Search

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

The emergence of SARS-CoV-2 and seasonal outbreaks of other respiratory viruses highlight the urgent need for broad-spectrum antivirals to treat respiratory tract infections. Stimulator of interferon genes (STING) is a key component of innate immune signaling and plays a critical role in protection of the host against viral infections. Previously the STING agonist diABZI-4, a diamidobenzimidazole-based compound, demonstrated protection against SARS-CoV-2 both in vitro and in vivo . However, its broad-spectrum antiviral activity against other respiratory viruses in human airway epithelial cells, which are the primary targets of these infections, is not well established. In this study, we demonstrated that diABZI-4 stimulated robust innate immune responses protecting lung cells against a wide range of respiratory viruses, including influenza A virus (IAV), common cold coronaviruses, SARS-CoV-2, human rhinovirus (HRV), and human parainfluenza virus. diABZI-4 was highly active in physiologically relevant human airway epithelial tissues grown at the air-liquid interface, blocking replication of IAV, SARS-CoV-2, and HRV in these tissues. Furthermore, treatment of macrophages with diABZI-4 resulted in the secretion of cytokines that protected the primary airway epithelial cells from IAV infection. Despite the promising in vitro pan-antiviral activity, intranasal administration of diABZI-4 in mice provided early, but not sustained, inhibition of IAV replication in the lungs. These data highlight the complexities of the relationship between timing of STING agonist-driven inflammatory responses and viral replication dynamics, emphasizing the development challenge posed by STING agonists as potential therapeutics against respiratory viruses.

Vector-borne diseases are among the most burdensome infectious diseases worldwide with high burden to health systems in developing regions in the tropics. For many of these diseases, vector control to reduce human biting rates or arthropod populations remains the primary strategy for prevention. New vector control interventions intended to be marketed through public health channels must be assessed by the World Health Organization for public health value using data generated from large-scale trials integrating epidemiological endpoints of human health impact. Such phase III trials typically follow large numbers of study subjects to meet necessary power requirements for detecting significant differences between treatment arms, thereby generating substantive and complex datasets. Data is often gathered directly in the field, in resource-poor settings, leading to challenges in efficient data reporting and/or quality assurance. With advancing technology, mobile data collection (MDC) systems have been implemented in many studies to overcome these challenges. Here we describe the development and implementation of a MDC system during a randomized-cluster, placebo-controlled clinical trial evaluating the protective efficacy of a spatial repellent intervention in reducing human infection with Aedes-borne viruses (ABV) in the urban setting of Iquitos, Peru, as well as the data management system that supported it. We discuss the benefits, remaining capacity gaps and the key lessons learned from using a MDC system in this context in detail., (© 2022. The Author(s).)

Objective: Empathy is an important modifiable quality of health care practitioners that relates to the quality of patient care. The educative process may adversely affect the empathy levels of health care students at key phases of training. This topic remains unexplored in chiropractic students to date., Methods: A voluntary and anonymous questionnaire was distributed to all chiropractic students in an Australian university-based program in April 2021. This questionnaire recorded age, sex, year of study, and Toronto Empathy Questionnaire scores., Results: Chiropractic student empathy scores approximated those of other Australian health care students. No statistical differences were found when comparing the mean scores of empathy levels across the 5 student cohorts. The empathy levels of female chiropractic students' were significantly higher than those of the male chiropractic students., Conclusion: This study provides a baseline from which further explorations on empathy may be conducted in chiropractic students. This holds the potential to improve practitioners' quality of life and patient outcomes and for educators to identify subject matter that may negatively affect empathy levels., (© 2022 Association of Chiropractic Colleges.)

Background: While chiropractic care is most commonly provided within a private practice context, the 'traditional' solo practice is now uncommon. Chiropractors, manual therapists and related health professionals commonly work within the same practice bringing obvious advantages to both the practitioners and their patients. However, multi-practitioner, multi-disciplinary clinics also carry often unrecognized liabilities. We refer here to vicarious liability and non-delegable duties. Vicarious liability refers to the strict liability imposed on one person for the negligent acts of another person. The typical example is an employer being held vicariously liable to the negligent acts of an employee. However, vicarious liability can arise outside of the employer-employee relationship. For example, under non-delegable duty provisions, an entity owing a non-delegable duty can be liable for an independent contractor's wrongdoing. After a plain English explanation of this complex area of law, we provide seven scenarios to demonstrate how vicarious liability can envelop practice principals when things go wrong. We also make suggestions for risk mitigation., Conclusion: Practice owners may unexpectedly find themselves legally liable for another's actions with dire consequences. A knowledge of vicarious liability along with implementing risk mitigation strategies has the potential to minimize the likelihood of this unwanted event. Recommendations are made to this end.

