Apoptotic bodies encapsulating Ti2N nanosheets for synergistic chemo-photothermal therapy.

Extracellular vesicles (EVs) have great potential in oncology drug delivery because of their unique biological origin. Apoptotic bodies (ABs), as a member of the EV family, offer distinct advantages in terms of size, availability and membrane properties, but have been neglected for a long time. Here, using ABs and Ti2N nanosheets, we propose a novel drug delivery system (Ti2N-DOX@ABs), which exhibit a homologous targeting ability for dual-strategy tumor therapy with intrinsic biological property. The experimental results demonstrate that such a drug delivery system possesses a drug loading capacity of 496.5% and a near-infrared photothermal conversion efficiency of 38.4%. In addition, the investigation of drug internalization process proved that Ti2N-DOX@ABs featured a supreme biocompatibility. Finally, the dual-strategy response based on photothermal and chemotherapeutic effects was studied under near-infrared laser radiation. This work explores the opportunity of apoptosome membranes in nanomedicine systems, which provides a technical reference for cancer-oriented precision medicine research.

Conjugate of Natural Bacteriochlorin with Doxorubicin for Combined Photodynamic and Chemotherapy.

Chemotherapy is among the main classical approaches to the treatment of oncologic diseases. Its efficiency has been comprehensively proven by clinical examinations; however, the low selectivity of chemotherapeutic agents limits the possibilities of this method, making it necessary to search for new approaches to the therapy of oncologic diseases. Photodynamic therapy is the least invasive method and a very efficient alternative for the treatment of malignant tumors; however, its efficiency depends on the depth of light penetration into the tissue and on the degree of oxygenation of the treatment zone. In this work, a hitherto unknown conjugate of a natural bacteriochlorin derivative and doxorubicin was obtained. In vitro and in vivo studies showed a more pronounced activity of the conjugate against MCF-7 and 4T1 cells and its higher tumorotropicity in animal tumor-bearing animals compared to free anthracycline antibiotic. The suggested conjugate implements the advantages of photodynamic therapy and chemotherapy and has great potential in cancer treatment.

Polytherapy versus monotherapy in the treatment of tibial non-unions: a retrospective study.

BACKGROUND: Treating tibial non-unions efficiently presents a challenge for orthopaedic trauma surgeons. The established gold standard involves implanting autologous bone graft with adequate fixation, but the addition of biologicals according to the so-called diamond concept has become increasingly popular in the treatment of non-unions. Previous studies have indicated that polytherapy, which involves implanting mesenchymal stem cells, bioactive factors and osteoconductive scaffolds, can improve bone healing. This study aims to evaluate the efficacy of polytherapy compared with monotherapy in treating tibial non-unions of varying severity. MATERIALS AND METHODS: Data from consecutive tibial non-unions treated between November 2014 and July 2023 were retrospectively analysed. The Non Union Scoring System (NUSS) score before non-union surgery, and the Radiographic Union Score for Tibial fractures (RUST), scored at 1, 3, 6, 9, 12 and 18 months post-surgery, were recorded. Initially, a comparison was made between the polytherapy and monotherapy groups. Subsequently, patients receiving additional surgical non-union treatment were documented, and the frequency of these treatments was tallied for a subsequent per-treatment analysis. RESULTS: A total of 34 patients were included and divided into a polytherapy group (n = 15) and a monotherapy group (n = 19). The polytherapy group demonstrated a higher NUSS score (44 (39, 52) versus 32 (29, 43), P = 0.019, z = -2.347) and a tendency towards a higher success rate (93% versus 68%, P = 0.104) compared with the monotherapy group. For the per-treatment analysis, 44 treatments were divided into the polytherapy per-treatment group (n = 20) and the monotherapy per-treatment group (n = 24). The polytherapy per-treatment group exhibited a higher NUSS score (48 (43, 60) versus 38 (30, 50), P = 0.030, z = -2.173) and a higher success rate (95% versus 58%, P = 0.006) than the monotherapy per-treatment group. Within the monotherapy per-treatment group, the NUSS score displayed excellent predictive performance (AUC = 0.9143). Setting the threshold value at 48, the sensitivity and specificity were 100.0% and 70.0%, respectively. CONCLUSIONS: Polytherapy is more effective than monotherapy for severe tibial non-unions, offering a higher success ratio. The NUSS score supports decision-making in treating tibial non-unions. LEVEL OF EVIDENCE: Level III.

