Exploring Definitions and Predictors of Severe Asthma Clinical Remission after Biologic Treatment in Adults.

Rationale: There is no consensus on criteria to include in an asthma remission definition in real life. Factors associated with achieving remission after biologic initiation remain poorly understood. Objectives: To quantify the proportion of adults with severe asthma achieving multidomain-defined remission after biologic initiation and identify prebiologic characteristics associated with achieving remission that may be used to predict it. Methods: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1 year before and after biologic initiation. A priori-defined remission cutoffs were: 0 exacerbations/yr, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted FEV1 ⩾ 80%. Remission was defined using two (exacerbations + LTOCS), three (+control or +lung function), and four of these domains. The association between prebiologic characteristics and postbiologic remission was assessed by multivariable analysis. Measurements and Main Results: A total of 50.2%, 33.5%, 25.8%, and 20.3% of patients met criteria for two-, three- (+control), three- (+lung function), and four-domain remission, respectively. The odds of achieving four-domain remission decreased by 15% for every additional 10 years of asthma duration (odds ratio, 0.85; 95% confidence interval, 0.73-1.00). The odds of remission increased in those with fewer exacerbations per year, lower LTOCS daily dose, better control, and better lung function before biologic initiation. Conclusions: One in five patients achieved four-domain remission within 1 year of biologic initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission after biologic treatment, indicating that biologic treatment should not be delayed if remission is the goal.

Correlation between magnesium pre-loading and cisplatin-induced nephrotoxicity in 5-fluorouracil/cisplatin combination therapy for esophageal cancer.

The use of cisplatin may cause nephrotoxicity in patients. Hydration solutions supplemented with magnesium could reduce cisplatin-induced nephrotoxicity. In this study, we evaluated the preventive effect of magnesium pre-loading on cisplatin-induced nephrotoxicity in patients with esophageal cancer. We retrospectively evaluated the prevalence of, and risk factors for, nephrotoxicity in 160 patients with esophageal cancer treated with the 5-fluorouracil/cisplatin regimen from 2014 to 2016 with and without magnesium supplementation. Significant differences were observed between the magnesium and non-magnesium groups in terms of frequency of estimated creatinine clearance of grade 2 or higher that was at 4% (n = 3) and 13% (n = 10) (p = 0.027), respectively. The logistic regression analysis revealed that eCcr of grade 2 or higher was significantly associated with the non-magnesium regimen (odds ratio (OR), 4.175; 95% confidence interval (CI) = 1.061-16.430; p = 0.041) and age ≥ 65 years (OR, 13.951; 95% CI = 1.723-112.974; p = 0.014). This study suggests that 20 mEq magnesium pre-loading significantly reduces the prevalence of cisplatin-induced nephrotoxicity. Furthermore, when cisplatin is administered to individuals older than 64 years, a close observation for the onset of cisplatin-induced nephrotoxicity is crucial.

Sclerostin in the development of osteoarthritis: A mini review.

Wnt signalling plays an important role in bone and cartilage metabolism. Activation of Wnt signalling promotes bone formation but cartilage degradation. Sclerostin (SOST) can inhibit Wnt signalling. It is expressed by chondrocytes in the articular cartilage and osteocytes in the subchondral bone. Since osteoarthritis (OA) is a joint degenerative disease involving both bone and joint compartments, SOST may have a role in mediating the progression of this disease. This review examined the current literature on the role of SOST in the pathogenesis of OA and its usefulness as a biomarker of OA. Most studies agree that SOST is upregulated as a rescue mechanism in OA to prevent further degenerative changes of the joint. It antagonises inflammation-induced cartilage catabolism while preserving chondrocyte anabolic activities. It also prevents abnormal bone mineralisation and osteophyte formation. However, studies on the performance of SOST as a biomarker to detect and stage OA are limited. Further studies are required to determine whether SOST can be a biomarker or therapeutic target for OA.

Ultrasound-guided fascial plane blocks of the chest wall: a state-of-the-art review.