Background: The COVID-19 pandemic has seen the emergence of unsubstantiated claims by vertebral subluxation-based chiropractors that spinal manipulative therapy has a role to play in prevention by enhancing the body's immune function. We contend that these claims are unprofessional and demonstrate a disturbing lack of insight into the doctrine of informed consent. As such it is timely to review how informed consent has evolved and continues to do so and also to discuss the attendant implications for contemporary health practitioner practice. We review the origins of informed consent and trace the duty of disclosure and materiality through landmark medical consent cases in four common law (case law) jurisdictions. The duty of disclosure has evolved from a patriarchal exercise to one in which patient autonomy in clinical decision making is paramount. Passing time has seen the duty of disclosure evolve to include non-medical aspects that may influence the delivery of care. We argue that a patient cannot provide valid informed consent for the removal of vertebral subluxation. Further, vertebral subluxation care cannot meet code of conduct standards because it lacks an evidence base and is practitioner-centered. The uptake of the expanded duty of disclosure has been slow and incomplete by practitioners and regulators. The expanded duty of disclosure has implications, both educative and punitive for regulators, chiropractic educators and professional associations. We discuss how practitioners and regulators can be informed by other sources such as consumer law. For regulators, reviewing and updating informed consent requirements is required. For practitioners it may necessitate disclosure of health status, conflict of interest when recommending "inhouse" products, recency of training after attending continuing professional development, practice patterns, personal interests and disciplinary findings., Conclusion: Ultimately such matters are informed by the deliberations of the courts. It is our opinion that the duty of a mature profession to critically self-evaluate and respond in the best interests of the patient before these matters arrive in court.

Background: Chiropractic emerged in 1895 and was promoted as a viable health care substitute in direct competition with the medical profession. This was an era when there was a belief that one cause and one cure for all disease would be discovered. The chiropractic version was a theory that most diseases were caused by subluxated (slightly displaced) vertebrae interfering with "nerve vibrations" (a supernatural, vital force) and could be cured by adjusting (repositioning) vertebrae, thereby removing the interference with the body's inherent capacity to heal. DD Palmer, the originator of chiropractic, established chiropractic based on vitalistic principles. Anecdotally, the authors have observed that many chiropractors who overtly claim to be "vitalists" cannot define the term. Therefore, we sought the origins of vitalism and to examine its effects on chiropractic today., Discussion: Vitalism arose out of human curiosity around the biggest questions: Where do we come from? What is life? For some, life was derived from an unknown and unknowable vital force. For others, a vital force was a placeholder, a piece of knowledge not yet grasped but attainable. Developments in science have demonstrated there is no longer a need to invoke vitalistic entities as either explanations or hypotheses for biological phenomena. Nevertheless, vitalism remains within chiropractic. In this examination of vitalism within chiropractic we explore the history of vitalism, vitalism within chiropractic and whether a vitalistic ideology is compatible with the legal and ethical requirements for registered health care professionals such as chiropractors., Conclusion: Vitalism has had many meanings throughout the centuries of recorded history. Though only vaguely defined by chiropractors, vitalism, as a representation of supernatural force and therefore an untestable hypothesis, sits at the heart of the divisions within chiropractic and acts as an impediment to chiropractic legitimacy, cultural authority and integration into mainstream health care.

