Gastrointestinal symptoms and complications in patients hospitalized due to COVID-19, an international multicentre prospective cohort study (TIVURON project).

BACKGROUND: Retrospective studies suggest that coronavirus disease (COVID-19) commonly involves gastrointestinal (GI) symptoms and complications. Our aim was to prospectively evaluate GI manifestations in patients hospitalized for COVID-19. METHODS: This international multicentre prospective cohort study recruited COVID-19 patients hospitalized at 31 centres in Spain, Mexico, Chile, and Poland, between May and September 2020. Patients were followed-up until 15 days post-discharge and completed comprehensive questionnaires assessing GI symptoms and complications. A descriptive analysis as well as a bivariate and multivariate analysis were performer using binary logistic regression. p<0.05 was considered significant. RESULTS: Eight hundred twenty-nine patients were enrolled; 129 (15.6%) had severe COVID-19, 113 (13.7%) required ICU admission, and 43 (5.2%) died. Upon admission, the most prevalent GI symptoms were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%), which were mild/moderate throughout the disease and resolved during follow-up. One-third of patients exhibited liver injury. Non-severe COVID-19 was associated with ≥2 GI symptoms upon admission (OR 0.679; 95% CI 0.464-0.995; p=0.046) or diarrhoea during hospitalization (OR 0.531; 95% CI 0.328-0.860; p=0.009). Multivariate analysis revealed that worse hospital outcomes were not independently associated with liver injury or GI symptoms. CONCLUSION: GI symptoms were more common than previously documented, and were mild, rapidly resolved, and not independently associated with COVID-19 severity. Liver injury was a frequent complication in hospitalized patients not independently associated with COVID-19 severity.

Impact of Physical Activity Intensity Levels on the Cardiometabolic Risk Status of Children: The Genobox Study.

Childhood obesity has been related to metabolic syndrome and low-grade chronic inflammation. This study aimed to evaluate the impact of physical activity intensities and practice on inflammation, endothelial damage, and cardiometabolic risk factors in children. There were 513 participants, aged 6-14 years, recruited for the study. Physical activity was measured by accelerometry, and the children were classified into four groups according to quartiles of moderate to vigorous physical activity (MVPA) practice as very low active, low active, moderate active, and high active. Anthropometric measures, blood pressure, and plasma metabolic and proinflammatory parameters were analyzed. Very low active group presented a worse lipid profile and higher insulin, leptin, adiponectin, resistin, matrix metallopeptidase-9, and tissue plasminogen activator inhibitor-1, while lower levels of tumor necrosis factor-alpha, Type 1 macrophages, and interleukin 8 than high-active children. Regression analyses showed that a higher MVPA practice was associated with lower levels of triacylglycerols (ß: -0.118; p = .008), resistin (ß: -0.151; p = .005), tPAI (ß: -0.105; p = .046), and P-selectin (ß: -0.160; p = .006), independently of sex, age, and body mass index (BMI). In contrast, a higher BMI was associated with higher levels of insulin (ß: 0.370; p < .001), Homeostasis Model Assessment (ß: 0.352; p < .001), triacylglycerols (ß: 0.209; p < .001), leptin (ß: 0.654; p < .001), tumor necrosis factor-alpha (ß: 0.182; p < .001), Type 1macrophages (ß: 0.181; p < .001), and tissue plasminogen activator inhibitor (ß: 0.240; p < .001), independently of sex, age, and MVPA. A better anthropometric, metabolic, and inflammatory profile was detected in the most active children; however, these differences were partly due to BMI. These results suggest that a higher MVPA practice and a lower BMI in children may lead to a better cardiometabolic status.

