age was 72.87 years old (± 12.33), while the mean BMI was 27.2 points (± 5.2). The mean follow-up was 2 years (± 1.4). The mean preoperative ADL and IADL scores were correlated with a positive independence of the patient, while the mean postoperative scores corresponded to a moderate-low independence. Also the mean Mental and Physical SF12 scores saw a decrease in values. NLR values were higher in the first group of patients with complications. CONCLUSIONS: A careful multiparametric and multidisciplinary patient selection is required to identify the suitable patient to this treatment.

Correlation between Neutrophil-to-lymphocyte ratio and Euthyroid Sick Syndrome in elderly patients with proximal femur fractures.

OBJECTIVE: Proximal femur fractures are among the most common type of trauma in elderly patients, and Euthyroid sick syndrome has already been related to fractures and trauma. The evidence of a consistent inflammatory state occurring during hip fracture, made us consider as a potential marker also the neutrophil-to-lymphocyte ratio (NLR), which is already in use to measure the prognosis and guide the therapeutic management in various conditions. PATIENTS AND METHODS: A retrospective observational analysis on patients affected by proximal femur fractures was conducted. Patients were divided between affected and non-affected by Euthyroid Sick Syndrome (ESS). Standard follow up was conducted at 1, 3, 6 and 12 months. RESULTS: 79 patients were enrolled in this study. There were 19 males and 60 females, the mean age was 83.8 ± 6.5 y.o., and 44 patients were affected by ESS. Affected patients showed higher NLR values (10.2 ± 9.4 vs. 6.9 ± 3.9; p= 0.001) and higher decrease in fT3 values in the 1st post-operative day (1.8 ± 0.4 vs. 2.2 ± 0.3; p= 0.001), higher values of PTH (97.9 ± 46.2 vs. 70.1 ± 36.2; p=0.004) and lower levels of Vitamin D (18.8 ± 7.8 vs. 23.5 ± 12.9; p= 0.04). As regards complications, we found them in 27% of patients in group A, while only in 8% in Group B, with a statistically significant difference (p= 0.03). CONCLUSIONS: ESS and NLR are promising prognostic markers in PFF in the elderly patients. If used together, they could help in the pre- and post-operative management of the patients.