Ultrasound-guided fascial plane blocks of the chest wall are increasingly popular alternatives to established techniques such as thoracic epidural or paravertebral blockade, as they are simple to perform and have an appealing safety profile. Many different techniques have been described, which can be broadly categorised into anteromedial, anterolateral and posterior chest wall blocks. Understanding the relevant clinical anatomy is critical not only for block performance, but also to match block techniques appropriately with surgical procedures. The sensory innervation of tissues deep to the skin (e.g. muscles, ligaments and bone) can be overlooked, but is often a significant source of pain. The primary mechanism of action for these blocks is a conduction blockade of sensory afferents travelling in the targeted fascial planes, as well as of peripheral nociceptors in the surrounding tissues. A systemic action of absorbed local anaesthetic is plausible but unlikely to be a major contributor. The current evidence for their clinical applications indicates that certain chest wall techniques provide significant benefit in breast and thoracic surgery, similar to that provided by thoracic paravertebral blockade. Their role in trauma and cardiac surgery is evolving and holds great potential. Further avenues of research into these versatile techniques include: optimal local anaesthetic dosing strategies; high-quality randomised controlled trials focusing on patient-centred outcomes beyond acute pain; and comparative studies to determine which of the myriad blocks currently on offer should be core competencies in anaesthetic practice.

Outcomes after curative therapy for hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: a meta-analysis and review of current literature.

BACKGROUND: This systematic review and meta-analysis aimed to compare the outcomes of curative therapy (resection, transplantation, ablation) for hepatocellular carcinoma (HCC) arising from non-alcoholic fatty liver disease (NAFLD) and non-NAFLD etiologies. METHODS: A systematic search of PubMed, EMBASE and Cochrane Library was conducted for studies comparing survival, peri- and post-operative outcomes. Quality assessment was performed using the Newcastle-Ottawa scale. RESULTS: Findings for 5579 patients were pooled across 9 studies and examined. Analysis demonstrated improved disease-free survival (DFS; HR 0.85, 95% CI 0.74-0.98, p = 0.03) and overall survival (OS; HR 0.87; 95% CI 0.81-0.93; p < 0.0001) in NAFLD-HCC patients undergoing liver resection as compared to non-NAFLD HCC patients. NAFLD-HCC patients undergoing all forms of curative therapy were similarly associated with improved OS (HR 0.96; 95% CI 0.86-1.06; p = 0.40) and DFS (HR 0.85; 95% CI 0.74-0.98; p = 0.03), albeit results being significant only for DFS. Only 2 studies reported higher rates of peri- and post-operative complications in patients with NAFLD-HCC. Significant inter-study heterogeneity precluded further analysis. CONCLUSION: NAFLD-HCC patients can enjoy long-term survival benefit with aggressive curative therapy. Peri- and post-operative morbidity should be mitigated with pre-operative optimization of comorbidities, and deliberately close post-operative monitoring.

International severe asthma registry (ISAR): protocol for a global registry.

BACKGROUND: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. METHODS: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. CONCLUSIONS: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

Advances in regional anaesthesia and acute pain management: a narrative review.

Regional anaesthesia has undergone several exciting advances in the past few decades. Ultrasound-guided techniques of peripheral nerve blockade have become the gold standard thanks to the associated improvements in efficacy, ease of performance and safety. This has increased the accessibility and utilisation of regional anaesthesia in the anaesthesia community at large and is timely given the mounting evidence for its potential benefits on various patient-centred outcomes, including major morbidity, cancer recurrence and persistent postoperative pain. Ultrasound guidance has also paved the way for refinement of the technical performance of existing blocks concerning simplicity and safety, as well as the development of new regional anaesthesia techniques. In particular, the emergence of fascial plane blocks has further broadened the application of regional anaesthesia in the management of painful conditions of the thorax and abdomen. The preliminary results of investigations into these fascial plane blocks are promising but require further research to establish their true value and role in clinical care. One of the challenges that remains is how best to prolong regional anaesthesia to maximise its benefits while avoiding undue harm. There is ongoing research into optimising continuous catheter techniques and their management, intravenous and perineural pharmacological adjuncts, and sustained-release local anaesthetic molecules. Finally, there is a growing appreciation for the critical role that regional anaesthesia can play in an overall multimodal anaesthetic strategy. This is especially pertinent given the current focus on eliminating unnecessary peri-operative opioid administration.

The role of serratus anterior plane and pectoral nerves blocks in cardiac surgery, thoracic surgery and trauma: a qualitative systematic review.

