Medical management of osteoarthritis during the CO-VID-19 pandemic: a challenge for the present and the future.

Abstract: The ongoing Covid-19 pandemic has inevitably changed the treatment of many chronic diseases which has been suspended or has suffered dangerous slowdowns. Osteoarthritis (OA) is the most common musculoskeletal disease. As a result, the medical management of Osteoarthritis was heavily impacted by the pandemic, and it required new therapeutic strategies. The purpose of this descriptive review is to provide an overview of how much the pandemic has affected the medical management of osteoarthritis and to outline a number of possible countermeasures. The COVID-19 pandemic requires a "multimodal approach": physicians are called to test the management of Osteoarthritis patients at a distance, through the tools made available by telemedicine, for all cases in which direct contact is avoidable. Therapies that instead require a direct intervention on the patient impose that all the procedures are carried out in complete safety, scrupulously keeping to the use of personal protective equipements.

[Determinants of time required by medical information technicians for quality control of hospital activity coding, in French medico-administrative system]. / Déterminants du temps nécessaire au contrôle qualité dans le cadre du programme de médicalisation des systèmes d'information (PMSI), dans le champ médecine, chirurgie et obstétrique (MCO) d'un centre hospitalier régional, par les techniciens d'information médicale.

BACKGROUND: Since 2008, in France, hospital funding is determined by the nature of activities provided (activity-based funding). Quality control of hospital activity coding is essential to optimize hospital remuneration. There is a need for reliable tools to allocate human resources wisely in order to improve these controls. METHODS: The main objective of this study was to identify the determinants of time needed by medical information technicians to control hospital activity coding in a Regional Hospital Center. From March 2016 to the beginning of January 2017, medical information technicians reported the time they spent on each quality control, and the time they needed when they had to code the entire stay. Multiple linear regressions were performed to identify the determinants of quality control or coding duration. A split sample validation was used: model was created on one half of the sample and validated on the remaining half. RESULTS: Among the controls, 5431 were included in the analysis of determinants of control duration (2715 kept aside for model validation). Seven determinants have been identified (stay duration, level of complexity, month of control, type of control, medical information technician, rank of classing information, and major diagnostic category). The correlation coefficient between predicted and real control duration was 0.71 (P<10-4); 808 stays were included in the analysis of determinants of coding duration (404 kept aside for model validation). Two determinants have been identified. The correlation coefficient, between predicted and real coding duration, was 0.47 (P<10-3). We performed the same multiple regression, on 2017 activity data, to estimate the weight of each hospital activity pole, regarding quality control of hospital activity coding. CONCLUSION: We succeeded in modeling time needed for quality control of hospital stays. These results helped to estimate human resources required for quality control of each hospital pole. Nevertheless, the second analysis did not give satisfactory results: we failed in modeling time needed to code hospital stays.

Migraine with aura white matter lesions: preliminary data on clinical aspects.

A few clinic-based magnetic resonance imaging studies report an increased risk of signal abnormalities in migraineurs brain's white matter, especially in migraine with aura subjects. A vascular genesis has been hypnotized and migraine with aura was considered an independent risk factor for stroke. Available data of magnetic resonance imaging alterations are often nonspecific and sometimes controversial. The aim of our study is to investigate migraine with aura patients with standardized brain magnetic resonance imaging to detect and to quantify the presence of white matter lesions and to analyze their relation with clinical data. We report preliminary data about first 90 subjects. We did not recognize any clinical aspect in close relationship with these alterations. The only clinical feature that seems to play a role in the presence of alterations is the age, and only in migraineurs women.

Pathogenesis of chronic cluster headache and bouts: role of tryptamine, arginine metabolism and α1-agonists.

The aim of this study was to explore the possible role of tryptamine in the pathogenesis of chronic cluster headache along with that of adrenaline and noradrenaline (α-agonists) together with arginine metabolism in the origin of cluster bouts. Plasma levels of tyramine, tryptamine, serotonin, 5-hydroxyindolacetic acid, noradrenalin, adrenalin and the markers of arginine metabolism such as arginine, homoarginine, citrulline, ADMA and NMMA, were measured in 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster) and 28 control subjects. The plasma levels of tyramine, tryptamine, noradrenalin and adrenalin were found several times higher in chronic cluster headache patients compared to controls, whereas the plasma levels of arginine, homoarginine and citrulline were significantly lower. No differences were found in the plasma levels of serotonin, 5-hydroxyindolacetic, ADMA and NMMA between chronic cluster headache patients and control subjects. These results provide support for a role of tryptamine in the pathogenesis of chronic cluster headache and, in particular, in the duration of the cluster bouts. In addition, the low levels of the nitric oxide substrates together with the high levels of noradrenalin and adrenalin suggest an activation of endothelial TAAR1 receptors followed by the release of nitric oxide in the circulation that may constitute the final step of the physiopathology of cluster crisis.