Patterns of antiseizure medication utilization in the Human Epilepsy Project.

OBJECTIVE: This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy. METHODS: The data were derived from the Human Epilepsy Project. Differences between the durations of the most commonly first prescribed ASM monotherapies were assessed using a Cox proportional hazards model. Subjects were classified into three groups: monotherapy, sequential monotherapy, and polytherapy. RESULTS: A total of 443 patients were included in the analysis, with a median age of 32 years (interquartile range [IQR] = 20-44) and median follow-up time of 3.2 years (IQR = 2.4-4.2); 161 (36.3%) patients remained on monotherapy with their initially prescribed ASM at the time of their last follow-up. The mean (SEM) and median (IQR) duration that patients stayed on monotherapy with their initial ASM was 2.1 (2.0-2.2) and 1.9 (.3-3.5) years, respectively. The most commonly prescribed initial ASM was levetiracetam (254, 57.3%), followed by lamotrigine (77, 17.4%), oxcarbazepine (38, 8.6%), and carbamazepine (24, 5.4%). Among those who did not remain on the initial monotherapy, 167 (59.2%) transitioned to another ASM as monotherapy (sequential monotherapy) and 115 (40.8%) ended up on polytherapy. Patients remained significantly longer on lamotrigine (mean = 2.8 years, median = 3.1 years) compared to levetiracetam (mean = 2.0 years, median = 1.5 years) as a first prescribed medication (hazard ratio = 1.5, 95% confidence interval = 1.0-2.2). As the study progressed, the proportion of patients on lamotrigine, carbamazepine, and oxcarbazepine as well as other sodium channel agents increased from a little more than one third (154, 34.8%) of patients to more than two thirds (303, 68.4%) of patients. SIGNIFICANCE: Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.

Combination of Targeted Therapies for Colorectal Cancer Treatment.

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (Bev), and a ß-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (MMAE), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of FOLFOX and Bev currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between Bev and MMAE selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody-drug conjugates employ MMAE as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with Bev, particularly for the therapy of colorectal cancer.

Opinion paper on the systematic application of integrated bioinformatic tools to actuate routine precision medicine in poly-treated patients.

Precision Medicine is a reality in selected medical areas, as oncology, or in excellent healthcare structures, but it is still far to reach million patients who could benefit from this medical concept. Here, we sought to highlight how the time is ripe to achieve horizontal delivery to a significant larger audience of patients, represented by the poly-treated patients. Combination therapies are frequent (especially in the elderly, to treat comorbidities) and are related to decreased drug safety and efficacy, disease's exacerbation, additional treatments, hospitalization. But the recent development and validation of bioinformatic tools, aimed to automatic evaluation and optimization of poly-therapies, according to the unique individual characteristics (including genotype), is ready to change the daily approach to pharmacological prescription.

Fifty years of research on status epilepticus: Seizures use hippocampal memory circuits to generate status epilepticus and disrupt brain development.