Serratus anterior plane and pectoral nerves blocks are recently described alternatives to established regional anaesthesia techniques in cardiac surgery, thoracic surgery and trauma. We performed a systematic review to establish the current state of evidence for the analgesic role of these fascial plane blocks in these clinical settings. We identified relevant studies by searching multiple databases and trial registries from inception to June 2019. Study heterogeneity prevented meta-analysis and studies were instead qualitatively summarised and stratified by type of surgery and comparator. We identified 51 studies: nine randomised control trials; 13 cohort studies; 19 case series; and 10 case reports. The majority of randomised controlled trials studied the serratus anterior plane block in thoracotomy or video-assisted thoracoscopic surgery, with only two investigating pectoral nerves blocks. The evidence in thoracic trauma comprised only case series and reports. Results indicate that single-injection serratus anterior plane and the pectoral nerves blocks reduce pain scores and opioid consumption compared with systemic analgesia alone in cardiothoracic surgery, cardiac-related interventional procedures and chest trauma for approximately 6-12 h. The duration of action appears longer than intercostal nerve blocks but may be shorter than thoracic paravertebral blockade. Block duration may be prolonged by a continuous catheter technique with potentially similar results to thoracic epidural analgesia. There were no reported complications and the risk of haemodynamic instability appears to be low. The current evidence, though limited, supports the efficacy and safety of serratus anterior plane and the pectoral nerves blocks as analgesic options in cardiothoracic surgery.

Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study.

Healthcare workers involved in aerosol-generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID-19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID-19. Information on tracheal intubation episodes, personal protective equipment use and subsequent provider health status was collected via self-reporting. The primary endpoint was the incidence of laboratory-confirmed COVID-19 diagnosis or new symptoms requiring self-isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure-related factors and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow-up of 32 (18-48 [0-116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1% and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in women, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID-19 subsequently reported a COVID-19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID-19 transmission.

Analgesic efficacy of the Pecs II block: a systematic review and meta-analysis.

Surgery is the primary therapeutic intervention for breast cancer and can result in significant postoperative pain. We searched the current literature and performed a meta-analysis in order to compare the analgesic efficacy of the pectoral type-2 (Pecs II) block with systemic analgesia alone and with a thoracic paravertebral block for breast cancer surgery. Primary outcome was postoperative opioid consumption in the first 24 h after surgery. Secondary outcomes were pain scores at 0, 3, 6, 9 and 24 h after surgery, intra-operative opioid consumption, time to first analgesic request and incidence of postoperative nausea and vomiting. We identified 13 randomised controlled trials that included 815 patients. The Pecs II block significantly reduced postoperative opioid consumption (standardised difference in means: -13.64 mg oral morphine equivalents; 95%CI: -21.22 to -6.05; p < 0.01) and acute postoperative pain at all intervals in the first 24 h after surgery compared with systemic analgesia alone. Compared with the thoracic paravertebral block, the Pecs II block resulted in similar postoperative opioid consumption (standardised difference in means: -8.73 mg oral morphine equivalents; 95%CI: -18.16 to 0.69; p = 0.07) and postoperative pain scores after first measurement. In conclusion, the Pecs II block offers improved analgesic efficacy compared with systemic analgesia alone and comparable analgesic efficacy to a thoracic paravertebral block for breast cancer surgery.

The effect of erector spinae plane block on respiratory and analgesic outcomes in multiple rib fractures: a retrospective cohort study.

Regional anaesthesia is often helpful in improving respiratory function and analgesia following multiple rib fractures. The erector spinae plane block has become the technique of choice in our institution due to its relative simplicity and purported safety. The aim of this retrospective cohort study was to determine its effectiveness in improving respiratory and analgesic outcomes. We reviewed electronic medical records of patients with traumatic rib fractures admitted to a level-one trauma centre between January 2016 and July 2017, who also received erector spinae plane blocks. We analysed the following outcomes before and up to 72 h after erector spinae plane blockade: incentive spirometry volume; maximum numerical rating scale static pain scores; and 12-h opioid consumption. Pre- and post-block data were compared. We included 79 patients, 77% of whom received continuous erector spinae plane block for a mean (SD) of 3.7 (1.9) days. The majority (85%) had other associated injuries. Incentive spirometry volumes improved from 784 (694) to 1375 (667) ml (p < 0.01) during the first 24 h following erector spinae plane blockade. Pain scores were reduced from 7.7 (2.5) to 4.7 (3.2) in the first three hours (p < 0.01). Reductions in opioid consumption were observed but did not achieve statistical significance. These improvements were largely sustained for up to 72 h. Mean arterial blood pressure remained unchanged from baseline. In conclusion, erector spinae plane blocks were associated with improved inspiratory capacity and analgesic outcomes following rib fracture, without haemodynamic instability. We propose that it should be considered to be a viable alternative to other regional analgesic techniques when these are not feasible.

