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ABSTRACT Carbapenemase-producing Klebsiella pneumoniae represents a major public health issue globally. Isolates with resistance to the newest drugs, like ceftazidime/avibactam (CZA), are increasingly reported. In this study, we analyzed the evolution of KPC-3-producing sequence type (ST) 512 K. pneumoniae strains isolated at three different times (hospitalization days 45, 56, and 78) from the same patient, two of which were observed in a pericholecystic liver abscess. The three K. pneumoniae isolates (295Kp, 304Kp, and hmv-318Kp) from the same patient were subjected to antimicrobial susceptibility testing, whole-genome sequencing, sedimentation assay, biofilm measurement, serum resistance assay, macrophage phagocytosis, and adhesion assays. KPC-producing isolate hmv-318Kp exhibited carbapenem susceptibility, hypermucoviscous (hmv) colony phenotype and CZA resistance. Virulence markers of hypervirulent Klebsiella were absent. Two non-synonymous mutations were identified in the hmv-318Kp genome comparing with isogenic strains: a single-nucleotide polymorphism (SNP) occurred in the pKpQIL plasmid, changing blaKPC-3 in the blaKPC-31 gene variant, conferring CZA resistance; and a second SNP occurred in the wzc gene of the capsular biosynthesis cluster, encoding a tyrosine kinase, resulting in the F557S Wzc protein mutation. The Klebsiella pneumoniae strain exhibiting an hmv phenotype (hmv-Kp) phenotype has been previously associated with amino acid substitutions occurring in the Wzc tyrosin kinase protein. We observed in vivo evolution of the ST512 strain to CZA resistance and acquisition of hypermucoviscosity. The pathogenetic role of the detected Wzc substitution is not fully elucidated, but other Wzc mutations were previously reported in hmv K. pneumoniae. Wzc mutants may be more frequent than expected and an underreported cause of hypermucoviscosity in K. pneumoniae clinical isolates.IMPORTANCEHere we describe the evolution of KPC-3-producing ST512 K. pneumoniae isolated at three different times from the same patient of which the last one, from a biliary abscess, showed CZA resistance by KPC-31 production and manifested hmv colony phenotype. Hypervirulent Klebsiella pneumoniae (hv-Kp) isolates are increasingly reported worldwide. Their hypervirulent traits are associated with the presence of rmpA/A2 genes and an hmv. In this study, we identified an hmv-Kp that lacked the rmpA-D cluster but showed an amino acid substitution in the Wzc tyrosin kinase protein, involved in the capsular biosynthesis. This hmv-Kp strain emerged in vivo and evolved resistance to ceftazidime/avibactam resistance in a liver abscess of a patient. Our findings suggest that wzc mutations may be underreported, making it challenging to distinguish hv-Kp from “classic” K. pneumoniae with an hmv phenotype.

Abstract Background COVID-19-associated pulmonary aspergillosis (CAPA) is burdened by high mortality. Data are lacking about non-ICU patients. Aims of this study were to: (i) assess the incidence and prevalence of CAPA in a respiratory sub-intensive care unit, (ii) evaluate its risk factors and (iii) impact on in-hospital mortality. Secondary aims were to: (i) assess factors associated to mortality, and (ii) evaluate significant features in hematological patients. Materials and methods This was a single-center, retrospective study of COVID-19 patients with acute respiratory failure. A cohort of CAPA patients was compared to a non-CAPA cohort. Among patients with CAPA, a cohort of hematological patients was further compared to another of non-hematological patients. Results Three hundred fifty patients were included in the study. Median P/F ratio at the admission to sub-intensive unit was 225 mmHg (IQR 155–314). 55 (15.7%) developed CAPA (incidence of 5.5%). Eighteen had probable CAPA (37.3%), 37 (67.3%) possible CAPA and none proven CAPA. Diagnosis of CAPA occurred at a median of 17 days (IQR 12–31) from SARS-CoV-2 infection. Independent risk factors for CAPA were hematological malignancy [OR 1.74 (95%CI 0.75–4.37), p = 0.0003], lymphocytopenia [OR 2.29 (95%CI 1.12–4.86), p = 0.02], and COPD [OR 2.74 (95%CI 1.19–5.08), p = 0.014]. Mortality rate was higher in CAPA cohort (61.8% vs 22.7%, p 65 years resulted a predictor of mortality [OR 5.09 (95% CI 1.20–26.92), p = 0.035]. No differences were observed in hematological cohort. Conclusion CAPA is a life-threatening condition with high mortality rates. It should be promptly suspected, especially in case of hematological malignancy, COPD and lymphocytopenia.

In February 2022, a critically ill patient colonized with a carbapenem-resistant K. pneumoniae producing KPC-3 and VIM-1 carbapenemases was hospitalized for SARS-CoV-2 in the intensive care unit of Policlinico Umberto I hospital in Rome, Italy. During 95 days of hospitalization, ceftazidime/avibactam, meropenem/vaborbactam, and cefiderocol were administered consecutively to treat 3 respiratory tract infections sustained by different bacterial agents. Those therapies altered the resistome of K. pneumoniae sequence type 512 colonizing or infecting the patient during the hospitalization period. In vivo evolution of the K. pneumoniae sequence type 512 resistome occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore gene, resulting in high levels of cefiderocol resistance. Cross-selection can occur between K. pneumoniae and treatments prescribed for other infective agents. K. pneumoniae can stably colonize a patient, and antimicrobial-selective pressure can promote progressive K. pneumoniae resistome evolution, indicating a substantial public health threat.