This is a review of my laboratory's interest in status epilepticus (SE), which spanned five decades. It started with a study of the role of brain mRNAs in memory, and with the use of electroconvulsive seizures to disrupt recently acquired memories. This led to biochemical studies of brain metabolism during seizures, and to the serendipitous development of the first model of self-sustaining SE. The profound inhibition of brain protein synthesis by seizures had implications for brain development, and we showed that severe seizures and SE in the absence of hypoxemia and other metabolic complications can disrupt brain and behavioral development, a concept that was not widely accepted at that time. We also showed that many experimental models of SE can cause neuronal death in the immature brain, even at very young ages. Our studies of self-sustaining SE showed that the transition from single seizures to SE is accompanied by internalization and transient inactivation of synaptic GABAA receptors, while extrasynaptic GABAA receptors are untouched. At the same time, NMDA and AMPA receptors move to the synaptic membrane, creating a "perfect storm" combining failure of inhibition and runaway excitation. Major maladaptive changes in protein kinases and neuropeptides, particularly galanin and tachykinins, also contribute to the maintenance of SE. The therapeutic implications of these results are that our current practice to start the treatment of SE with benzodiazepine monotherapy leaves the changes in glutamate receptors untreated and that sequential use of drugs gives seizures more time to aggravate changes in receptor trafficking. In experimental SE, we showed that drug combinations based on the receptor trafficking hypothesis are far superior to monotherapy in stopping SE late in its course. Combinations that include an NMDA receptor blocker such as ketamine are much better than combinations that follow current evidence-based guidelines, and simultaneous delivery of the drugs is far more effective than sequential delivery of the same drugs at the same dose. This paper was presented as a Keynote Lecture at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Antipsychotic prescribing practices for outpatients with schizophrenia and reasons for non-clozapine treatment - Data from a Danish quality assessment audit.

BACKGROUND: Clozapine is the gold standard for treating treatment-resistant schizophrenia (TRS) although widely underutilised. Both organisational, patient- and clinician related reasons for the underutilisation have been reported, however, the clinical impact of either in real-world settings is not fully elucidated. AIM: This audit aimed to evaluate the local antipsychotic (AP) prescribing practices for outpatients with schizophrenia and to assess the spectrum and prevalence of journalised reasons for non-clozapine treatment amongst eligible outpatients. METHODS: Data on demographics, current and former AP treatments, as well as documented reasons for non-clozapine treatment, was extracted through chart audit. RESULTS: Of the 668 affiliated outpatients with schizophrenia, 43% were treated with AP polytherapy (APP) and 19.6% with clozapine. The most prevalent reason for clozapine discontinuation was related to side effects whereas the most prevalent reason for refusal or omission of clozapine treatment was related to the associated monitoring regimen. CONCLUSIONS: This audit showed that APP prescribing is a highly prevalent practice in our services when treating outpatients with schizophrenia and that clozapine is underutilised in a 'last resort' manner. The blood-monitoring regimen associated with clozapine treatment was found to be an important factor in the underutilisation. It seemed, however, that the monitoring constituted a barrier for different reasons, requiring different approaches to remedy. Future studies, directly involving both patients and clinicians in the identification and management of the most clinically relevant barriers and their corresponding facilitators, are warranted.

The importance of drug titration in the management of patients with epilepsy.

The variable response to antiseizure medication (ASM) treatment and the numerous drug- and patient-related factors that must be considered when initiating therapy make drug titration to an optimal and tolerable dose an essential component in the pharmacologic treatment of patients with epilepsy. When initiating a new ASM, a "start low, go slow" titration approach is generally recommended and has been shown to reduce the risk of severe idiosyncratic reactions with certain medications and improve tolerability with regard to many frequently occurring central nervous system-related adverse effects (e.g., somnolence, dizziness). Many patients with epilepsy will require medication changes due to lack of efficacy or intolerability of the initial regimen. When this occurs, patients may be switched from one monotherapy to another or receive adjunctive therapy. When transitioning a patient from one ASM to another (referred to as monotherapy conversion or transitional polytherapy), there are several strategies for tapering the baseline ASM depending on the clinical scenario. Regardless of the particular strategy, the goal should be to discontinue the baseline ASM in order to prevent increased toxicity due to drug load. When adding on ASM therapy, flexible titration of the new ASM and adjustment of concomitant ASMs to achieve disease control with the lowest possible drug load (lowest numbers and lowest doses) may help improve tolerability of the add-on therapy. Communication with patients during the initiation of a new therapy may help patients adhere to the titration schedule, allowing them to reach their optimal maintenance dose.