Potential and Limitations of the New P2Y12 Inhibitor, Cangrelor, in Preventing Heparin-Induced Platelet Aggregation During Cardiac Surgery: An In Vitro Study.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) can put cardiac surgery patients at a high risk of lethal complications. If anti-PF4/heparin antibodies (anti-PF4/Hep Abs) are present, 2 strategies exist to prevent intraoperative aggregation during bypass surgery: first, using an alternative anticoagulant, and second, using heparin combined with an antiaggregant. The new P2Y12 inhibitor, cangrelor, could be an attractive candidate for the latter strategy; several authors have reported its successful use. The present in vitro study evaluated cangrelor's ability to inhibit heparin-induced platelet aggregation in the presence of anti-PF4/Hep Abs. METHODS: Platelet-poor plasma (PPP) from 30 patients with functional anti-PF4/Hep Abs was mixed with platelet-rich plasma (PRP) from 5 healthy donors.Light transmission aggregometry was used to measure platelet aggregation after adding 0.5 IU·mL of heparin (HIT) to the plasma, and this was compared with samples spiked with normal saline (control) and samples spiked with cangrelor 500 ng·mL and heparin 0.5 IU·mL (treatment). Friedman test with post hoc Dunn-Bonferroni test was used for between-group comparisons. RESULTS: Heparin 0.5 IU·mL triggered aggregation in 22 of 44 PPP-PRP mixtures, with a median aggregation of 86% (interquartile range [IQR], 69-91). The median aggregation of these 22 positive samples' respective control tests was 22% (IQR, 16-30) (P < .001). Median aggregation in the cangrelor-treated samples was 29% (IQR, 19-54) and significantly lower than the HIT samples (P < .001). Cangrelor inhibited heparin-induced aggregation by a median of 91% (IQR, 52-100). Cangrelor only reduced heparin-induced aggregation by >95% in 10 of the 22 positive samples (45%). Cangrelor inhibited heparin-induced aggregation by <50% in 5 of the 22 positive samples (22%) and by <10% in 3 samples (14%). CONCLUSIONS: This in vitro study found that cangrelor was an unreliable inhibitor of heparin-induced aggregation in the presence of anti-PF4/Hep Abs. We conclude that cangrelor should not be used as a standard antiaggregant for cardiac patients affected by HIT during surgery. Unless cangrelor's efficacy in a particular patient has been confirmed in a presurgery aggregation test, other strategies should be chosen.

Characterization of Procoagulant COAT Platelets in Patients with Glanzmann Thrombasthenia.

Patients affected by the rare Glanzmann thrombasthenia (GT) suffer from defective or low levels of the platelet-associated glycoprotein (GP) IIb/IIIa, which acts as a fibrinogen receptor, and have therefore an impaired ability to aggregate platelets. Because the procoagulant activity is a dichotomous facet of platelet activation, diverging from the aggregation endpoint, we were interested in characterizing the ability to generate procoagulant platelets in GT patients. Therefore, we investigated, by flow cytometry analysis, platelet functions in three GT patients as well as their ability to generate procoagulant collagen-and-thrombin (COAT) platelets upon combined activation with convulxin-plus-thrombin. In addition, we further characterized intracellular ion fluxes during the procoagulant response, using specific probes to monitor by flow cytometry kinetics of cytosolic calcium, sodium, and potassium ion fluxes. GT patients generated higher percentages of procoagulant COAT platelets compared to healthy donors. Moreover, they were able to mobilize higher levels of cytosolic calcium following convulxin-plus-thrombin activation, which is congruent with the greater procoagulant activity. Further investigations will dissect the role of GPIIb/IIIa outside-in signalling possibly implicated in the regulation of platelet procoagulant activity.

Cortisol and IgA are Involved in the Progression of Alzheimer's Disease. A Pilot Study.

It is known that stress and immune systems are related with Alzheimer's disease (AD). However, the relationship of both systems in the progression of disease is not clearly demonstrated. Hair cortisol and salivary immunoglobulin A (IgA) were quantified in 49 patients with mild, moderate, and severe AD. A significant change was seen in both molecules as AD progressed from mild to moderate and severe. Low levels of cortisol were observed in mild AD patients compared with moderate and severe. However, IgA showed a contrary pattern. High levels were observed in mild AD patientes but low in moderate and severe AD subjects. The secretion of cortisol and IgA seems to be very different at the start compared with posterior development of AD suggesting that neuroinflammation can be involved. Both molecules could be used as possible therapeutical tools.