Difficulties in work activities and the pervasive effect over disability in patients with episodic and chronic migraine.

Migraine is associated with reduced productivity in work-related activities. The degree to which problems with work are, in turn, associated to the level of migraine-related disability as well as to headache frequency has been poorly explored. The aim of the study was to assess if migraine patients with different degrees of work difficulties showed a different level of migraine-related disability. A consecutive sample of patients with episodic migraine (EM) or with chronic migraine (CM) with medication overuse (MO) attending the Headache Centre of the Neurological Institute C. Besta of Milan was studied. All patients completed the MIDAS and the WHODAS 2.0 questionnaires. The total scores of both questionnaires, frequency of headaches, average pain intensity, and the scores of each subscale of the WHODAS 2.0 were calculated separately for EM and CM patients. The score of WHODAS 2.0 "Work difficulties" subscale was used to divide the studied patients into two groups, i.e. those above and those below the median "Work difficulties" subscale score. Independent sample t test was used to compare these two groups as far as all the other studied variables. A total of 296 patients (102 with EM and 194 with CM-MO) were enrolled. Patients with higher work difficulties score also displayed higher scores in the other WHODAS 2.0 subscales; for those with CM-MO, the differences were significant. The results of this study indicate that having more and more severe workplace problems is associated to a higher disability level in migraineurs. Further studies are needed to better understand workplace disability in different migraine forms, particularly in a qualitative way.

Electromyography data in chronic migraine patients by using neurostimulation with the Cefaly® device.

The objective of this observational study is to report clinical and instrumental results obtained in 23 chronic migraine sufferers treated with transcutaneous neurostimulation with the Cefaly(®) device. The electrom yography (EMG) parameters of the patients monitored before and during neurostimulation with the Cefaly(®) device showed a significant increase in the EMG amplitude and frequency values in the frontalis, anterior temporalis, auricularis posterior and middle trapezius muscles. The Cefaly(®) device could act on the inhibitory circuit in the spinal cord thus causing a neuromuscular facilitation and may help reduce contraction of frontalis muscles.

Study of parafunctions in patients with chronic migraine.

The purpose of this paper is to present the results of a questionnaire investigating parafunctions (particularly clenching and grinding) in patients with chronic migraine presenting sign of temporomandibular disorder. The questionnaire was elaborated by the Dental Clinic of the University of Milano and completed by 125 patients experiencing chronic migraine and attending the Neurological Institute Carlo Besta for an inpatient withdrawal protocol to treat medication overuse. Our results showed high percentages of parafunctions, which were present in 80 % of patients. We note that patient information on possible behaviours and coexisting conditions which may be involved in the mechanisms of chronic headaches, as well as education about these factors, are crucial aspects in the management of chronic headache patients. We suggest that patients suffering from chronic migraine with medication overuse headache should be evaluated in relation to the possible presence of parafunctions, and as far as the need for interocclusal devices, in order to limit the role of temporomandibular dysfunctions as trigger factors or coexisting conditions favouring the development/maintaining of headache chronification.

Occipital neurostimulation in primary headaches: update.

A subset of headache patients are chronic and results refractory to standard medical treatments, they are unsatisfied or unable to tolerate the side effects of medications. In the lack of more effective prophylactic treatment, there is need of alternative approach. Migraine is conceptualized as a chronic and potentially progressive disorder. It is conceivable that more aggressive therapeutic efforts could be warranted in drug-refractory chronic migraine. In this prospective, the new, device-based therapies that allow to affect brain function in less invasive ways may represent a therapeutic opportunity. Peripheral occipital neurostimulation resulted in several trials and case reports to be beneficial in a large variety of headache and craniofacial pain disorders, with chronic primary headache the most studied. We comment on our experience in the application of ONS in drug-refractory chronic cluster headache and chronic migraine patients.

A 14-month study of change in disability and mood state in patients with chronic migraine associated to medication overuse.