Background: Internet analytics are increasingly being integrated into public health regulation. One specific application is to monitor compliance of website and social media activity with respect to jurisdictional regulations. These data may then identify breaches of compliance and inform disciplinary actions. Our study aimed to evaluate the novel use of internet analytics by a Canadian chiropractic regulator to determine their registrants compliance with three regulations related to specific health conditions, pregnancy conditions and most recently, claims of improved immunity during the COVID-19 crisis., Methods: A customized internet search tool (Market Review Tool, MRT) was used by the College of Chiropractors of British Columbia (CCBC), Canada to audit registrants websites and social media activity. The audits extracted words whose use within specific contexts is not permitted under CCBC guidelines. The MRT was first used in October of 2018 to identify words related to specific health conditions. The MRT was again used in December 2019 for words related to pregnancy and most recently in March 2020 for words related to COVID-19. In these three MRT applications, potential cases of word misuse were evaluated by the regulator who then notified the practitioner to comply with existing regulations by a specific date. The MRT was then used on that date to determine compliance. Those found to be non-compliant were referred to the regulator's inquiry committee. We mapped this process and reported the outcomes with permission of the regulator., Results: In September 2018, 250 inappropriate mentions of specific health conditions were detected from approximately 1250 registrants with 2 failing to comply. The second scan for pregnancy related terms of approximately1350 practitioners revealed 83 inappropriate mentions. Following notification, all 83 cases were compliant within the specified timeframe. Regarding COVID-19 related words, 97 inappropriate mentions of the word "immune" were detected from 1350 registrants with 7 cases of non-compliance., Conclusion: Internet analytics are an effective way for regulators to monitor internet activity to protect the public from misleading statements. The processes described were effective at bringing about rapid practitioner compliance. Given the increasing volume of internet activity by healthcare professionals, internet analytics are an important addition for health care regulators to protect the public they serve.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF., Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [ 18 F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V T ), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V T  > 0%) of ≥80%., Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V T at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in V T  > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination., Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug., Trial Registration: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.

Background: Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations., Objectives: We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation., Methods: Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing., Results: Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype., Conclusions: These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown., (© 2019 British Association of Dermatologists.)

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF.Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p < 0.001; PRO-C6 p = 0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as 'slope to month 3': HIGH slope, slope > 0 vs. LOW slope, slope < =0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p = 0.080); PINP (HR 0.76, p = 0.309); PRO-C6 (HR 1.14, p = 0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR = 1.84, CI 1.03-3.27, p = 0.038, HR = 2.44, CI 1.39-4.31, p = 0.002; HR = 2.19, CI 1.25-3.82, p = 0.006; HR = 2.13 CI 1.21-3.75, p = 0.009 respectively).Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.

Background: Society expects professionals to promote their businesses in an ethical manner, refraining from misleading or deceptive marketing due to the potential to harm members of the community. In Australia this expectation resides in the Australian registration board advertising guidelines or the Health Practitioner Regulation National Law. Registration board data indicate there are many health care professionals failing to meet these expectations. The aims of this research were to determine the frequency, type and nature of at-risk advertising by Australian chiropractors and physiotherapists and whether there is a correlation between professional association membership and advertising guideline compliance., Method: A cross sectional audit examining practitioner advertising was performed on representative samples of Australian chiropractors and physiotherapists. Two auditors examined advertising by 380 physiotherapists and 359 chiropractors for material potentially in breach of the regulatory authorities' advertising guidelines. The advertising appeared on practitioner websites and linked Facebook pages., Results: Two-hundred and fifty-eight (72%) audited chiropractors and 231 (61%) audited physiotherapists had breaches of the Advertising Guidelines on their websites and linked Facebook pages. The frequency of breaches by chiropractors was higher. The type and nature of the breaches by chiropractors was potentially more harmful. Membership in a professional association influenced neither the frequency nor the severity of breaches with chiropractors., Discussion: Advertising breaches were common in both samples even though regulators and professional associations provide practitioners with explicit information on how to comply with advertising guidelines. Breaches by chiropractors were more numerous and more serious due to their greater potential to lead consumers to make inappropriate and potentially harmful healthcare decisions.Stronger enforcement strategies may have a positive effect on compliance., Competing Interests: Competing interestsThe author declares that he has no competing interests.

Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease. We aimed to determine if patient response to a palliative assessment survey could predict disease progression or death.We undertook a cross-sectional study in a UK clinical cohort of incident cases. Rasch-based methodology provided a disease distress value from an abridged 11-item model of the original 45-item survey. Distress values were compared with measures of lung function. Disease progression or mortality alone was predicted at 12 months from survey completion, with risk of death assessed at 3, 6 and 12 months.Disease distress values were negatively correlated with lung function (r=-0.275 for the percentage predicted diffusing capacity of the lung for carbon monoxide). Expected survey scores computed from distress values could distinguish disease progression (n=8.8, p=0.004) and death (n=10.2, p=0.002) from no disease progression (n=6.9). Actual survey scores predicted disease progression and death with an area under the curve of 0.60 and 0.64, respectively. Each point increment in actual score increased risk of 12-month mortality by 10%; almost 43% of people scoring above 18 did not survive beyond 105 days.We define a short questionnaire that can score disease distress and predict prognosis, thus assisting clinical decision-making in progressive fibrosis., Competing Interests: Conflict of interest: I. Stewart has nothing to disclose. Conflict of interest: T. McKeever has nothing to disclose. Conflict of interest: R. Braybrooke has nothing to disclose. Conflict of interest: E. Oballa is an employee of GlaxoSmithKline. Conflict of interest: J.K. Simpson is an employee of and shareholder in GlaxoSmithKline. Conflict of interest: T.M. Maher has, via his institution, received industry–academic funding from GlaxoSmithKline R&D and UCB, and has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, Indalo, Pliant, ProMetic, Roche, Samumed and UCB. Conflict of interest: R.P. Marshall was a paid employee of GlaxoSmithKline when the work was carried out and remains a shareholder in GlaxoSmithKline. Conflict of interest: P.T. Lukey reports that during the PROFILE study, she was an employee of, and still owns shares in, GlaxoSmithKline. For the last 3 years, she has worked, and in some cases is still working, as an independent consultant to GlaxoSmithKline R&D, the Francis Crick Institute, Syncona, Peptinnovate, Mereo BioPharma, LiFT BioScience, DJS antibodies, BergenBio and Galecto. Conflict of interest: W.A. Fahy is an employee of and shareholder in GlaxoSmithKline. Conflict of interest: G. Jenkins reports grants from GlaxoSmithKline during the conduct of the study; grants from Biogen and Galecto, personal fees from Boehringer Ingelheim, Galapagos, Heptares, Pliant and Roche, grants and personal fees from GlaxoSmithKline and MedImmune, and service on advisory boards (no fees received) for NuMedii and Redex, outside the submitted work; and is a trustee of the British Thoracic Society and Action for Pulmonary Fibrosis. Conflict of interest: G. Saini has nothing to disclose., (Copyright ©ERS 2019.)

Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18 F-2 - fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18 F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs., Competing Interests: Conflict of interest: P.T. Lukey was a GSK employee at the time of the study and is still a shareholder. P.T. Lukey now works or has worked as an independent consultant to GSK R&D, the Francis Crick Institute, Syncona, Mereo BioPharma, Peptinnovate, BerGenBio, Morphic Therapeutics and LifT BioSciences. Conflict of interest: S.A. Harrison reports that the study was funded by GlaxoSmithKline; and is an employee of and holds shares in GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Yang reports that the study was funded by GlaxoSmithKline; and is an employee of and holds shares in GlaxoSmithKline, outside the submitted work. Conflict of interest: Y. Man has nothing to disclose. Conflict of interest: B.F. Holman reports grants from EPSRC, during the conduct of the study. Conflict of interest: A. Rashidnasab reports grants from GSK, during the conduct of the study. Conflict of interest: G. Azzopardi has nothing to disclose. Conflict of interest: M. Grayer reports that the study was funded by GlaxoSmithKline; and received personal fees as a contractor on assignment at GSK to complete statistical analyses, from GlaxoSmithKline, outside the submitted work. Conflict of interest: J.K. Simpson is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: P. Bareille is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: L. Paul has nothing to disclose. Conflict of interest: H.V. Woodcock reports grants from GlaxoSmithKline, during the conduct of the study. Conflict of interest: R. Toshner has nothing to disclose. Conflict of interest: P. Saunders has nothing to disclose. Conflict of interest: P.L. Molyneaux has nothing to disclose. Conflict of interest: K. Thielemans reports grants from GSK, during the conduct of the study; grants from GE Healthcare, outside the submitted work. Conflict of interest: F.J. Wilson is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: P.F. Mercer was funded through a collaborative framework agreement with GlaxoSmithKline. Conflict of interest: R.C. Chambers reports grants from GlaxoSmithKline (GSK), during the conduct of the study; and R.C. Chambers’ spouse is an employee of GSK. Conflict of interest: A.M. Groves has nothing to disclose. Conflict of interest: W.A. Fahy is an employee of and holds shares in GlaxoSmithKline. Conflict of interest: R.P. Marshall is an employee of and holds shares in GlaxoSmithKline, outside the submitted work. Conflict of interest: T.M. Maher has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speaker's fees from Apellis, Astra Zeneca, aTyr Pharma, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche, Sanumed and UCB., (Copyright ©ERS 2019.)