Asthma and allergic rhinitis associate with the rs2229542 variant that induces a p.Lys90Glu mutation and compromises AKR1B1 protein levels.

Asthma and rhinitis are two of the main clinical manifestations of allergy, in which increased reactive oxygen or electrophilic species can play a pathogenic role. Aldose reductase (AKR1B1) is involved in aldehyde detoxification and redox balance. Recent evidence from animal models points to a role of AKR1B1 in asthma and rhinitis, but its involvement in human allergy has not been addressed. Here, the putative association of allergic rhinitis and asthma with AKR1B1 variants has been explored by analysis of single-strand variants on the AKR1B1 gene sequence in 526 healthy subjects and 515 patients with allergic rhinitis, 366 of whom also had asthma. We found that the rs2229542 variant, introducing the p.Lys90Glu mutation, was significantly more frequent in allergic patients than in healthy subjects. Additionally, in cells transfected with expression vectors carrying the wild-type or the p.Lys90Glu variant of AKR1B1, the mutant consistently attained lower protein levels than the wild-type and showed a compromised thermal stability. Taken together, our results show that the rs2229542 variant associates with asthma and rhinitis, and hampers AKR1B1 protein levels and stability. This unveils a connection between the genetic variability of aldose reductase and allergic processes.

Dual Therapy With Darunavir and Ritonavir Plus Lamivudine vs Triple Therapy With Darunavir and Ritonavir Plus Tenofovir Disoproxil Fumarate and Emtricitabine or Abacavir and Lamivudine for Maintenance of Human Immunodeficiency Virus Type 1 Viral Suppression: Randomized, Open-Label, Noninferiority DUAL-GESIDA 8014-RIS-EST45 Trial.

BACKGROUND: Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. METHODS: This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. RESULTS: A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. CONCLUSIONS: Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. CLINICAL TRIALS REGISTRATION: NCT02159599.

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins.

Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently to proteins and exert anti-inflammatory and antiproliferative effects in numerous settings. By pursuing targets for modification by cyPGs we have found that the cyPG PGA1 binds to and inactivates AKR1B1. A PGA1-AKR1B1 adduct was observed, both by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and by SDS-PAGE using biotinylated PGA1 (PGA1-B). Insight into the molecular interactions between AKR1B1 and PGA1 was advanced by molecular modeling. This anticipated the addition of PGA1 to active site Cys298 and the potential reversibility of the adduct, which was supported experimentally. Indeed, loss of biotin label from the AKR1B1-PGA1-B adduct was favored by glutathione, indicating a retro-Michael reaction, which unveils new implications of cyPG-protein interaction. PGA1 elicited only marginal inhibition of aldehyde reductase (AKR1A1), considered responsible for the severe adverse effects of many AKR1B1 inhibitors. Interestingly, other prostaglandins (PGs) inhibited the enzyme, including non-electrophilic PGE1 and PGE2, currently used in clinical practice. Moreover, both PGA1 and PGE1 reduced the formation of sorbitol in an ex-vivo model of diabetic cataract to an extent comparable to that attained by the known AKR inhibitor epalrestat. Taken together, these results highlight the role of PGs as AKR1B1 inhibitors and the interest in PG-related molecules as leads for the development of novel pharmacological tools.

Defects in subventricular zone pigmented epithelium-derived factor niche signaling in the senescence-accelerated mouse prone-8.

We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model.

A novel strategy for global analysis of the dynamic thiol redox proteome.

Nitroxidative stress in cells occurs mainly through the action of reactive nitrogen and oxygen species (RNOS) on protein thiol groups. Reactive nitrogen and oxygen species-mediated protein modifications are associated with pathophysiological states, but can also convey physiological signals. Identification of Cys residues that are modified by oxidative stimuli still poses technical challenges and these changes have never been statistically analyzed from a proteome-wide perspective. Here we show that GELSILOX, a method that combines a robust proteomics protocol with a new computational approach that analyzes variance at the peptide level, allows a simultaneous analysis of dynamic alterations in the redox state of Cys sites and of protein abundance. GELSILOX permits the characterization of the major endothelial redox targets of hydrogen peroxide in endothelial cells and reveals that hypoxia induces a significant increase in the status of oxidized thiols. GELSILOX also detected thiols that are redox-modified by ischemia-reperfusion in heart mitochondria and demonstrated that these alterations are abolished in ischemia-preconditioned animals.