New antimicrobial molecules effective against Pseudomonas aeruginosa, known as an antibiotic-resistant “high-priority pathogen”, are urgently required because of its ability to develop biofilms related to healthcare-acquired infections. In this study, for the first time, the anti-biofilm and anti-virulence activities of a polyphenolic extract of extra-virgin olive oil as well as purified oleocanthal and oleacein, toward P. aeruginosa clinical isolates were investigated. The main result of our study was the anti-virulence activity of the mixture of oleacein and oleocanthal toward multidrug-resistant and intermediately resistant strains of P. aeruginosa isolated from patients with ventilator-associated pneumonia or surgical site infection. Specifically, the mixture of oleacein (2.5 mM)/oleocanthal (2.5 mM) significantly inhibited biofilm formation, alginate and pyocyanin production, and motility in both P. aeruginosa strains (p < 0.05); scanning electron microscopy analysis further evidenced its ability to inhibit bacterial cell adhesion as well as the production of the extracellular matrix. In conclusion, our results suggest the potential application of the oleacein/oleocanthal mixture in the management of healthcare-associated P. aeruginosa infections, particularly in the era of increasing antimicrobial resistance.

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin condition whose pathogenesis involves genetic predisposition, epidermal barrier dysfunction, alterations in the immune responses and microbial dysbiosis. Clinical studies have shown a link between Staphylococcus aureus and the pathogenesis of AD, although the origins and genetic diversity of S. aureus colonizing patients with AD is poorly understood. The aim of the study was to investigate if specific clones might be associated with the disease. MethodsWGS analyses were performed on 38 S. aureus strains, deriving from AD patients and healthy carriers. Genotypes (i.e. MLST, spa-, agr- and SCCmec-typing), genomic content (e.g. virulome and resistome), and the pan-genome structure of strains have been investigated. Phenotypic analyses were performed to determine the antibiotic susceptibility, the biofilm production and the invasiveness within the investigated S. aureus population. ResultsStrains isolated from AD patients revealed a high degree of genetic heterogeneity and a shared set of virulence factors and antimicrobial resistance genes, suggesting that no genotype and genomic content are uniquely associated with AD. The same strains were characterized by a lower variability in terms of gene content, indicating that the inflammatory conditions could exert a selective pressure leading to the optimization of the gene repertoire. Furthermore, genes related to specific mechanisms, like post-translational modification, protein turnover and chaperones as well as intracellular trafficking, secretion and vesicular transport, were significantly more enriched in AD strains. Phenotypic analysis revealed that all of our AD strains were strong or moderate biofilm producers, while less than half showed invasive capabilities.ConclusionsWe conclude that in AD skin, the functional role played by S. aureus may depend on differential gene expression patterns and/or on post-translational modification mechanisms rather than being associated with peculiar genetic features.

Alcohol consumption is associated with oxidative stress and an increased risk of carcinoma of the upper aero-digestive tract (UADT). Recently, it has been found that some microorganisms in the human oral cavity may locally metabolize ethanol, forming acetaldehyde, a carcinogenic metabolite of alcohol. In a cohort of patients first visited for UADT cancers, we estimated their alcohol consumption by measuring Ethyl Glucuronide/EtG (a long-lasting metabolite of ethanol) in the hair and carbohydrate-deficient transferrin/CDT (short-term index of alcohol intake) in the serum. Moreover, we analyzed, by culture-based methods, the presence of Neisseria subflava, Streptococcus mitis, Candida albicans, and glabrata (microorganisms generating acetaldehyde) in the oral cavity. According to the EtG values, we correlated drinking alcohol with endogenous oxidative stress and the investigated microorganism’s presence. We found that 55% of heavy drinkers presented microorganisms generating acetaldehyde locally. Moreover, we found that the presence of oral acetaldehyde-producing bacteria correlates with increased oxidative stress compared to patients without such bacteria. As for the study of alcohol dehydrogenase gene polymorphisms (the enzyme that transforms alcohol to acetaldehyde), we found that only the “CGTCGTCCC” haplotype was more frequent in the general population than in carcinoma patients. This pilot study suggests the importance of estimating alcohol consumption (EtG), the presence of bacteria producing acetaldehyde, and oxidative stress as risk factors for the onset of oral carcinomas.