This paper aims to evaluate changes in disease severity, disability and mood state in patients with chronic migraine associated to medication overuse (CM-MO). MIDAS was used for assessing disease activity, WHO-DAS-2 for disability, DBI-2 for mood state. ANOVA was used to test change over time; t-test to assess follow-up differences in WHO-DAS-2 and BDI-2 between patients with MIDAS ≤20 and ≥21. Change in MIDAS, WHO-DAS-2 and BDI-2 scores were computed: Pearson's index was used to assess correlation between them; linear regression to assess change in WHO-DAS-2, using MIDAS and BDI-2 change as predictors. Mean MIDAS decreased significantly (from 101.9 to 52.0). In 26.1 % of the sample, MIDAS fell below 21 at follow-up: these patients had lower WHO-DAS-2 score. WHO-DAS-2 change was little correlated to MIDAS change and strongly correlated to changes in BDI-2 scores. 57.1 % of WHO-DAS-2 change variance is explained by change in BDI-2 and MIDAS scores. There was a clear clinical improvement 14 months after detoxification, and a modest reduction in disability which is explained by reduced disease activity and improved mood state. An appropriate treatment of CM-MO, based on detoxification and prophylaxis, is likely to reduce disease burden: recognition and treatment of mood problems may be a key factor to reduce disability.

Positive outcome of occlusal freeway space reestablishment in patients with medication overuse due to chronic migraine.

Considering the great chapter of migraines, it is important to note the signs and symptoms caused by an alteration of the relationship of the facial musculature and the occlusal freeway space (FWS) that is the distance from maximal intercuspation to the habitual rest position (measurable in 1.4-2.5 mm). To any mandible position changing (detected by periodontal, muscle and joint proprioceptors), there is an influence on the neuromuscular system and then an alteration of the FWS. A group of 60 patients with chronic migraine (CM) underwent a withdrawal of overused medication and were subjected to electromyographic and kinesiographic evaluation. All those who presented an alteration of the FWS at rest position have been subjected to treatment with orthosis device for about 12 months. The aim of our work is to obtain and define a correct mandibular position, physiological, in agreement with the neuromuscular structures of the patient. Clinical results obtained on this pool of patients, in terms of reduction of the VAS, let us understand the importance of the inviolability of the FWS and to eliminate any type of mandibular deviation with respect to the closure trajectory induced by TENS in patients suffering from CM.

Machine learning to predict overall short-term mortality in cutaneous melanoma.

BACKGROUND: Cutaneous malignant melanoma (CMM) ranks among the ten most frequent malignancies, clinicopathological staging being of key importance to predict prognosis. Artificial intelligence (AI) has been recently applied to develop prognostically reliable staging systems for CMM. This study aims to provide a useful machine learning based tool to predict the overall CMM short-term survival. METHODS: CMM records as collected at the Veneto Cancer Registry (RTV) and at the Veneto regional health service were considered. A univariate Cox regression validated the strength and direction of each independent variable with overall mortality. A range of machine learning models (Logistic Regression classifier, Support-Vector Machine, Random Forest, Gradient Boosting, and k-Nearest Neighbors) and a Deep Neural Network were then trained to predict the 3-years mortality probability. Five-fold cross-validation and Grid Search were performed to test the best data preprocessing procedures, features selection, and to optimize models hyperparameters. A final evaluation was carried out on a separate test set in terms of balanced accuracy, precision, recall and F1 score. The best model was deployed as online tool. RESULTS: The univariate analysis confirmed the significant prognostic value of TNM staging. Adjunctive clinicopathological variables not included in the AJCC 8th melanoma staging system, i.e., sex, tumor site, histotype, growth phase, and age, were significantly linked to overall survival. Among the models, the Neural Network and the Random Forest models featured the best prognostic performance, achieving a balanced accuracy of 91% and 88%, respectively. According to the Gini importance score, age, T and M stages, mitotic count, and ulceration appeared to be the variables with the greatest impact on survival prediction. CONCLUSIONS: Using data from patients with CMM, we developed an AI algorithm with high staging reliability, on top of which a web tool was implemented ( unipd.link/melanomaprediction ). Being essentially based on routinely recorded clinicopathological variables, it can already be implemented with minimal effort and further tested in the current clinical practice, an essential phase for validating the model's accuracy beyond the original research context.

A workflow for the development of template-assisted membrane crystallization downstream processing for monoclonal antibody purification.