Invasive dermatophyte infection, with extension beyond the dermis, in immunocompetent hosts is exceptionally rare. Dermatophytes are keratinophilic and are usually confined to the stratum corneum, hair and nails. Susceptibility to dermatophyte infections is incompletely understood, but inherited mutations in key signalling pathways of the innate immune system have been identified. We report the first case of an invasive dermatophyte infection associated with abrupt onset of a prurigo-induced pseudoperforation and a loss-of-function mutation in signal transducer and activator of transcription 3 (STAT3)., (© 2017 British Association of Dermatologists.)

Purpose: Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants., Methods: Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1-3000 mcg given by nebulisation., Results: A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100-3000 mcg). Dose normalised geometric mean C max increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety., Conclusions: In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300-3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF.

Background: Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF)., Methods: The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99m Technetium-labelled monodisperse salbutamol (1.5 μm or 6 μm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 μg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4)., Results: Small monodisperse particles (1.5 μm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 μm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 μm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 μm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 μm and 6 μm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation., Conclusion: Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF., Trial Registration: This trial was registered on clinicaltrials.gov ( NCT01457261 ).

Since its inception, the chiropractic profession has been divided along ideological fault lines. These divisions have led to a profession wide schism, which has limited mainstream acceptance, utilisation, social authority and integration. The authors explore the historical origins of this schism, taking time to consider historical context, religiosity, perpetuating factors, logical fallacies and siege mentality. Evidence is then provided for a way forward, based on the positioning of chiropractors as mainstream partners in health care., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF., Methods: PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital)., Findings: In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493-4·328, p=0·00059)., Interpretation: We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF., Funding: GlaxoSmithKline R&D and the UK Medical Research Council., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: This paper examines appeal to fear in general: its perceived positive aspects, its negative characteristics, its appropriate as well as its fallacious use., Background: Appeal to fear is a commonly used marketing method that attempts to change behaviour by creating anxiety in those receiving a fearful message. It is regularly used in public health initiatives such as anti-smoking, anti-drunk driving campaigns as well as in hypertension awareness campaigns. Some chiropractors appear to use appeal to fear to promote subluxation awareness and thereby encourage the use of chiropractic treatment. Research supporting its use is equivocal; nevertheless, when used judiciously, appeal to fear probably has sufficient strengths to warrant its continued conditional use. When used to promote care for which there is no supporting evidence, its use is fallacious., Discussion: Appeal to fear has been used in health promotion campaigns for sixty years or more with the intent of modifying behaviours. While there is evidence to suggest that appeal to fear may motivate some individuals to modify offending behaviour or adopt recommended behaviour there is growing resistance to the use of appeal to fear on ethical and psychological grounds. Using appeal to fear as a tool of persuasion can be valid or fallacious depending on the truth of the premises within the argument. When used to raise awareness about genuine health concerns such as smoking, drunk driving and hypertension appeal to fear is considered to be a valid approach with certain caveats. However, when appeal to fear, not based on evidence or reason, is used as motivator to get others to accept unnecessary interventions for unproven disorders, the use of appeal to fear is fallacious., Conclusion: In spite of the evidence against its use, it seems likely that appeal to fear will continue to be used in conjunction with other public awareness initiatives to modify recognized detrimental behaviours such as smoking and drunk driving as well as silent killers such as hypertension. However, when used to promote a treatment that has no evidentiary basis such as subluxation based practice in chiropractic the appeal to fear is a fallacy and must be stopped.

Background: Psoriasis is a long-term inflammatory skin disorder, with negative effects on employment, relationships and social function, frequently causing reduced quality of life. People with psoriasis often present to secondary care late into their condition but the reasons for this are unknown., Objectives: To examine the patient pathway, health-seeking behaviour and drivers for referral to secondary care in patients with psoriasis., Methods: Sixteen patients with mild-to-severe psoriasis, newly referred to secondary care participated in a semi-structured interview. Scripts were analysed by a thematic framework., Results: The median duration of time living with psoriasis was 15 years at referral. Drivers of secondary care referral included rapid deterioration or extremis, development of comorbidities, knowledge of treatment options, and influence of partners and friends. Reasons for late presentation to secondary care include familial experience of psoriasis, lack of follow-up after the initiation of treatments, beliefs that psoriasis is incurable and must be tolerated, and that psoriasis is not life threatening and therefore not worthy of medical help and difficulty in obtaining a secondary care referral. A common pathway from seeking help at psoriasis onset, evolving into the development of delayed health seeking later in the pathway, was identified., Conclusions: Identifying the causes of delay in presentation to secondary care and effective treatment ascertains key areas to target. Health seeking early in the disease pathway provides a 'window of opportunity' for intervention, which may enable people with psoriasis to obtain early, effective treatment and achieve their full life potential., (© 2017 British Association of Dermatologists.)

