Surgical and oncological score to estimate the survival benefit of resection and chemoradiotherapy in elderly (≥70 years) glioblastoma patients: A preliminary analysis.

Background: Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment. Methods: The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). Results: The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-total and subtotal resection were associated with improved survival compared to biopsy alone (respective mOS 65.3 and 28.1 vs 15.7 weeks, P < .001). Hypofractionated radiotherapy (40Gy in 15 fractions) with Temozolomide was noninferior to the Stupp protocol, P = .72. Exploratory subgroup analysis revealed a significant benefit of Temozolomide-based approaches in MGMT-methylated patients as well as a trend towards improved survival in MGMT-unmethylated patients. Our EGSS and EGOS scores successfully estimated survival in this retrospective cohort with 65% and 73% accuracy. Conclusions: Where appropriate and safe, elderly glioblastoma patients may benefit from surgical resection and combined chemoradiotherapy with Temozolomide. The proposed EGSS and EGOS scores take into account important prognostic factors to help guide which patients should receive such treatment.

Combination fixed-dose ß agonist and steroid inhaler as required for adults or children with mild asthma: a Cochrane systematic review.

BACKGROUND: In people with mild asthma poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. The use of fixed-dose combination inhalers containing an inhaled corticosteroid (ICS) and a fast-acting ß2-agonist (FABA) is established in moderate asthma, but they may also have potential utility in mild asthma. OBJECTIVES: To evaluate the efficacy and safety of single combined FABA/ICS inhaler only used as needed in people with mild asthma. DESIGN AND SETTING: Cochrane meta-analysis of available trial data. PARTICIPANTS: Children aged 12+ and adults with mild asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE and Embase, ClinicalTrials.gov and the WHO trials portal on 19 March 2021. INTERVENTIONS: A single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA.We included randomised controlled trials (RCTs) and cross-over trial. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures and applied the GRADE approach to assess the evidence. MAIN OUTCOME MEASURES: We included six studies from which 9657 participants contributed to the meta-analyses. All used dry powder budesonide and formoterol as the combination inhaler. Two studies included children aged 12+ years and two studies were open-label. FABA/ICS AS-REQUIRED VERSUS FABA AS-REQUIRED: Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared with 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence). Changes in asthma control were small and less than the minimal clinically important difference (MCID). FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reducing the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95) and may reduce total systemic steroid dose (mean difference (MD) -9.90, 95% CI -19.38 to -0.42). FABA/ICS AS REQUIRED VERSUS REGULAR ICS PLUS FABA AS REQUIRED: There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroids with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared with 65 (95% CI 49 to 86) out of 1000 in the FABA/ICS as-required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence). Changes in asthma control were small and less than MCID. Adverse events and total systemic corticosteroid doses were similar between groups. FABA/ICS as required was likely associated with less average daily exposure to ICS than those on regular ICS (MD -154.51 mcg/day, 95% CI -207.94 to -101.09). CONCLUSIONS: FABA/ICS as required is clinically effective in adults and adolescents with mild asthma and reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events compared with FABA as required alone. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely associated with increased adverse events.

Management of non-cystic fibrosis bronchiectasis.

Bronchiectasis is a common respiratory condition, characterised by abnormal bronchial dilatation, that often leads to recurrent airway infection and inflammation. It is an increasingly recognised respiratory condition, both as a primary lung disease but also co-existing with other respiratory diseases, such as chronic obstructive pulmonary disease and asthma. Diagnosis can have important treatment implications. There are shared systematic approaches to treatment, such as sputum clearance techniques, prompt treatment of exacerbations and, in certain circumstances, regular antibiotic therapy. It is vital to target antibiotic therapy appropriately, and knowledge of the patient's airway microbiology can assist with this. Certain infective and colonising organisms, such as Pseudomonas aeruginosa, cause worse patient outcomes and so need prompt treatment with appropriate antibiotics. In addition to this general management approach, there are many different underlying causes of bronchiectasis that should be identified wherever possible, to support more targeted therapy and prevent disease progression. This article provides a guide to the key principles of diagnosing and managing bronchiectasis, and outlines situations where more specialist respiratory support is required.

Management of an unusual cause of life-threatening haemoptysis: a multidisciplinary approach.

We present to you a case of life-threatening haemoptysis secondary to non-cystic fibrosis bronchiectasis complicated by bronchial artery pseudoaneurysms. We discuss this patient's emergency medical management using intravenous tranexamic acid, which resulted in successful resuscitation and eventual survival, and evaluate the need for urgent anaesthetic and interventional radiology input in such a case.

Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma.