Monoclonal antibodies (mAbs) are commonly used biologic drugs for the treatment of diseases such as rheumatoid arthritis, multiple sclerosis, COVID-19 and various cancers. They are produced in Chinese hamster ovary cell lines and are purified via a number of complex and expensive chromatography-based steps, operated in batch mode, that rely heavily on protein A resin. The major drawback of conventional procedures is the high cost of the adsorption media and the extensive use of chemicals for the regeneration of the chromatographic columns, with an environmental cost. We have shown that conventional protein A chromatography can be replaced with a single crystallization step and gram-scale production can be achieved in continuous flow using the template-assisted membrane crystallization process. The templates are embedded in a membrane (e.g., porous polyvinylidene fluoride with a layer of polymerized polyvinyl alcohol) and serve as nucleants for crystallization. mAbs are flexible proteins that are difficult to crystallize, so it can be challenging to determine the optimal conditions for crystallization. The objective of this protocol is to establish a systematic and flexible approach for the design of a robust, economic and sustainable mAb purification platform to replace at least the protein A affinity stage in traditional chromatography-based purification platforms. The procedure provides details on how to establish the optimal parameters for separation (crystallization conditions, choice of templates, choice of membrane) and advice on analytical and characterization methods.

Treatment of upper limb spasticity after stroke: one-year safety and efficacy of botulinum toxin type A NT201.

A new preparation of botulinum toxin type A called NT 201, free from complexing proteins, potentially with low antigenicity has been used in the therapy of spasticity in stroke patients. This was an open-label study reported the safety and the efficacy of one-year treatment with NT 201 evaluating the therapeutic effect on functional disability and on quality of life in upper limb spasticity after stroke. Patients received a botulinum toxin therapy in the upper injected intramuscularly. After inoculation, patients were submitted to a motor rehabilitation program for upper limb injected three times/week. Re-treatment was permitted at 12 weeks after the prior treatment. Safety assessment included evaluation of adverse events and efficacy was measured by Modified Ashworth Scale for spasticity (MAS), Spasm Frequency Score (SFS) for the daily spasms, and Disability Assessment Scale (DAS) for disability. Of 35 consecutive patients (13 women and 12 men) screened for study eligibility, 20 (6 women and 14 men) patients (mean age 63,4±7,03) were included in this study and were submitted to NT 201 therapy for one year. At the baseline, botulinum toxin dose in the upper limb ranged from 160 to 450U, whereas total dose in the last treatment administrated was reduced respect the first injections ranging from 120 to 350U. All the enrolled patients completed the year-long study and reported an improvement of clinical picture. MAS, was statistically (px003C;0,001) reduced in all muscles at T1 (mean score ±SD: 2.65±0.67) and T2 (mean score±SD: 2.55±0.60) in comparison to the baseline T0 (mean score±SD: 3.9 ±0.78). Significant reduction (px003C;0,001) from baseline T0 (mean score ±SD: 3.25±0.78) was also noted in SFS at T1 (mean score ±SD: 1.55±0.51) and T2 (mean score±SD :1.30±0.47). The DAS score showed a reduction of the T1score (mean score ±SD: 1.70±0.47) and T2 score (mean score ±SD: 1,40 ±0,50) respect to baseline T0 score (mean score ±SD: 2,65 ±0,48) statistically significant (p≤003C;0,001). No adverse effects were observed in these patients. NT 201 appeared to be an efficacious and well-tolerated long-term treatment option for patients with upper limb spasticity after stroke, obtaining a substantial improvement in functional disability, muscle hypertone, and daily spasms.

Combined antimuscarinics for treatment of neurogenic overactive bladder.

Antimuscarinic drugs are the first line pharmacotherapy for overactive bladder, but they are not always effective to achieve complete continence. Nevertheless in some patients urodynamic investigations reveal insufficient effects with continuing incontinence events even with dose optimization. The aim of this study is to evaluate the effect of association of Oxybutynin chloride, Trospium chloride and Solifenacin succinate administered orally for a minimum of 12 weeks in subjects with suprasacral spinal cord injury with urge-incontinence, urodynamic–proven neurogenic detrusor overactivity dysfunction and detrusor-external sphincter dyssynergia to improve level of continence, reduce the risks of urologic complications and enhance QOL. This study was a randomized, double blind, controlled, balanced-parallel-groups investigation of orally administed Oxybutynin in addition to Trospium chloride in the first group and Oxybutynin in addition to Solifenacin in the other group. A total of 12 patients with neurogenic detrusor overactivity and clean intermittent catheterization were allocated into two treatment groups: 5 mg tablet of Oxibutinin and 20 mg tablet of Trospium Chloride were administered respectively 3 times a day and 4 times a day in the first group (Group A). 5 mg tablet of Oxibutinin and 10 mg tablet of Solifenacin were administered respective 3 times a day and once daily in the second group (Group B). In both group of patients we found a significant decrease in incontinence episodes, with an improvement of bladder compliance, bladder capacity and volume voided. Side effects were higher in patients of group B, but in generally well tolerated. In conclusion, a combined antimuscarinic treatment might be a right option for patients affected by neurogenic bladder refractory to previous antimuscarinic monotherapy, and might slow down or delay other more invasive treatments.