Providencia stuartii is a member of the Morganellaceae family, notorious for its intrinsic resistance to several antibiotics, including last-resort drugs such as colistin and tigecycline. Between February and March 2022, a four-patient outbreak sustained by P. stuartii occurred in a hospital in Rome. Phenotypic analyses defined these strains as eXtensively Drug-Resistant (XDR). Whole-genome sequencing was performed on the representative P. stuartii strains and resulted in fully closed genomes and plasmids. The genomes were highly related phylogenetically and encoded various virulence factors, including fimbrial clusters. The XDR phenotype was primarily driven by the presence of the blaNDM-1 metallo-β-lactamase alongside the rmtC 16S rRNA methyltransferase, conferring resistance to most β-lactams and every aminoglycoside, respectively. These genes were found on an IncC plasmid that was highly related to an NDM-IncC plasmid retrieved from a ST15 Klebsiella pneumoniae strain circulating in the same hospital two years earlier. Given its ability to acquire resistance plasmids and its intrinsic resistance mechanisms, P. stuartii is a formidable pathogen. The emergence of XDR P. stuartii strains poses a significant public health threat. It is essential to monitor the spread of these strains and develop new strategies for their control and treatment.

Abstract Inorganic metal halide perovskites are relevant semiconductors for optoelectronic devices. The successful deposition of thin films of CsPbBr3 and CsPbCl3 has recently been obtained by Radio-Frequency magnetron sputtering. In this work we compare the morphological, structural and optical characteristics of the two materials obtained with this deposition technique. A detailed photoluminescence (PL) spectroscopy study of the as-grown samples was conducted at the macro and micro scale in a wide temperature range (10-300 K) to fully characterize the PL on sample areas of square centimeters, to assess the origin of the inhomogeneous broadening and to quantify the PL quantum yield quenching. Our results prove that this technique allows for the realization of high quality nanometric films with controlled thickness of relevance for optoelectronic applications.

Extra virgin olive oil (EVOO) from Olea europaea L. drupes, a cornerstone in the Mediterranean diet, is well known for its nutritional and health properties, especially for prevention of cardiovascular diseases and metabolic disorders. Traditionally, beneficial health effects have been largely attributed to the high concentration of monounsaturated fatty acids, and in recent years, these have also been related to other components including oleacein and oleocanthal. Here, we evaluated, for the first time, the antimicrobial activity of different green extra virgin olive oil-based formulations in natural deep eutectic solvents (NaDESs) emerging as powerful and biocompatible solvents. Specifically, the antimicrobial activity of the EVOO extract, as well as purified oleocanthal and oleacein in two NaDESs (choline/glycerol and choline/propylene glycol), against several drug-resistant clinical isolates and standard microbial strains has been evaluated. The main result was the inhibitory activity of the EVOO extract in choline/glycerol as well as oleacein in choline/propylene glycol toward drug-resistant Gram-positive and -negative strains. Specifically, the EVOO extract in choline/glycerol showed the highest antibacterial activity against several clinical strains of Staphylococcus aureus, whereas oleacein in choline/propylene glycol was the most effective toward various clinical strains of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. In addition, all the formulations tested were effective against Candida spp. In conclusion, our results suggest EVOO-based formulations in NaDESs as an interesting strategy that may help in reducing the risk of development of drug resistance. Under this perspective, the usage of NaDESs for the preparation of new antimicrobial formulations may represent a promising approach.

Background: The incidence of candidemia in severe COVID-19 patients (0.8–14%) is two- to ten-fold higher than in non-COVID-19 patients. Methods: This retrospective analysis aimed to analyse the incidence of bloodstream infections (BSI) due to Candida in a cohort of COVID-19 patients supported with ECMO. Results: Among 138 intubated and ventilated patients hospitalized for ≥10 days in the intensive care unit of a teaching hospital, 45 (32.6%) patients received ECMO support, while 93 patients (67.4%) did not meet ECMO criteria and were considered the control group. In the ECMO group, 16 episodes of candidaemia were observed, while only 13 in patients of the control group (36.0% vs. 14.0%, p-value 0.004). It was confirmed at the survival analysis (SHR: 2.86, 95% CI: 1.39–5.88) and at the multivariable analyses (aSHR: 3.91, 95% CI: 1.73–8.86). A higher candida score seemed to increase the hazard for candidemia occurrence (aSHR: 3.04, 95% CI: 2.09–4.42), while vasopressor therapy was negatively associated with the outcome (aSHR: 0.15, 95% CI: 0.05–0.43). Conclusions: This study confirms that the incidence of candidemia was significantly higher in critically ill COVID-19 patients supported with VV-ECMO than in critically ill COVID patients who did not meet criteria for VV-ECMO.

Two mutually related pandemics are ongoing worldwide: the COVID-19 and antimicrobial resistance pandemics. This study aims to evaluate the impact of COVID-19 on multi-drug-resistant Gram-negative bacteria (MDR-GN) bloodstream infections (BSIs) in a single intensive care unit (ICU). We conducted a retrospective study including patients admitted to the ICU, reorganized for COVID-19 patients’ healthcare, with at least one confirmed MDR-GN BSI during 2019–2020. We compared clinical and microbiological features, incidence density, antibiotic therapy and mortality rate in pre- and during-COVID-19 pandemic periods. We estimated the impact of COVID-19 on mortality by means of univariate Cox regression analyses. A total of 46 patients were included in the study (28 non-COVID-19/18 COVID-19). Overall, 63 BSI episodes occurred (44/19), and non-COVID-19 patients had a higher incidence of MDR-GN BSIs and were more likely to present K. pneumoniae BSIs, while the COVID-19 group showed more A. baumannii BSIs with higher per pathogen incidence. COVID-19 patients presented more critical conditions at the BSI onset, a shorter hospitalization time from BSI to death and higher 30-day mortality rate from BSI onset. COVID-19 and septic shock were associated with 30-day mortality from MDR-GN BSIs, while early active therapy was a protective factor. In conclusion, COVID-19 showed a negative impact on patients with MDR-GN BSIs admitted to the ICU.