BACKGROUND: Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta2-agonists, typically taken as required to relieve bronchospasm, and inhaled corticosteroids (ICS) as regular preventive therapy. Poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. Fixed-dose combination inhalers containing both a steroid and a fast-acting beta2-agonist (FABA) in the same device simplify inhalers regimens and ensure symptomatic relief is accompanied by preventative therapy. Their use is established in moderate asthma, but they may also have potential utility in mild asthma. OBJECTIVES: To evaluate the efficacy and safety of single combined (fast-onset beta2-agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 19 March 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials with at least one week washout period. We included studies of a single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA. We planned to include cluster-randomised trials if the data had been or could be adjusted for clustering. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We analysed dichotomous data as odds ratios (OR) or rate ratios (RR) and continuous data as mean difference (MD). We reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. Primary outcomes were exacerbations requiring systemic steroids, hospital admissions/emergency department or urgent care visits for asthma, and measures of asthma control. MAIN RESULTS: We included six studies of which five contributed results to the meta-analyses. All five used budesonide 200 µg and formoterol 6 µg in a dry powder formulation as the combination inhaler. Comparator fast-acting bronchodilators included terbutaline and formoterol. Two studies included children aged 12+ and adults; two studies were open-label. A total of 9657 participants were included, with a mean age of 36 to 43 years. 2.3% to 11% were current smokers. FABA / ICS as required versus FABA as required Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared to 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence). Compared with as-required FABA alone, any changes in asthma control or spirometry, though favouring as-required FABA/ICS, were small and less than the minimal clinically-important differences. We did not find evidence of differences in asthma-associated quality of life or mortality. For other secondary outcomes FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reduces the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95, 2 RCTs, 3002 participants, moderate-certainty evidence) and may reduce total systemic steroid dose (MD -9.90, 95% CI -19.38 to -0.42, 1 RCT, 443 participants, low-certainty evidence), and with an increase in the daily inhaled steroid dose (MD 77 µg beclomethasone equiv./day, 95% CI 69 to 84, 2 RCTs, 2554 participants, moderate-certainty evidence). FABA/ICS as required versus regular ICS plus FABA as required There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroid with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared to 65 (95% CI 49 to 86) out of 1000 FABA/ICS as required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence). Compared with regular ICS, any changes in asthma control, spirometry, peak flow rates (PFR), or asthma-associated quality of life, though favouring regular ICS, were small and less than the minimal clinically important differences (MCID). Adverse events, serious adverse events, total systemic corticosteroid dose and mortality were similar between groups, although deaths were rare, so confidence intervals for this analysis were wide. We found moderate-certainty evidence from four trials involving 7180 participants that FABA/ICS as required was likely associated with less average daily exposure to inhaled corticosteroids than those on regular ICS (MD -154.51 µg/day, 95% CI -207.94 to -101.09). AUTHORS' CONCLUSIONS: We found FABA/ICS as required is clinically effective in adults and adolescents with mild asthma. Their use instead of FABA as required alone reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely to be associated with an increase in adverse events. Further research is needed to explore use of FABA/ICS as required in children under 12 years of age, use of other FABA/ICS preparations, and long-term outcomes beyond 52 weeks.

Adenoid cystic carcinoma and chronic lymphocytic leukaemia: synchronous presentations in the lung.

A 59-year-old male active smoker presented with a 6-month history of cough and breathlessness and was found to have a right upper lobe mass. Histology revealed this to be an adenoid cystic carcinoma (ACC) of the lung, while local lymph node dissection revealed a synchronous diagnosis of chronic lymphocytic leukaemia (CLL). The connection between CLL and solid organ malignancy is well documented, but the reporting of ACC in this context is novel. Mechanisms linking the two processes are revealed with the possibility of causality, and heightened vigilance for the development of primary lung tumours in CLL, and their management, is recommended.

Modified Needleman-Wunsch algorithm for clinical pathway clustering.

Clinical pathways are used to guide clinicians to provide a standardised delivery of care. Because of their standardisation, the aim of clinical pathways is to reduce variation in both care process and patient outcomes. When learning clinical pathways from data through data mining, it is common practice to represent each patient pathway as a string corresponding to their movements through activities. Clustering techniques are popular methods for pathway mining, and therefore this paper focuses on distance metrics applied to string data for k-medoids clustering. The two main aims are to firstly, develop a technique that seamlessly integrates expert information with data and secondly, to develop a string distance metric for the purpose of process data. The overall goal was to allow for more meaningful clustering results to be found by adding context into the string similarity calculation. Eight common distance metrics and their applicability are discussed. These distance metrics prove to give an arbitrary distance, without consideration for context, and each produce different results. As a result, this paper describes the development of a new distance metric, the modified Needleman-Wunsch algorithm, that allows for expert interaction with the calculation by assigning groupings and rankings to activities, which provide context to the strings. This algorithm has been developed in partnership with UK's National Health Service (NHS) with the focus on a lung cancer pathway, however the handling of the data and algorithm allows for application to any disease type. This method is contained within Sim.Pro.Flow, a publicly available decision support tool.