Background: Gene regulatory variation has been proposed to play an important role in the adaptation of plants to environmental stress. In the central highlands of Mexico, farmer selection has generated a unique group of maize landraces adapted to the challenges of the highland niche. In this study, gene expression in Mexican highland maize and a reference maize breeding line were compared to identify evidence of regulatory variation in stress-related genes. It was hypothesised that local adaptation in Mexican highland maize would be associated with a transcriptional signature observable even under benign conditions., Methods: Allele specific expression analysis was performed using the seedling-leaf transcriptome of an F 1 individual generated from the cross between the highland adapted Mexican landrace Palomero Toluqueño and the reference line B73, grown under benign conditions. Results were compared with a published dataset describing the transcriptional response of B73 seedlings to cold, heat, salt and UV treatments., Results: A total of 2,386 genes were identified to show allele specific expression. Of these, 277 showed an expression difference between Palomero Toluqueño and B73 alleles under benign conditions that anticipated the response of B73 cold, heat, salt and/or UV treatments, and, as such, were considered to display a prior stress response. Prior stress response candidates included genes associated with plant hormone signaling and a number of transcription factors. Construction of a gene co-expression network revealed further signaling and stress-related genes to be among the potential targets of the transcription factors candidates., Discussion: Prior activation of responses may represent the best strategy when stresses are severe but predictable. Expression differences observed here between Palomero Toluqueño and B73 alleles indicate the presence of cis -acting regulatory variation linked to stress-related genes in Palomero Toluqueño. Considered alongside gene annotation and population data, allele specific expression analysis of plants grown under benign conditions provides an attractive strategy to identify functional variation potentially linked to local adaptation., Competing Interests: Jeffrey Ross-Ibarra is an Academic Editor for PeerJ.

Wells syndrome is a rare disorder of unknown etiology. Precipitants include insect bites, infections, medications, malignancies, and vaccinations. Possible mechanisms include hypersensitivity reactions to antigens. There are four reports in the literature of Wells syndrome precipitated by vaccinations (hepatitis B vaccine, tetanus vaccine, tetanus-diptheria vaccine and triple antigen vaccine). We present a further case of Wells syndrome in a 22-month-old child after influenza vaccine as a novel trigger not previously reported., (© 2015 Wiley Periodicals, Inc.)