While blue LED (b-LED) light is increasingly being studied for its cytotoxic activity towards bacteria in therapy of skin-related infections, its effects on eukaryotic cells plasticity are less well characterized. Moreover, since different protocols are often used, comparing the effect of b-LED towards both microorganisms and epithelial surfaces may be difficult. The aim of this study was to analyze, in the same experimental setting, both the bactericidal activity and the effects on human keratinocytes. Exposure to b-LED induced an intense cytocidal activity against Gram-positive (i.e, Staphylococcus aureus) and Gram-negative (i.e., Pseudomonas aeruginosa) bacteria associated with catheter-related infections. Treatment with b-LED of a human keratinocyte cell line induced a transient cell cycle arrest. At the molecular level, exposure to b-LED induced a transient downregulation of Cyclin D1 and an upregulation of p21, but not signs of apoptosis. Interestingly, a transient induction of phosphor-histone γ-H2Ax, which is associated with genotoxic damages, was observed. At the same time, keratinocytes underwent a transient epithelial to mesenchymal transition (EMT)-like phenotype, characterized by E-cadherin downregulation and SNAIL/SLUG induction. As a functional readout of EMT induction, a scratch assay was performed. Surprisingly, b-LED treatment provoked a delay in the scratch closure. In conclusion, we demonstrated that b-LED microbicidal activity is associated with complex responses in keratinocytes that certainly deserve further analysis.

Multidrug-resistant microbial infections and the scarce availability of new antibiotics capable of eradicating them are posing a serious problem to global health security. Among the microorganisms that easily acquire resistance to antibiotics and that are the etiological cause of severe infections, there is Acinetobacter baumannii. Carbapenems are the principal agents used to treat A. baumannii infections. However, when strains develop resistance to this class of antibiotics, colistin is considered one of the last-resort drugs. However, the appearance of resistance to colistin also makes treatment of the Acinetobacter infections very difficult. Antimicrobial peptides (AMP) from the innate immunity hold promise as new alternative antibiotics due to their multiple biological properties. In this study, we characterized the activity and the membrane-perturbing mechanism of bactericidal action of a derivative of a frog-skin AMP, namely Esc(1-21), when used alone or in combination with colistin against multidrug-resistant A. baumannii clinical isolates. We found that the mixture of the two compounds had a synergistic effect in inhibiting the growth and killing of all of the tested strains. When combined at dosages below the minimal inhibitory concentration, the two drugs were also able to slow down the microbial growth and to potentiate the membrane-perturbing effect. To the best of our knowledge, this is the first report showing a synergistic effect between AMPs, i.e., Esc(1-21), and colistin against colistin-resistant A. baumannii clinical isolates, highlighting the potential clinical application of such combinational therapy.

Head and neck cancer (HNC) concerns more than 890,000 patients worldwide annually and is associated with the advanced stage at presentation and heavy outcomes. Alcohol drinking, together with tobacco smoking, and human papillomavirus infection are the main recognized risk factors. The tumorigenesis of HNC represents an intricate sequential process that implicates a gradual acquisition of genetic and epigenetics alterations targeting crucial pathways regulating cell growth, motility, and stromal interactions. Tumor microenvironment and growth factors also play a major role in HNC. Alcohol toxicity is caused both directly by ethanol and indirectly by its metabolic products, with the involvement of the oral microbiota and oxidative stress; alcohol might enhance the exposure of epithelial cells to carcinogens, causing epigenetic modifications, DNA damage, and inaccurate DNA repair with the formation of DNA adducts. Long-term markers of alcohol consumption, especially those detected in the hair, may provide crucial information on the real alcohol drinking of HNC patients. Strategies for prevention could include food supplements as polyphenols, and alkylating drugs as therapy that play a key role in HNC management. Indeed, polyphenols throughout their antioxidant and anti-inflammatory actions may counteract or limit the toxic effect of alcohol whereas alkylating agents inhibiting cancer cells’ growth could reduce the carcinogenic damage induced by alcohol. Despite the established association between alcohol and HNC, a concerning pattern of alcohol consumption in survivors of HNC has been shown. It is of primary importance to increase the awareness of cancer risks associated with alcohol consumption, both in oncologic patients and the general population, to provide advice for reducing HNC prevalence and complications.