Prognostic impact of FOXF1 polymorphisms in gastric cancer patients.

A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.

(Radio)fluoroclick Reaction Enabled by a Hydrogen-Bonding Cluster.

We have developed a widely applicable nucleophilic (radio)fluoroclick reaction of ynamides with readily available and easy-to-handle KF(18 F). The reactions exhibited high functional-group tolerance and needed only an ambient atmosphere. This 18 F addition to C-C unsaturated bonds proceeded with extraordinarily high radiochemical yields.

The analgesic efficacy of pre-operative bilateral erector spinae plane (ESP) blocks in patients having ventral hernia repair.

Laparoscopic ventral hernia repair is an operation associated with significant postoperative pain, and regional anaesthetic techniques are of potential benefit. The erector spinae plane (ESP) block performed at the level of the T5 transverse process has recently been described for thoracic surgery, and we hypothesised that performing the ESP block at a lower vertebral level would provide effective abdominal analgesia. We performed pre-operative bilateral ESP blocks with 20-30 ml ropivacaine 0.5% at the level of the T7 transverse process in four patients undergoing laparoscopic ventral hernia repair. Median (range) 24-h opioid consumption was 18.7 mg (0.0-43.0 mg) oral morphine. The highest and lowest median (range) pain scores in the first 24 h were 3.5 (3.0-5.0) and 2.5 (0.0-3.0) on an 11-point numerical rating scale. We also performed the block in a fresh cadaver and assessed the extent of injectate spread using computerised tomography. There was radiographic evidence of spread extending cranially to the upper thoracic levels and caudally as far as the L2-L3 transverse processes. We conclude that the ESP block is a promising regional anaesthetic technique for laparoscopic ventral hernia repair and other abdominal surgery when performed at the level of the T7 transverse process. Its advantages are the ability to block both supra-umbilical and infra-umbilical dermatomes with a single-level injection and its relative simplicity.

A radiologic and anatomic assessment of injectate spread following transmuscular quadratus lumborum block in cadavers.

We performed bilateral transmuscular quadratus lumborum blocks in six cadavers using iodinated contrast and methylene blue. Computed tomography imaging was performed in four cadavers and anatomical dissection was completed in five. This demonstrated spread to the lumbar paravertebral space in 63% of specimens, laterally to the transversus abdominis muscle in 50% and caudally to the anterior superior iliac spine in 63% of specimens. There was no radiographic evidence of spread to the thoracic paravertebral space. Anatomical dissection revealed dye staining of the upper branches of the lumbar plexus and the psoas major muscle in 70% of specimens. Further clinical studies are required to confirm if the quadratus lumborum block might be a suitable alternative to lumbar plexus block.

Failure of neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma.