Changing the education paradigm in pediatric dentistry.

Traditional curricula of pediatric dental residency programs have overemphasized restorative dentistry while failing to give adequate attention to early diagnosis, preventive disease management, risk assessment, cultural competency, advocacy, community partnerships and interprofessional education. The University of California, Los Angeles, Community Health and Advocacy Training Program in Pediatric Dentistry emphasizes these lesser-taught areas, integrating them within a structured education in classical restorative techniques and Commission on Dental Accreditation-approved standards, providing a diverse curriculum and preparing residents for practice in increasingly diverse communities.

Global coagulation assays detect an early prothrombotic state in children with acute lymphoblastic leukemia.

BACKGROUND: Pediatric patients with acute lymphoblastic leukemia (ALL) are at highest risk of venous thromboembolism during the induction therapy (IT). These events are not predictable by conventional coagulation assays. OBJECTIVES: To investigate the utility of global coagulation assays (GCAs) for assessing the hemostatic state in children with ALL during IT. METHODS: We included children with ALL (n = 15) and healthy controls (n = 15). Analyses were performed at different time points during IT of the AIEOP-BFM protocols. In addition to prothrombotic biomarkers, natural anticoagulant proteins, and in vivo thrombin generation (TG) markers, ex vivo TG was measured using the gold standard calibrated automated thrombogram method, automated ST Genesia, and thrombodynamics analyzer (TD). The latter also provided measurement of fibrin clot formation. RESULTS: Different from conventional coagulation assays and in vivo TG markers, ex vivo GCAs detected increasing prothrombotic changes during IT. Particularly, TG measured with TD as expressed by endogenous thrombin potential was already significantly elevated at days 8 to 12 (P < .01) and continued to increase during IT compared with prior to beginning treatment, indicating a very early shift toward a procoagulant state. A similar pattern was observed for the rate of fibrin clot formation (stationary rate of clot growth: P < .01 at days 8-12). Remarkably, in patients developing thrombotic complications (n = 5), both GCAs, ST Genesia and TD, showed a significantly higher endogenous thrombin potential very early (already at days 8-12, P < .05), well before clinical manifestation. CONCLUSION: GCAs capture prothrombotic changes early during IT in ALL pediatric patients. If confirmed, this approach will allow tailoring thromboprophylaxis in children with ALL at highest risk for venous thromboembolism.

Barriers to adherence to secondary prevention therapy in patients with ischemic heart disease: a cross-sectional study of a Mexican reference center.

Objective: This article aims to assess the adherence level to second-line therapy for cardiovascular prevention in a tertiary hospital in Mexico City and identify key barriers to adequate pharmacological adherence. Methods: A single-center prospective cross-sectional study was conducted between August 2018 and February 2020. Sociodemographic data were collected, and the Morisky medication adherence scale was performed. Directed interviews during medical consultations were also conducted to determine reasons for non-adherence. Results: Showed that out of 991 patients included with a median age of 65 (58.72) years, 70.3% exhibited inadequate adherence, with forgetfulness being the most common reason (55.4%). Patients receiving combined therapy with coronary revascularization showed higher adherence compared to those on optimal medical therapy alone. Low educational level (OR 1.68, IC 95% 1.23-2.23, p = 0.0001) and the use of optimal medical therapy alone (OR 1.2, I 95% 1.11-2.007 p = 0.007) were identified as predictors of poor adherence. Conclusion: Among patients with ischemic heart disease and pharmacological therapy for secondary prevention, inadequate adherence is observed in 70% of cases. Factors associated with poor pharmacological adherence were low educational level and prescription of medical therapy without revascularization.