Effects of antiepileptic drugs polytherapy on pregnancy outcomes in women with epilepsy: An observation study in northwest China.

OBJECTIVE: The management of pregnant women with epilepsy (WWE) treated with antiepileptic drugs (AEDs) polytherapy poses a great challenge. The purpose of this study was to evaluate the major congenital malformations (MCMs) associated with AED polytherapy, to assess the impacts of polytherapy regimens on seizure control and breastfeeding, and to determine the potential predictors for pregnancy outcomes. METHODS: This study was based on prospectively acquired data from a registry enrolling WWE in early pregnancy from Feb 2010 to July 2019, in which 123 pregnancies in 110 WWE were exposed to 27 different AED combinations. RESULTS: There were 123 pregnancies in 110 WWE analyzed in our study. The live birth rate was 86.2 % and the risk of MCMs was 10.4 %. Multivariate analysis indicated that prenatal exposure to phenobarbital (odds ratio [OR], 17.424; 95 %CI, 1.510-201.067; P = 0.022) and topiramate (OR, 9.469; 95 %CI, 1.149-62.402; P = 0.036) was associated with increased risk of MCMs. Valproate (OR, 4.441; 95 %CI, 1.165-16.934; P = 0.029), phenobarbital (OR, 13.636; 95 %CI, 2.146-86.660; P = 0.006) and topiramate (OR, 7.527; 95 %CI, 1.764-32.118; P = 0.006) were significantly correlated with adverse pregnancy outcomes. Among 67 pregnancies in four combinations over 10 patients, 15 (22.4 %) remained seizure free through pregnancy, seizure frequency increased in 17 (25.4 %), decreased in 24 (35.8 %) women, in 26 (38.8 %) remained unchanged. Only 23.6 % of mothers undertook exclusive breastfeeding. Planned pregnancy was the only independent factor significantly associated with decreased risk of adverse pregnancy outcomes (OR, 0.139; 95 % CI, 0.051-0.382; P < 0.001). Notably, no adverse pregnancy outcome was recorded in pregnancies exposed to the combination of lamotrigine plus levetiracetam. CONCLUSION: Prenatal exposure to the combinations containing valproate, phenobarbital, or topiramate was associated with increased risk of adverse pregnant outcomes. AED-related teratogenicity may be reduced by planned pregnancy in WWE exposed to polytherapy. Our findings also suggest the combination of lamotrigine and levetiracetam seems to be most desirable to balance seizure control and fetal safety.

Antipsychotic drug dose in real-life settings results from a Nationwide Cohort Study.

Despite national and international recommendations and while there is no evidence for increased efficacy of higher doses, several studies suggested that the prescribed doses in routine practice are higher than the maximal recommended doses in 20-40% of schizophrenia patients worldwide. METHODS: the aims of the present study were: (1) to describe the patterns of antipsychotic daily dose prescriptions in routine clinical practice in a large and representative cohort of French schizophrenia patients and, (2) to study the characteristics of patients receiving higher doses. RESULTS: in all cases, regardless of the antipsychotic treatment used, the average dose was greater than 1.0 defined daily dose (DDDeq), which is the average recommended dose. For SGA, the mean DDDeq ranged from 1.2 for aripiprazole to 1.6 for olanzapine and clozapine, respectively. For a given patient, the mean ± S.D. total daily cumulative dose (TCD) of antipsychotic was 1.9 ± 2.4 DDDeq. A "high dose" was defined as a TCD ≥ 1.5 DDDeq, 789 (45.2%) patients received a "high dose". Patients in the "high dose" group were more frequently suffering from a more severe paranoid schizophrenia, had more often a comorbid antisocial personality disorder and/or a substance use disorder. CONCLUSIONS: the present study suggests that in France, antipsychotic drugs doses prescribed by psychiatrists are higher, compared to other countries. All recommendations agree on the fact that the preferential dose should be the "minimum-effective" dose. Optimizing prescribing practices would be important to optimize the benefit/risk ratio and to minimize the risks side effects.