Associated with intrathecal baclofen treatment and duloxetine in patients with multiple sclerosis.

Baclofen is now used in treatment of patients with severe spasticity secondary to neurological diseases through the direct infusion of the drug into the subarachnoid space with an implanted programmable pump. Among patients whose quality of life improved after the use of intrathecal systems, a very important role belongs to people with multiple sclerosis (MS): a disease that due to a great variety of symptoms and signs, seriously affects the activities of daily living. Among the clinical manifestations of MS are also found mental health problems including depression mood. The drugs most commonly offered, for treatment of depression in patients with MS, are selective serotonin reuptake inhibitors (SSRIs), reuptake inhibitors of serotonin and norepinephrine (SNRIs) and tricyclic antidepressants (TCA). Duloxetine presents a high affinity for transporters reuptake of serotonin and noradrenalin, and exerts its activity on both molecules. In addiction, Duloxetine has demonstrated very effective in treatment of depressive disorders of mood as demonstrated by scientific evidences about the utility of Duloxetine in the modulation of painful physical symptoms associated with depression and in treatment of pain associated with diabetic neuropathy. The purpose of our study is to evaluate the effects of antidepressant therapy with duloxetine, 60 mg/day in 7 patients with multiple sclerosis treated with intrathecal baclofen for spastic modulation of tone. The experience we gained, according to data from several multicenter trials confirmed the efficacy of Baclofen intrathecally administered, especially with regards to modulation of spasticity. Our study also showed, although the limitations of a small sample size still, a good clinical response to combined treatment Baclofen intrathecal/duloxetine 60 mg/day.

Evaluation of Selected Quality Parameters of "Agristigna" Monovarietal Extra Virgin Olive Oil and Its Apple Vinegar-Based Dressing during Storage.

This study aimed to investigate the quality parameters and the oxidative stability (180 days of storage) of a water-oil emulsion formulated with Calabrian (Italy) monovarietal Agristigna extra virgin olive oil and apple vinegar. The best extra virgin olive oil/apple vinegar ratio was found to be 85/15 (v/v) and lecithin (2% w/v) was the best additive to reach proper stability and viscosity over time. An increase of lightness parameters was evidenced in both products in a storage time-dependent manner. During storage, both oil and dressing showed a free acidity level beyond the accepted limit for extra virgin olive oil, whereas a slight increase of the peroxide value was observed only for Glasoil at the end of the observation time without affecting sensory attributes. A general decrease of phytochemicals was observed for extra virgin olive oil and Glasoil, with different reduction trends and degrees depending on the chemical class. A lower stability of Glasoil during shelf-life was confirmed by the worsening of the rheological features and by the polyunsaturated fatty acids reduction (up to -21.71%) with a corresponding increase of the monounsaturated fatty acids/polyunsaturated fatty acids ratio (about +25.69%).

CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.

Multivariate Metal-Organic Framework/Single-Walled Carbon Nanotube Buckypaper for Selective Lead Decontamination.

The search for efficient technologies empowering the selective capture of environmentally harmful heavy metals from wastewater treatment plants, at affordable prices, attracts wide interest but constitutes an important technological challenge. We report here an eco-friendly single-walled carbon nanotube buckypaper (SWCNT-BP) enriched with a multivariate amino acid-based metal-organic framework (MTV-MOF) for the efficient and selective removal of Pb2+ in multicomponent water systems. Pristine MTV-MOF was easily immobilized within the porous network of entangled SWCNTs, thus obtaining a stable self-standing adsorbing membrane filter (MTV-MOF/SWCNT-BP). SWCNT-BP alone shows a moderately good removal performance with a maximum adsorption capacity of 180 mg·g-1 and a considerable selectivity for Pb(II) ions in highly concentrated multi-ion solutions over a wide range of lead concentration (from 200 to 10000 ppb). Remarkably, these features were outperformed with the hybrid membrane filter MTV-MOF/SWCNT-BP, exhibiting enhanced selectivity and adsorption capacity (310 mg·g-1, which is up to 42% higher than that of the neat SWCNT-BP) and consequently enabling a more efficient and selective removal of Pb2+ from aqueous media. MTV-MOF/SWCNT-BP was able to reduce [Pb2+] from the dangerous 1000 ppb level to acceptable limits for drinking water, below 10 ppb, as established by the current EPA and WHO limits. Thus, the eco-friendly composite MTV-MOF/SWCNT-BP shows the potential to be effectively used several times as a reliable adsorbent for Pb2+ removal for household drinking water or in industrial treatment plants for water and wastewater lead decontamination.