Gram-negative bacilli septic thrombosis (GNB-ST) represents a subtle and often misleading condition, potentially fatal if not recognized early and requiring prolonged antimicrobial therapy and anticoagulation. Herein, reported for the first time, is a very challenging case of Klebsiella producing carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) ST unresponsive to ceftazidime/avibactam (CZA) relapsed first with meropenem/vaborbactam (MVB) monotherapy and subsequently cured with MVB plus fosfomycin (FOS) combination. The present case highlights the possibility of CZA underexposure on the infected thrombus and the risk of in vivo emergence of CZA resistance in the setting of persistent bacteremia and sub-optimal anticoagulation. Pharmacokinetic analyses showed that both MVB and FOS were in the therapeutic range. In vitro studies demonstrated a high level of MVB + FOS synergism that possibly allowed definitive resolution of the endovascular infection.

Candida bloodstream infection (BSI) represents a growing infective problem frequently associated to biofilm production due to the utilization of intravascular devices. Candida species distribution (n = 612 strains), their biofilm production and hospital antifungal drug consumption were evaluated in different wards of a tertiary care academic hospital in Italy during the years 2011-2016. In the considered time window, an increasing number of Candida BSI (p = 0.005) and of biofilm producing strains were observed (p

Caesium lead halide perovskites were recently demonstrated to be a relevant class of semiconductors for photonics and optoelectronics. Unlike CsPbBr3 and CsPbI3, the realization of high-quality thin films of CsPbCl3, particularly interesting for highly efficient white LEDs when coupled to converting phosphors, is still a very demanding task. In this work we report the first successful deposition of nanocrystalline CsPbCl3 thin films (70–150 nm) by radio frequency magnetron sputtering on large-area substrates. We present a detailed investigation of the optical properties by high resolution photoluminescence (PL) spectroscopy, resolved in time and space in the range 10–300 K, providing quantitative information concerning carriers and excitons recombination dynamics. The PL is characterized by a limited inhomogeneous broadening (~15 meV at 10 K) and its origin is discussed from detailed analysis with investigations at the micro-scale. The samples, obtained without any post-growth treatment, show a homogeneous PL emission in spectrum and intensity on large sample areas (several cm2). Temperature dependent and time-resolved PL spectra elucidate the role of carrier trapping in determining the PL quenching up to room temperature. Our results open the route for the realization of large-area inorganic halide perovskite films for photonic and optoelectronic devices.

Acinetobacter baumannii is involved in life-threatening nosocomial infections, mainly in the intensive care units (ICUs), and often colistin may represent the last therapeutic opportunity. The susceptibility to colistin of 51 epidemiologically typed A. baumannii strains isolated in 2017 from clinical samples of patients hospitalized in the ICU of a tertiary care academic hospital was investigated. All isolates were carbapenem-resistant due to the presence of the blaOXA-23 gene in sequence group 1 (international clonal lineage II) and sequence group 4 (related to international clonal lineage II) isolates, and to the blaOXA-24/40 gene in sequence group 2 (international clonal lineage I) isolates. Vitek®2, agar diffusion, and broth microdilution tests showed major discordancy (≥2 dilution factors) in the minimum inhibitory concentration (MIC) values for colistin in 24 out of 51 isolates, resulting in erroneous reporting of qualitative susceptibility data for eight isolates. In growth kinetics experiments in the presence of colistin, five isolates grew with drug concentrations above the susceptibility breakpoint when incubated for >12 h, and three isolates showed the presence of heteroresistant subpopulations. This study highlights that the high frequency of isolation of carbapenem-resistant A. baumannii strains in high-risk infectious wards requires an accurate application of methods for detecting susceptibility to antibiotics, in particular to colistin, so as to ensure a correct therapeutic approach.