Background: Idiopathic pulmonary fibrosis, a progressive and inevitably fatal disorder, has a highly variable clinical course. Biomarkers that reflect disease activity are urgently needed to inform patient management and for use as biomarkers of therapeutic response (theragnostic biomarkers) in clinical trials. We aimed to determine whether dynamic change in markers of extracellular matrix (ECM) turnover predicts progression of idiopathic pulmonary fibrosis as determined by change in forced vital capacity and death., Methods: In this ongoing prospective, multicentre, observational cohort study (PROFILE), participants with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia diagnosed within the preceding 6 months were recruited from two coordinating centres (Nottingham, UK, and, Royal Brompton Hospital, London, UK). Serum samples were prospectively collected at baseline, 1 month, 3 months, and 6 months and were analysed for a panel of novel matrix metalloprotease (MMP)-degraded ECM proteins, by ELISA-based, neoepitope assay. 11 neoepitopes were tested in a discovery cohort of 55 patients to identify biomarkers of sufficient rigour for more detailed analyses. Eight were then further assessed in a validation cohort of 134 patients with 50 age-matched and sex-matched controls. Changes in biomarker concentrations were related to subsequent progression of idiopathic pulmonary fibrosis (defined as death or decline in forced vital capacity >10% at 12 months after study enrolment) using a repeated measures model. The PROFILE study is registered on ClinicalTrials.gov, numbers NCT01134822 and NCT01110694., Findings: Of 214 eligible participants recruited between Sept 1, 2010, and March 31, 2012, 189 had a confirmed diagnosis of idiopathic pulmonary fibrosis and were included in subsequent analyses. In the discovery cohort, mean concentrations of seven neoepitopes (BGM, p=0·009; C1M, p=0·009; C3M, p=0·046; C6M, p=0·032; CRPM, p=0·008; ELM2, p=0·02; and VICM, p=0·0007) differed significantly between healthy controls and participants with idiopathic pulmonary fibrosis. Baseline concentrations of six neoepitopes (C1M, p=0·012; C3A, p=0·012; C3M, p=0·0005; C6M, p=0·0003; CRPM, p=0·021; and VICM, p=0·046) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=32) than in those with stable disease (n=23). In the validation cohort, mean concentrations of C1M (p=0·001), C3M (p=0·044), C6M (p=0·003), and CRPM (p=0·024) at baseline were higher in patients with idiopathic pulmonary fibrosis than in healthy controls. When assessed longitudinally, concentrations of six neoepitopes (BGM, C1M, C3A, C3M, C6M, and CRPM) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=71) than in patients with stable idiopathic pulmonary fibrosis (n=60) by 6 months. Baseline concentrations of two neoepitopes were associated with increased mortality (C1M: HR 1·62 [95% CI 1·14-2·31], p=0·0069; C3A: 1·91 [1·06-3·46], p=0·032). The rate of change between baseline and 3 months of six neoepitopes (BGM: HR 1·084 [95% CI 1·03-1·14], p=0·0019; C1M: 1·01 [1·003-1·017], p=0·0039; C3M: 1·106 [1·045-1·170], p=0·0005; C5M: 1·003 [1·001-1·005], p=0·0011; C6M: 1·042 [1·007-1·078], p=0·017; and CRPM: 1·38 [1·16-1·63], p=0·0002) was strongly predictive of overall survival, and the increased risk was proportional to the magnitude of change in neoepitope concentrations. The strongest association with 3-month rate of biomarker change was recorded for CRPM; greater than 0 ng/mL per month conferred a HR of 2·16 (95% CI 1·15-4·07), whereas a rate greater than 1 ng/mL per month resulted in an HR 4·08 (2·14-7·8), and a rate greater than 1·7 ng/mL per month was associated with an HR 6·61 (2·74-15·94)., Interpretation: Concentrations of protein fragments generated by MMP activity are increased in the serum of individuals with idiopathic pulmonary fibrosis compared with healthy controls. Increased neoepitope concentrations were associated with disease progression, and the rate of this increase predicted survival. Serial measurements of neoepitopes have potential to be used as theragnostic biomarkers in clinical trials and to guide management of idiopathic pulmonary fibrosis., Funding: GlaxoSmithKline R&D and the Medical Research Council., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The discovery and development of biomarkers for fibrotic diseases have potential utility in clinical decision-making as well as in pharmaceutical research and development. This review describes strategies for identifying diagnostic, prognostic and theranostic biomarkers. A range of technologies and platforms for biomarker discovery are highlighted, including several with specific relevance for fibrosis. Some challenges specific to fibrotic diseases are outlined including; benchmarking biomarkers against imperfect clinical measures of fibrosis, the complexity resulting from diverse aetiologies and target organs, and the availability of samples (including biopsy) from well-characterised patients with fibrotic disease. To overcome these challenges collaboration amongst clinical specialities as well as between academia and industry is essential. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We describe a 51-year-old white man with discoid lupus erythematosus (DLE) of the head, neck, trunk, and upper extremities of more than 20 years' duration who developed rapidly progressive squamous cell carcinoma (SCC) of the bilateral ear helices. Human papillomavirus (HPV) was detected from excised specimens from the ears via tissue immunohistochemistry. Human papillomavirus infection of discoid lesions may be responsible for the rapid progression of SCC of this patient's bilateral ear helices.

Purpose: This paper reviews the origins of the learned professions, the foundational concepts of professionalism, and the common elements within various healer's oaths. It then reveals the development of the Murdoch Chiropractic Graduate Pledge., Methods: A committee comprised of three Murdoch academics performed literature searches on the topic of professionalism and healer's oaths and utilized the Quaker consensus process to develop the Murdoch Chiropractic Graduate Pledge., Results: The committee in its deliberations utilized over 200 relevant papers and textbooks to formulate the Murdoch Chiropractic Graduate Pledge that was administered to the 2010 Murdoch School of Chiropractic and Sports Science graduates. The School of Chiropractic and Sports Science included professionalism as one of its strategic goals and began the process of curriculum review to align it with the goal of providing a curriculum that recognizes and emphasizes the development of professionalism., Conclusions: The reciting of a healer's oath such as the Hippocratic Oath is widely considered to be the first step in a new doctor's career. It is seen as the affirmation that a newly trained health care provider will use his or her newfound knowledge and skill exclusively for the benefit of mankind in an ethical manner. Born from the very meaning of the word profession, the tradition of recitation of a healer's oath is resurgent in health care. It is important for health care instructors to understand that the curriculum must be such that it contributes positively to the students' professional development.