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort.

INTRODUCTION: Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). METHODS: We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. RESULTS: One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. CONCLUSION: Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach.

Significant Association of Antiepileptic Drug Polytherapy with Decreased FT4 Levels in Epileptic Patients.

Epileptic patients have to continue anti-epileptic drugs (AED) over a long period of time which can have deleterious effects on the endocrine system including the thyroid hormones with rare check. Risk factors for the development of thyroid dysfunction are still unclear. Therefore the aim of study was to evaluate thyroid functions in epileptic patients receiving anti-epileptic drugs (AED) as monotherapy and polytherapy and to determine potential risk of low thyroid function in epileptic patients receiving treatment. This cross-sectional study included 100 epilepsy patients more than 12 years of age. Serum levels of free thyroxin (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) were evaluated in all subjects in addition to serum AED levels. TSH levels were found to be significantly higher in the polytherapy subgroup (p < 0.05) in comparison to the monotherapy group. 44% of the patients in the VPA monotherapy group had raised TSH levels and 41.2% of the patients on CBZ had low FT4. A significant negative correlation was observed between CBZ and FT4 (p < 0.05). Female sex and old age were additional risk factors detected for deranged thyroid function. Female patients with epilepsy, an older age and AED polytherapy were found to be associated with a higher risk of thyroid dysfunction. Thus, Thyroid function in these patients should be monitored closely. In conclusion, we observed significant changes in thyroid hormone levels in patients receiving antiepileptic treatment in both monotherapy and polytherapy. Elevated CBZ levels were significantly associated with decreased FT4 levels.

Concomitant Medication Usage with Levodopa-Carbidopa Intestinal Gel: Results from the COSMOS Study.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels. OBJECTIVE: The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD. METHODS: The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter. RESULTS: Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment. CONCLUSIONS: LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A narrative review of the importance of pharmacokinetics and drug-drug interactions of preventive therapies in migraine management.

OBJECTIVE: To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug-drug interactions (DDIs) with the use of these therapies in migraine management. BACKGROUND: Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions. METHODS: A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene-related peptide pathway with medications that may be used for comorbid conditions. RESULTS: Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs. CONCLUSIONS: DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine-specific evidence-based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.

Effects of long-term antiepileptic polytherapy on bone biochemical markers in ambulatory children and adolescents and possible benefits of vitamin D supplementation: a prospective interventional study.

PURPOSE: Our aim was to investigate any adverse effects of long-term polytherapy (VPA and add-on-therapy) on bone biochemical markers in ambulatory children and adolescents with epilepsy and the possible benefits of vitamin D supplementation on the same markers. METHODS: In this prospective interventional study, the levels of 25(OH)D and the bone turnover markers of CrossLaps (CTX), total alkaline phosphatase (tALP), osteoprotegerin (OPG), and the receptor activator for nuclear factor kB (RANK) ligand (sRANKL) were determined in forty-two ambulatory children with epilepsy on polytherapy (valproic acid + one or more other from levetiracetam, topiramate, lamotrigine, or rufinamide). The same markers were assessed after a year's supplementation of vitamin D (400 IU/d) and were compared with those of clinically healthy controls. The respective mean (±SD) ages were 11.9 ±â€¯4.6 and 11.4 ±â€¯4.4 yrs. RESULTS: The basal mean 25(OH)D levels in the patients did not differ from controls (23.9 ±â€¯11.5 vs 27.4 ±â€¯13.3 ng/ml), but increased significantly after the vitamin D intake (31.1 ±â€¯13.3 ng/ml, p < 0.01). In parallel, basal serum CTX levels were found to be significantly lower in the patients than controls (0.89 ±â€¯0.63 vs 1.22 ±â€¯0.58 ng/ml, p < 0.02), but not tALP. Osteoprotegerin was higher in the patients (5.7 ±â€¯7.7 pmol/L vs 2.6 ±â€¯1.0 pmol/L, p < 0.03), while sRANKL did not differ. After vitamin D, the CTX levels increased to comparable levels in controls (0.99 ±â€¯0.57 ng/ml), and those of OPG decreased to levels that did not differ from controls (4.9 ±â€¯5.1 pmol/L). The ratio of OPG/sRANKL was higher in patients than controls before treatment (0.030 ±â€¯0.045 vs 0.009 ±â€¯0.005, p < 0.03), but decreased (0.026 ±â€¯0.038) to comparable values in controls later. CONCLUSIONS: These findings imply a lower bone turnover in the young patients on long-term polytherapy (VPA and add-on-therapy), but after one year's vitamin D intake, bone biochemical markers improved.