Objectives: To assess real-world effectiveness, safety, and usage of erenumab in Canadian patients with episodic and chronic migraine with prior ineffective prophylactic treatments., Background: In randomized controlled trials, erenumab demonstrated efficacy for migraine prevention in patients with ≤4 prior ineffective prophylactic migraine therapies. The "Migraine prevention with AimoviG: Informative Canadian real-world study" (MAGIC) assessed real-world effectiveness of erenumab in Canadian patients with migraine., Methods: MAGIC was a prospective open-label, observational study conducted in Canadian patients with chronic migraine (CM) and episodic migraine (EM) with two to six categories of prior ineffective prophylactic therapies. Participants were administered 70 mg or 140 mg erenumab monthly based on physician's assessment. Migraine attacks were self-assessed using an electronic diary and patient-reported outcome questionnaires. The primary outcome was the proportion of subjects achieving ≥50% reduction in monthly migraine days (MMD) after the 3-month treatment period., Results: Among the 95 participants who mostly experienced two (54.7%) or three (32.6%) prior categories of ineffective prophylactic therapies and who initiated erenumab, treatment was generally safe and well tolerated; 89/95 (93.7%) participants initiated treatment with 140 mg erenumab. At week 12, 32/95 (33.7%) participants including 17/64 (26.6%) CM and 15/32 (48.4%) EM achieved ≥50% reduction in MMD while 30/86 (34.9%) participants including 19/55 (34.5%) CM and 11/31 (35.5%) EM achieved ≥50% reduction in MMD at week 24. Through patient-reported outcome questionnaires, 62/95 (65.3%) and 45/86 (52.3%) participants reported improvement of their condition at weeks 12 and 24, respectively. Physicians observed improvement in the condition of 78/95 (82.1%) and 67/86 (77.9%) participants at weeks 12 and 24, respectively., Conclusion: One-third of patients with EM and CM achieved ≥50% MMD reduction after 3 months of erenumab treatment. This study provides real-world evidence of erenumab effectiveness, safety, and usage for migraine prevention in adult Canadian patients with multiple prior ineffective prophylactic treatments., (© 2022 Novartis Pharmaceuticals Canada Inc. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line., Methods: A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses., Results: Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention., Interpretation: We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Patients with chronic migraine and medication overuse are significant consumers of health care resources., Objective: To determine whether botulinum toxin type A prophylaxis reduces the cost of acute migraine medications in patients with chronic migraine and triptan overuse., Methods: In this multicenter, open-label study, patients with chronic migraine (≥ 15 headache days/month) who were triptan overusers (triptan intake ≥ 10 days/month for ≥ 3 months) received botulinum toxin type A (95-130 U) at baseline and month three. Headache (HA) frequency and medication use were assessed with patient diaries, and headache-related disability by means of the MIDAS and Headache Impact Test-6 questionnaires., Results: Of 53 patients enrolled (mean age ± standard deviation, 46.5 years ± 8.4; 47 [88.7%] females), 48 (90.6%) completed the study at month six. Based on headache diaries, significant (P ≤ 0.0002) decreases from baseline were observed for days per month with headache/migraine, days with any acute headache medication use, days with triptan use, and triptan doses taken per month. A significant (P < 0.0001) increase from baseline in headache-free days per month was also observed. Prescription medication costs for acute headache medications decreased significantly, including significant reductions in triptan costs (mean reduction of -C$106.32 ± 122.87/month during botulinum toxin type A prophylaxis; P < 0.0001). At baseline, 78% of patients had severe disability (MIDAS score) and 86.8% had severe impact due to headache (HIT-6 scores); at month six, this decreased to 60% and 68%, respectively., Conclusions: Botulinum toxin type A prophylactic therapy markedly decreased costs related to acute headache medication use in patients with chronic migraine and triptan overuse.

Objective: The objective of this study was to compare the headache impact test (HIT-6) and the migraine disability assessment scale (MIDAS) as clinical measures of headache-related disability., Background: The degree of headache-related disability is an important factor in treatment planning. Many quality of life and headache disability measures exist but it is unclear which of the available disability measures is the most helpful in planning and measuring headache management., Methods: We compared HIT-6 and MIDAS scores from 798 patients from the Canadian Headache Outpatient Registry and Database (CHORD). Correlation and regression analyses were used to examine the relationships between the HIT-6 and MIDAS total scores, headache frequency and intensity, and Beck Depression Inventory (BDI-II) scores., Results: A positive correlation was found between HIT-6 and MIDAS scores (r = 0.52). The BDI-II scores correlated equally with the HIT-6 and the MIDAS (r = 0.42). There was a non-monotonic relationship between headache frequency and the MIDAS, and a non-linear monotonic relationship between headache frequency and the HIT-6 (r = 0.24). The correlation was higher between the intensity and the HIT-6 scores (r = 0.46), than MIDAS (r = 0.26) scores. Seventy-nine percent of patients fell into the most severe HIT-6 disability category, compared with the 57% of patients that fell into the most severe MIDAS disability category. Significantly more patients were placed in a more severe category with the HIT-6 than with the MIDAS (McNemar chi-square = 191 on 6 d.f., P < .0001)., Conclusions: The HIT-6 and MIDAS appear to measure headache-related disability in a similar fashion. However, some important differences may exist. Headache intensity appears to influence HIT-6 score more than the MIDAS, whereas the MIDAS was influenced more by headache frequency. Using the HIT-6 and MIDAS together may give a more accurate assessment of a patient's headache-related disability.

The goal of the Canadian Migraine Forum was to work towards improving the lives of Canadians with migraine by reducing their migraine-related disability. Migraine has been ranked 19th by the World Health Organization among causes of years of life lived with disability. To improve management of migraine in Canada, the participants in the forum identified several important needs and strategies. There is a need for more leaders in the field of migraine to work with other stakeholders to obtain funding and develop treatment programs across Canada. Leadership is also required to address the under use of both migraine specific symptomatic medications and prophylactic medications in Canada. More non-physician health professionals are required to work with physicians in migraine treatment teams. This could assist with a shortage of physician resources, and could also help to better meet the needs of the migraine patient. Individuals with migraine need to be identified who could work with health care professionals to help meet the needs of the migraine patients in our communities. Application of the chronic disease management model for migraine treatment was also seen as an important factor for the management of migraine. Programs are needed to promote earlier diagnosis, long-term follow-up, comprehensive patient education, and the use of multidisciplinary treatment teams where appropriate. Also considered important was the need to increase knowledge about migraine through public awareness campaigns, websites, medical education, and appropriate reading material for patients. The public needs to be aware that migraine is a biological disorder that can cause significant disability and suffering. Lastly, there is a pressing need to promote more migraine research, including careful outcome assessments for treatment programs that involve non-pharmacological treatments and a team based approach to migraine management. There are many challenges that must be overcome if we are to be successful in reducing migraine related disability in Canada. Success will depend upon the joint efforts of physicians, other healthcare professionals, individuals with migraine, and the public at large.