Objetivo: Determinar el nivel de adherencia a la terapia secundaria de prevención cardiovascular en un hospital terciario de la Ciudad de México e identificar las barreras que contribuyen a la inadecuada adherencia farmacológica. Métodos: Se realizó un estudio transversal entre agosto de 2018 y febrero de 2020. Se obtuvieron los datos sociodemográficos, la escala de adherencia a la medicación de Morisky, y se realizó una entrevista sobre las razones de la no adherencia. Resultados: 991 pacientes fueron incluidos con una mediana de edad de 65 (58,72) años. La adherencia inadecuada fue de 70.3%, siendo el olvido la causa más frecuente (55.4%). Aquellos pacientes en terapia farmacológica combinada con revascularización coronaria fueron más adherentes que aquellos en terapia médica óptima. El bajo nivel educativo (OR 1.68, IC95%1.23-2.3, p = 0.001) y el uso de tratamiento médico óptimo solo (OR 1.52, IC95%1.11-2.07, p = 0.007) fueron predictores de mala adherencia. Conclusión: En pacientes con cardiopatia isquemica y terapia farmacológica para prevención secundaria se observa adherencia inadecuada en 70%. Los factores asociados a mala adherencia farmacológica fueron el bajo nivel educativo y la prescripción de tratamiento médico sin revascularización.

S-glutathionylation: relevance in diabetes and potential role as a biomarker.

Glutathione is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying deleterious molecules. The oxidative stress induced as a result of a variety of stimuli promotes protein oxidation, usually at cysteine residues, leading to changes in their activity. Mild oxidative stress, which may take place in physiological conditions, induces the reversible oxidation of cysteines to sulfenic acid form, while pathological conditions are associated with higher rates of reactive oxygen species production, inducing the irreversible oxidation of cysteines. Among these, neurodegenerative disorders, cardiovascular diseases and diabetes have been proposed to be pathogenetically linked to this state. In diabetes-associated vascular complications, lower levels of glutathione and increased oxidative stress have been reported. S-glutathionylation has been proposed as a posttranslational modification able to protect proteins from over-oxidizing environments. S-glutathionylation has been identified in proteins involved in diabetic models both in vitro and in vivo. In all of them, S-glutathionylation represents a mechanism that regulates the response to diabetic conditions, and has been described to occur in erythrocytes and neutrophils from diabetic patients. However, additional studies are necessary to discern whether this modification represents a biomarker for the early onset of diabetic vascular complications.

Clinical features and 123I-FP-CIT SPECT imaging in vascular parkinsonism and Parkinson's disease.

OBJECTIVES: To analyse the differences in the clinical features and characteristics of (123)I-labelled 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT) single photon emission CT (SPECT) imaging among patients with vascular parkinsonism (VP) and Parkinson's disease (PD). METHODS: We performed a case-control study to compare clinical features and qualitative and semi-quantitative analyses of (123)I-FP-CIT SPECT images between 106 patients with VP and 280 patients with PD. A case series study was used to search for clinical features related to SPECT or neuroimaging findings among patients with VP. RESULTS: Patients with VP had a higher age at symptom onset and lower disease duration than patients with PD. The most frequent symptom at onset was gait disorder in VP and tremor in PD. Gait disorder, postural instability and falls were more frequent in VP. Rest and mixed tremor were more prevalent in PD. Of the patients who received levodopa treatment in the VP group, only about half had a good response. Qualitatively (123)I-FP-CIT SPECT images were normal in 32.5% of patients with VP and abnormal in all patients with PD. The use of different visual score patterns showed higher ability to differentiate VP from PD. Semi-quantitative analysis showed significantly higher uptake in the striatum, caudate and putamen in VP. The asymmetry index was higher in patients with PD. Among patients with VP, falls were the only clinical feature that demonstrated a correlation with the SPECT visual pattern. CONCLUSION: Our data contribute to the confirmation that VP and PD are two different clinical entities. Neurological signs, response to treatment and qualitative and semi-quantitative (123)I-FP-CIT SPECT analyses may help to make the diagnosis.

Oral health considerations in HIV-infected children.