Risk factors of fetal deaths and major birth defects in newborns of women with epilepsy: An Egyptian prospective study.

OBJECTIVES: Pregnancy registries for women with epilepsy (WWE) are arising all over the world. The aim of this work was to assess the risk factors of pregnancy losses and major birth defects (MBDs) of WWE through the Egyptian Registry of Anti-seizure medications and Pregnancy system. METHODS: An observational prospective study was conducted over 24 months (2018-2020). The following data were assessed: seizure control during pregnancy, Anti-seizure medications (ASMs) regimen, folic acid supplementation, and birth outcome. RESULTS: This study included 211 pregnant WWE, with mean age of 27.30 ±â€¯5.51 years. One hundred eighty-six (89.9%) patients were on ASMs, from which 110 (59.1%) patients were on monotherapy. One hundred sixty-nine (80.0%) had healthy living babies, while fetal deaths occurred in 27 patients (12.8%) (25 abortions and 2 stillbirth), two patients (1%) had neonatal deaths, while 13 patients (6.2%) had living babies with MBDs. Although taking folic acid in the first trimester was a protective of fetal deaths (RR < 1, P 0.011), it was not a protective of MBDs. Seizure freedom during the entire pregnancy regardless of seizure type was another protective factor against fetal deaths (RR < 1, P < 0.001). Polytherapy exposure significantly increased the risk of MBDs compared with monotherapies (RR > 1, P 0.014). History of previous MBD was another risk factor of MBDs (RR > 1, P 0.027). CONCLUSION: History of previous MBD and polytherapy exposure increased the risk of MBDs. Taking folic acid during first trimester and being seizure free during pregnancy were protective factors against fetal deaths.

Gender differences in seizure recurrence and antiepileptic drug polytherapy predicting health-related quality of life of persons 1 year after diagnosis of epilepsy.

PURPOSE: The aim of this study was to determine whether gender influences the prediction of health-related quality of life (HRQoL) in persons with newly diagnosed epilepsy (NDE). METHODS: This was a 1-year longitudinal study. Persons with NDE were assessed with the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), the Hospital Anxiety Depression Scale (HADS), the Stigma Scale, and the Rosenberg Self-esteem Scale. An analysis of covariance (ANCOVA) with interaction terms was used. RESULTS: Among 134 adults with NDE, there were no gender differences in the scores of the QOLIE-31 and its subscales. A multivariate linear regression analysis showed that the HADS-anxiety scores at diagnosis (p = 0.005) and seizure recurrence after diagnosis (p = 0.050) negatively predicted QOLIE-31 scores in persons with NDE. There were significant effects of the gender interaction with seizure recurrence (F = 8.745, p = 0.004, partial eta2 = 0.066) and antiepileptic drug (AED) polytherapy (F = 6.320, p = 0.013, partial eta2 = 0.049) in the adjusted model. Specifically, seizure recurrence negatively predicted the QOLIE-31 scores only in men. By contrast, AED polytherapy negatively predicted the QOLIE-31 scores only in women. CONCLUSIONS: There are gender differences in certain epilepsy-related factors predicting HRQoL at 1 year in persons with NDE.