Neoadjuvant treatment has become standard care for patients with resectable esophageal cancer. However, some patients cannot undergo surgery or curative resection because of disease progression during neoadjuvant treatment. The aim of this study is to identify the pretreatment characteristics of patients in whom neoadjuvant treatment failed. The study enrolled 231 patients who underwent chemotherapy with cisplatin and 5-fluorouracil (CF) as neoadjuvant therapy for T1N1-3 or T2-3 any-N esophageal squamous cell carcinoma (ESCC). Of these patients, 201 (87.0%) underwent curative resection (R0) and 30 (13.0%) could not undergo curative resection; 19 patients (8.2%) underwent incomplete resection (R1 or R2), and 11 patients (4.8%) could not undergo surgery because of disease progression. We compared clinical characteristics and survival between patients who underwent curative resection (curative group) and those who could not undergo curative resection (noncurative group) to determine the factors predicting noncurative treatment. The noncurative group had significantly worse disease-specific survival than the curative group (P < 0.001). All patients in the noncurative group had cT3 tumors. In 141 patients with cT3 tumors, those in the noncurative group were more likely to have higher serum SCC antigen concentration (P = 0.021), location of the main tumor in the upper to the middle third of the esophagus (P = 0.071), intramural metastases (P < 0.001), advanced N category (P = 0.016), and bulky lymph node metastases (P = 0.060). Multivariate logistic regression analysis identified location of the main tumor in the upper to the middle third of the esophagus (P = 0.047), intramural metastases (P = 0.002), and nodal metastases (N1, P = 0.014; N2, P = 0.015, respectively) as independent predictors of treatment failure in patients with cT3 tumors. Neoadjuvant CF therapy alone may not be effective for patients with cT3 tumors accompanied by these risk factors, and the efficacy of alternative strategies, such as triplet chemotherapy or chemoradiotherapy, should be evaluated.

Assessment of radiopharmaceutical retention for vascular access ports using positron emission tomography imaging.

PURPOSE: The purpose of this study was to resolve the issue of whether various generations of CR Bard peripheral vascular access ports and catheters are prone to retain PET radiopharmaceuticals. The study evaluates the residual radioactivity remaining following injection for two PET radiopharmaceuticals currently used extensively in the clinic, FDG and Na18 F. METHODS: FDG was purchased from a local cyclotron facility and Na18 F was prepared in-house. Three generations of currently marketed vascular access ports were tested. A total of five (n = 5) of each model was tested. Radiopharmaceutical of 2-3 mCi of each was injected into each port and flushed with 10, 30, 60, and 120 ml of saline. MicroPET scans were performed after each flush to detect the residual radioactivity on each port. A dose calibrator was used to detect the retention of radioactivity after each flush. RESULTS: Radioactivity retention for all vascular port models measured by microPET imaging was similar for both FDG and Na18 F, with less than 1% residual activity following a 10 ml saline flush. Based on the microPET images, all the subsequent flushes of 30, 60, and 120 ml were also considered. Dose calibrator activity measurements validated microPET measurements as negligible for all the ports, even with the first 10 ml flush. CONCLUSIONS: MicroPET imaging was more sensitive than the dose calibrator in determining the radioactivity retention of the vascular access ports from CR Bard. These ports may be used for the injection of FDG and Na18 F to track glucose metabolism and bone uptake with PET imaging. It is recommended to apply at least a 10 ml flush after radiopharmaceutical administration, to reduce residual activity to baseline levels.

Mouth breathing, another risk factor for asthma: the Nagahama Study.

BACKGROUND: Allergic rhinitis, a known risk factor for asthma onset, often accompanies mouth breathing. Mouth breathing may bypass the protective function of the nose and is anecdotally considered to increase asthma morbidity. However, there is no epidemiological evidence that mouth breathing is independently associated with asthma morbidity and sensitization to allergens. In this study, we aimed to clarify the association between mouth breathing and asthma morbidity and allergic/eosinophilic inflammation, while considering the effect of allergic rhinitis. METHODS: This community-based cohort study, the Nagahama Study, contained a self-reporting questionnaire on mouth breathing and medical history, blood tests, and pulmonary function testing. We enrolled 9804 general citizens of Nagahama City in the Shiga Prefecture, Japan. RESULTS: Mouth breathing was reported by 17% of the population and was independently associated with asthma morbidity. The odds ratio for asthma morbidity was 1.85 (95% CI, 1.27-2.62) and 2.20 (95% CI, 1.72-2.80) in subjects with mouth breathing alone and allergic rhinitis alone, which additively increased to 4.09 (95% CI, 3.01-5.52) when mouth breathing and allergic rhinitis coexisted. Mouth breathing in nonasthmatics was a risk for house dust mite sensitization, higher blood eosinophil counts, and lower pulmonary function after adjusting for allergic rhinitis. CONCLUSION: Mouth breathing may increase asthma morbidity, potentially through increased sensitization to inhaled allergens, which highlights the risk of mouth-bypass breathing in the 'one airway, one disease' concept. The risk of mouth breathing should be well recognized in subjects with allergic rhinitis and in the general population.