Background: The buildup time of migraine headaches has not been well delineated in publications to date and we are aware of patients whose migraines last well over 72 hours. More concentration on these factors in the assessment of patients might lead to more appropriate therapeutic choices., Method: Prospective ascertainment of such data through a questionnaire completed by 253 informed and willing patients with IHS migraine with or without aura consulting Canadian headache specialists. Data were electronically sent to a central computer from each center, tabulated and analyzed using standard statistical parameters., Results: In 253 patients with migraine ascertained using applied IHS criteria, nausea was a feature in over 90% of cases, especially in those with aura. This inhibited the ingestion of oral medications in about a quarter of all subjects. The time to build from no pain to moderate/severe pain was shorter in subjects with auras and was less than 2 hours in 97% of those with and 86% of those without auras. However, we also identified a group of subjects with migraine (over 10% of all) in whom the build time to maximum pain is delayed for over 2 hours. Nausea was experienced by 91.7% of subjects, slightly but significantly later in those without auras. While most headaches in each group lasted from 4 to 72 hours, 24.3% of those with and 20.6% of those without aura expected to experience pain for more than 72 hours, while in untreated cases disability due to pain, nausea, or malaise usually persisted for over 3 days in 24.3% and 16.7% of those with and without aura, respectively. One-fifth of migraineurs may be in pain and/or disabled by accompanying symptoms for over 3 days in a typical migraine attack. Over half of our subjects reported that their medications worked well or excellently., Conclusions: Attacks of migraine in real-life clinical situations vary somewhat from the IHS criteria in that they are more often associated with nausea that interferes with oral therapy; can persist for over 72 hours; may have slow (>2 hours) buildup to maximum pain in 10% of cases; and may cause disability for over 3 days. Nevertheless, current therapeutic regimens (including prescribed medications) work well for a substantial majority.

Objective: To examine demographic characteristics and clinical features of headache patients referred to neurologists specializing in headache in Canada., Methods: Demographic and clinical data were collected at the time of consultation for 865 new headache patients referred to five headache-specialty clinics in Canada. The Headache Impact Test (HIT-6) and Migraine Disability Questionnaire (MIDAS) were used to measure headache impact and disability. Data were analyzed as part of the Canadian Headache Outpatient Registry and Database (CHORD) Project., Results: The average age of the patients was 40 years and the majority were female (78%). Most were employed either full time (49%) or part time (13%). The majority of patients were diagnosed with either migraine or tension-type headache (78%). Over a third of patients experienced headache every day, and half had experienced a headache in the previous month which was of severe intensity. Most (80%) scored in the "very severe" category of the HIT-6 and over half (55%) were severely disabled as measured by the MIDAS., Conclusion: Patients referred to headache specialists in Canada are severely disabled by their headache disorders. These patients are in the most productive phase of their lives in terms of age and employment. It is important to provide the best available treatment to headache patients in order to minimize the disability and impact of their headache disorders.

Objective: To determine which medications UK migraineurs have access to and assess the usage of these products in a 'real-life' setting., Research Design and Methods: Data were collected using an online questionnaire, which subjects were directed to by advertisements in pharmacies, a UK national newspaper, on the internet and information on the Migraine Action Association website and newsletters. Respondents were eligible for inclusion if attacks fulfilled International Headache Society criteria for migraine and/or if previously diagnosed by a physician as having migraine., Main Outcome Measures: Respondents were asked to specify which products had been prescribed or purchased for migraine treatment. The pattern of use of these products was determined, including the reasons why respondents chose particular products to treat attacks., Results: Of 3072 eligible respondents, the majority had purchased a variety of over-the-counter (OTC) medicines for treatment of attacks. Eighty-seven per cent had been diagnosed by a physician and were prescribed multiple products (average 1.68); 45% received triptans, but 26% were still prescribed products that were also available OTC. Over half (52%) of respondents initially used an OTC medicine to treat the last migraine attack. However, 73% required a second dose/product, mainly as a result of lack of efficacy of the first dose/product. Respondents using triptans were less likely to require a second dose/product than those not using triptans (52% vs. 78%, respectively). The two main reasons for choosing a triptan to treat an attack were the need for quick control and the severity of the attack. Satisfaction with regard to migraine medication was higher among triptan-users than nontriptan users., Conclusions: Medicines that are available OTC are often used as first-line therapy for migraine despite many migraineurs having access to prescription therapies such as triptans. Many migraineurs require a second dose/product, possibly indicating sub-optimal treatment efficacy. Physicians should consider the range of migraine-specific treatments available, including triptans, in order to develop a treatment plan that is based on the patient's needs and preferences.