Chronic polytherapy after myocardial infarction: the trade-off between hospital and community-based providers in determining adherence to medication.

BACKGROUND: The benefits of chronic polytherapy in reducing readmissions and death after myocardial infarction (MI) have been clearly shown. However, real-world evidence shows poor medication adherence and large geographic variation, suggesting critical issues in access to optimal care. Our objectives were to measure adherence to polytherapy, to compare the amount of variation attributable to hospitals of discharge and to community-based providers, and to identify determinants of adherence to medications. METHODS: This is a population-based study. Data were obtained from the information systems of the Lazio and Tuscany Regions, Italy (9.5 million inhabitants). Patients hospitalized with incident MI in 2010-2014 were analyzed. The outcome measure was medication adherence, defined as a Medication Possession Ratio (MPR) ≥ 0.75 for at least 3 of the following drugs: antiplatelets, ß-blockers, ACEI/ARBs, statins. A 2-year cohort-study was performed. Cross-classified multilevel models were applied to analyze geographic variation. The variance components attributable to hospitals of discharge and community-based providers were expressed as Median Odds Ratio (MOR). RESULTS: A total of 32,962 patients were enrolled. About 63% of patients in the Lazio cohort and 59% of the Tuscan cohort were adherent to chronic polytherapy. Women and patients aged 85 years and over were most at risk of non-adherence. In both regions, adherence was higher for patients discharged from cardiology wards (Lazio: OR = 1.58, p < 0.001, Tuscany: OR = 1.59, p < 0.001) and for patients with a percutaneous coronary intervention during the index admission. Relevant variation between community-based providers was observed, though when the hospital of discharge was included as a cross-classified level, in both Lazio and Tuscany regions the variation attributable to hospitals of discharge was the only significant component (Lazio: MOR = 1.30, p = 0.001; Tuscany: MOR = 1.31, p = 0.001). CONCLUSION: Adherence to best practice treatments after MI is not consistent with clinical guidelines, and varies between patient groups as well as within and between regions. The variation attributable to providers is affected by the hospital of discharge, up to two years from the acute episode. This variation is likely to be attributable to hospital discharge processes, and could be reduced through appropriate policy levers.

Factors associated with stigma and depressive symptoms in family members of patients with epilepsy.

PURPOSE: Literature regarding family stigma related to epilepsy is scarce. This study investigated the prevalence of family stigma and depressive symptoms and the associated factors among the family members of patients with epilepsy. METHODS: In a cross-sectional study, Stigma Scale-Revised score ≥ 4 and Patient Health Questionnaire-9 score ≥ 10 were considered indicative of moderate-to-severe stigma and depressive symptoms, respectively. Stepwise logistic regression analyses were performed. RESULTS: Of the 482 family members, a mean age was 47.1 ±â€¯9.4 years, and 73.4% were female. Of the patients, a mean age was 25.5 ±â€¯16.7 years, and 45.0% were female. Idiopathic generalized epilepsy and focal epilepsy were noted in 22.4% and 65.6% of patients, respectively. Family stigma and depressive symptoms were noted in 10.0% and 11.2% of family members, respectively. Family stigma was significantly associated with high seizure frequency and being a sibling or offspring of a patient independent of their depressive symptoms. By contrast, depressive symptoms in family members were significantly associated with polytherapy, being parents of a patient, and neurological comorbidities independent of family stigma. In a subset of patients and their family, patients had higher proportion of stigma and depressive symptoms than their family. Depressive symptoms and stigma among patients were significantly correlated with those among parents, but not spouse. CONCLUSION: Family stigma is common in families with epilepsy and is closely related to depressive symptoms. Frequent seizures, polytherapy, neurological comorbidities, and the relationship to a patient may be factors that are independently associated with family stigma and depressive symptoms in family members.