Prioritisation of specialist health care services; not NICE, not easy but it can be done.

The challenges of delivering healthcare within budget constraints are ever present. Highly specialised technologies (HSTs) have high costs of provision inevitably contributing to NHS cost pressures. Between 2012-2015 the Welsh Health Specialised Services Committee (WHSSC) developed prioritisation methods to make recommendations for HST funding in Wales. Methods adapted as the process continued but was always evidence based and supported by a prioritisation panel of stakeholders. Methods changed from discreet choice to the Portsmouth Score Card, a simple multi-criteria decision analysis (MCDA) method. A strength of MCDA is that the impact on a decision of relevant criteria and their relative importance is explicit. This was, later, augmented by group decision support techniques. The prioritisation panel workload was on average eight HST condition treatment pairs in each l meeting, covering 133 HSTs over 3 years. Available evidence, information and value judgements were used to make decisions. The WHSSC framework identifies investment, dis-investment and recommendations transparently. The 'real-world' need for timely decisions was met, in the absence of National Institute for Health and Care Excellence (NICE) guidance on HSTs (initiated 2013, covering only drugs). In mid-2015 the prioritisation process was benchmarked against the EVIDEM framework, identifying areas of best practice and improvement: need for greater public and patient engagement. Some implementation issues for decisions based on panel recommendations remain to be resolved.

Problem-based review: Immune-mediated complications of 'Checkpoint Inhibitors' for the Acute Physician.

Immunotherapy with 'checkpoint-inhibitors' has significantly improved outcomes for patients with a range of malignancies. However, significant immune-mediated toxicities of these therapies are well-described. These immune-mediated toxicities can affect virtually all organ systems and are potentially fatal. The timing of onset of the adverse effects is dependent on the organ system affected and can occur after completion of the treatment. The increasing utilisation of 'checkpoint-inhibitors' means that Acute Physicians are likely to see a number of immune-mediated complications presenting to the AMU. The fundamental principles of management of immune-mediated toxicities are early recognition, supportive treatment, escalating steroid therapy (dependent on the severity of the toxicity), close liaison with Oncology and specialist organ team input. Research into the optimal strategies and pathways for the management of immune-mediated toxicity, as well as increased collaboration between Acute Physicians and Oncologists, will be necessary.

Enigma: infection or allergy? Vancomycin-induced DRESS syndrome with dialysis-dependent renal failure and cardiac arrest.

A man aged 73 years with infective endocarditis presented with septic shock and was started on immediate antimicrobial therapy. His blood culture yielded no organism. Subsequently, he developed a severe allergic reaction to prolonged empirical vancomycin therapy. This manifested as fever, widespread maculopapular rash and severe progressive acute kidney injury ultimately requiring dialysis. In the context of eosinophilia, this was determined to be drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Deciphering this complication as allergy in the context of severe infection required extreme caution due to the polarity of treatment with immunosuppression. Ultimately, this was used, with improvement of renal function, resolution of symptoms and absence of recurrence of infection. In summary, we present a case of vancomycin-related DRESS syndrome leading to dialysis-which is unique in the literature-complicating the treatment of culture-negative infective endocarditis.

Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones.

AIMS: Loss of nuclear TDP-43 characterizes sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether (1) RNA splicing dysregulation is present in lower motor neurones in ALS and in a motor neurone-like cell model; and (2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. METHODS: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurones obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. RESULTS: We found altered expression of spliceosome components in motor neurones and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43-depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, which were not present in fibroblasts from patients with sporadic or SOD1-related ALS. CONCLUSION: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurones, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism.

Composition of chemical attractants affects trap catches of the Australian sheep blowfly, Lucilia cuprina, and other blowflies.

Numbers of Lucilia cuprina (Australian sheep blowfly), Chrysomya spp., and Calliphora spp. blowflies caught on sticky traps baited with various synthetic attractants or a standard liver/sodium sulfide attractant in western Queensland were recorded. Numbers of each genus collected were influenced by the composition of the chemical attractants. Attractant mixtures based on 2-mercaptoethanol, indole, butanoic/pentanoic acid, and a sodium sulfide solution gave 5- to 20-fold higher L. cuprina catches than the liver standard. These blends attracted similar numbers of Chrysomya spp. (0.85-2.7x) and fewer Calliphora spp. (0.02-0.2x) compared to the liver standard. These synthetic attractants were more effective and selective for L. cuprina than the standard liver/sodium sulfide attractant, and they can be packaged in controlled-release dispensers to generate constant, prolonged release of the attractant.