Chronic Inflammatory Demyelinating Polyneuropathies (CIDP) are characterized by demyelination of peripheral nerves with mononuclear cell infiltrates, electrical conduction slowing or block and elevated cerebrospinal fluid protein with no cells. An immune mediated pathogenesis has been suggested. Immune suppressive therapy, as well as plasmapheresis and intravenous immunoglobulins have been used with variable success. Our objective was to review our results of plasma exchange in this disease in 20 patients with very different underlying diseases, none of them eligible for the Canadian CIDP plasmapheresis study, and define certain guidelines of predictability for the effectiveness of plasma exchange. Five patients had monoclonal gammopathies of unknown significance, two had lung cancer, one breast cancer, one hairy cell leukemia and later carcinoma of the pancreas; two had hepato-splenomegaly and hemolytic anemia; nine were idiopathic (two with autoimmune markers). Plasmapheresis varied from 4 to 31 plasma volumes and procedures with a median of 12, always with 5% albumin. Two excellent responses, one very good, two moderate transient and 12 had no change in clinical or conduction status. Best response occurred in paraproteinemias. Thus immune modulation with plasma exchange may be useful in CIDPs with paraproteinemias and autoimmune manifestations.

The muscular makeup of the sprint-trained athlete may make him especially susceptible to severe lactic acidosis from cocaine-induced seizures. Because of a high percentage of glycolytic muscle fibers (compared to the muscle fiber type of the endurance-trained athlete), the lactic acidosis and heat generated from muscular activity is much greater in the sprint-trained athlete than in the endurance-trained athlete. The role of cocaine in producing seizures and increasing glycolysis, both of which produce lactic acidosis, is discussed. The hypothesis is presented that the elite athlete may be at greater risk of death than the general population from lactic acidosis produced as a result of cocaine-induced seizures.

The purpose of this study was to determine the effect of acute furosemide administration on urine acidification. U-B Pco2 was used to assess collecting-duct hydrogen ion secretion in rabbits infused with bicarbonate. Prior to furosemide administration, the U-B Pco2 was virtually zero, indicating very low or absent hydrogen ion secretion in the collecting duct. Intravenous furosemide infusion resulted in a significant increase in the U-B Pco2. This increase could not be attributed to changes in blood Pco2, plasma potassium concentration, or urine phosphate concentration and buffer capacity. Furthermore, the rise in U-B Pco2 was independent of any change in urine bicarbonate concentration. We conclude that furosemide leads to an augmentation of collecting-duct hydrogen ion secretion in the rabbit, perhaps by increasing sodium reabsorption in the collecting duct.

A young woman presented with typical diabetic ketoacidosis. Five hours after insulin had been given hyperchloremic metabolic acidosis developed. This could not be attributed to gastrointestinal loss of bacarbonate, ingestion of HCI or carbonic anhydrase inhibitor, or the administered fluids and electrolytes. The combination of hyperchloremic metabolic acidosis and a urine pH of 5.6 during acidemia prompted specific studies that established the presence of disorders of renal acidification. A transient defect of hydrogen ion secretion in the distal nephron was suggested by the decrease in urine-blood Pco-2 gradient after administration of sodium bicarbonate. Proximal renal tubular acidosis was indicated by the reduced bicarbonate threshold that persisted for approximately 7 weeks.

We used technetium Tc 99m medronate (methylene diphosphonate) scanning in the treatment of seven patients with rhabdomyolysis. In three patients the intense, diffuse, symmetric nature of the scans was suggestive of an underlying metabolic muscle disorder. The scans defined the extent of the muscle injury in three patients and demonstrated muscle injury that was not initially suspected in two patients. The scan also demonstrated clinically unsuspected metastatic pulmonary and gastric calcifications in one patient. All scans showed evidence of renal dysfunction. In conclusion, these cases demonstrate that Tc 99m medronate scanning helps to define the extent and location of muscle injury in rhabdomyolysis, and that diffuse muscle uptake of Tc 99m medronate may be associated with metabolic muscle disease.

The purpose of this study was to investigate distal nephron hydrogen ion secretion in the intact animal. The rabbit was chosen as the experimental model because it produces acid urine containing little ammonium. Upon replacement of the usual rabbit diet with milk, plus administration of an acid load (10 mEq/kg), the urine pH fell consistently from very alkaline values (PH greater than 7.4) to 4.8 +/- 0.2. Despite the ability to achieve high urine-to-blood hydrogen ion concentration gradients, the U-B PCO2, an index of collecting duct hydrogen ion secretion, was virtually zero. In these studies, the urine bicarbonate and buffer concentration were comparable to those observed in dog, rat, and man in which a high U-B PCO2 gradient was achieved. The rabbits studied had low plasma potassium concentrations (less than 3 mEq/L). Since potassium deficiency has been implicated in impaired urine acidification, potassium was administered, and it resulted in an increase in collecting duct hydrogen ion secretion as evidenced by a further fall in minimum urine pH during acidemia and a prompt rise in the U-B PCO2 during alkali administration. In summary, rabbits had a very low but not absent rate of collecting duct hydrogen ion secretion. Potassium administration increased the rate of hydrogen ion secretion in a segment of the collecting duct in which hydrogen ion secretion is reflected by an increase U-B PCO2.