Children with the human immunodeficiency virus (HIV) have a higher probability of hard and soft oral tissue diseases because of their compromised immune systems and socioeconomic factors such as poor access to medical and dental care and limited availability of fluoridated water or toothpaste. To improve health outcomes and help monitor the progression of HIV, a preventive, child-specific oral health protocol for children with HIV that is easy to use and appropriate for all different resource settings should be established. Further, both medical and dental health practitioners should incorporate such a protocol into their care routine for HIV-infected children. Using proactive oral health risk assessments complemented by scheduled follow-up visits based on individual risk determination can prevent opportunistic infection, track the HIV disease trajectory, and monitor the effectiveness of highly active antiretroviral therapy (HAART) while improving the quality of life and longevity of children living with HIV.

Botulinum toxin type A in chronic plantar fasciitis: clinical effects one year after injection.

OBJECTIVE: To determine whether the efficacy of botulinum toxin type A in chronic plantar fasciitis was maintained for more than six months after treatment. DESIGN: Observational follow-up study. SUBJECTS: Twenty-four patients who received botulinum toxin type A injection in a previous randomized study of chronic plantar fasciitis (active treatment group) and who presented a benefit one month after treatment. METHODS: A visual analogue scale for pain and the Foot Health Status Questionnaire were used to re-evaluate results 12 months after the botulinum toxin injection. No further injections of botulinum toxin had been administered during the follow-up period. Patients were also asked to give a subjective assessment of treatment outcome. RESULTS: At 12 months, compared with the six-month evaluation, there was a further improvement in foot pain measured using the visual analogue scale, though this did not reach significance (1.78 at 6 months versus 1.22 at 12 months; P = 0.142). However, there were significant improvements in two domains of Foot Health Status Questionnaire: foot pain (91.11 at 6 months versus 80.00 at 12 months; P = 0.001) and foot function (96.19 at 6 months versus 89.38 at 12 months; P = 0.047). There was a small, non-significant deterioration in the shoe and foot health domains. Satisfaction with the outcome was good or very good in the large majority of patients. CONCLUSIONS: In patients with chronic plantar fasciitis, the positive effect detected six months after treatment with botulinum toxin type A was maintained at 12 months and there was a further improvement in pain and foot function.

Pharmacodynamics Monitoring of Emicizumab in Patients with Hemophilia A.

BACKGROUND: Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved in vivo. Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab. MATERIALS AND METHODS: Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1 4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors. RESULTS: TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement. CONCLUSION: Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.

Consensus-based recommendations on physical activity and exercise in patients with diabetes at risk of foot ulcerations: a Delphi study.

BACKGROUND: Patients with diabetes mellitus are exposed to important complications. Currently little evidence exist on the guidelines that these patients, at some risk of foot ulceration, should follow for physical exercise. OBJECTIVES: To reach a consensus among multidisciplinary and international experts on physical activity/exercise recommendations for patients with diabetes, according to foot ulcer risk. METHODS: Using a three-round Delphi method, a panel composed of 28 multidisciplinary experts in the management of diabetic foot assessed 109 recommendations on physical activity/exercise for patients with diabetes mellitus, according to their risk of foot ulcer. Consensus was assumed when 80% of responses matched the same category (agreement/disagreement). RESULTS: Twenty-nine experts participated in the first and second rounds of consultation, and twenty-eight did so in the third, reaching final agreement on 86 of the 109 recommendations considered (78.9%). The study, thus, generated a consensus set of recommendations concerning different aspects of diabetic footcare before, during, and after exercise (e.g. when to examine the foot, how to assess it, what type of sock and insole to use, what types of exercise to perform, and when it is advisable to return to activity after an ulceration). CONCLUSION: This Delphi study generated recommendations based on the consensus of international experts on physical activity and exercise by patient with diabetes at risk of ulceration. Recommendations considered the state of the foot and the patient's history and status before physical activity and included information on intensity, duration, frequency, and progressions of physical activity/exercise, and the use of custom-made plantar orthoses, shoe prescription, and the convenience of returning to physical activity after an ulceration.