As urbanisation accelerates within less-economically developed countries, populations in cities such as Rio de Janeiro are subject to numerous health risks relating to "heavy metal", sewage and vehicle pollution. These risks apply especially to children, through inhalation and dermal contact with pollutant-rich street sediments that reflect contamination from atmospheric deposition and act as effective sinks for heavy metals and oxalates. To assess the nature and extent of these risks street sediments were collected from industrial, commercial, residential and recreational areas with varying traffic densities within Rio de Janeiro. A modified selective extraction procedure was used to study the geochemical partitioning and bioavailability of Fe, Mn, Zn, Cu, Cr, Ni, Pb and C(2)O(4) (-). Oxalate partitioning has not been studied by traditional sequential methods and results from this procedure highlight the potential bioavailability of both oxalates and "heavy metals", especially Pb and C(2)O(4) (-) in industrial and recreational areas.

Background: Treatment of various diseases has been noted to vary by patient demographics. There is reason to suspect that there may be sex and racial differences in the treatment of severe acne., Objective: We sought to determine if treatment of severe acne with oral isotretinoin varied with patient sex, race, or both., Methods: We analyzed the demographics of patients with acne and patients using oral isotretinoin, minocycline, and tetracycline recorded in the 1990 to 1997 National Ambulatory Medical Care Survey., Results: There were 35 million visits to physicians for the treatment of acne between 1990 and 1997, and isotretinoin was prescribed at 5.8 million (17%) of these visits. Per capita visit rates for acne among whites was 2.3 times that of blacks, and whites were 1.8 times more likely to receive isotretinoin at acne visits. Per capita, women had 1.4 times as many visits for acne as men, but men were 1.7 times more likely than women to receive isotretinoin at an acne visit. Dermatologists managed 83% of all isotretinoin visits. Dermatologists accounted for 100% of isotretinoin visits for which pregnancy prevention education and counseling was reported., Conclusions: Patients who are black receive less oral isotretinoin than those who are white, and the expense of isotretinoin appears to be one factor in this difference. Women are less likely than men to receive isotretinoin at acne visits. Expense does not appear to be a factor in this difference. Dermatologists have more experience than nondermatologists managing acne, prescribing isotretinoin, and counseling women treated with isotretinoin concerning pregnancy prevention. Pregnancy prevention is an essential component of isotretinoin use in women that must not be ignored.

In an aging population, the number of patients with cancer continues to rise. Little research has focused on the treatment of cancer in the elderly. Therefore, the treatment for various cancers differs across the healthcare system. A uniform approach in assessing the elderly person with cancer is lacking. This article describes two case studies in the elderly population, focusing on two common cancers: acute myelogenous leukemia and breast cancer. Common side effects of treatment and determinants of treatment options are discussed. It is important that the elderly receive appropriate screening, early detection, treatment, and management of comorbidities.

Objectives: To provide information on the assessment and management of the nutritional needs of patients with severe neutropenia., Data Sources: Textbook chapters, research articles, and review articles., Conclusions: Malnutrition is a common result of high-dose chemotherapy treatment. Clinical outcomes are directly related to careful assessment, early intervention, and ongoing evaluation and monitoring in the severely neutropenic population., Implications for Nursing Practice: Early assessment, management, and psychological support are essential in meeting the needs of this patient population.

Background: In Queensland, Australia, patients with work-related injuries must receive a referral from a general medical practitioner to receive treatment from such "nontraditional" practitioners as physiotherapists, chiropractors or osteopaths, even though these nontraditional practitioners are primary care providers outside of the workers' compensation system. The Chiropractors' Association of Australia (Queensland Branch) (CAAQ) believed that injured workers wishing to receive chiropractic care stood little chance of obtaining a medical referral. On the other hand, the General Manager of the Workers' Compensation Board of Queensland maintained that injured workers had little difficulty obtaining such a referral for chiropractic care., Objective: To canvass general medical practitioner attitudes and referral patterns to chiropractors, osteopaths, physiotherapists and other nontraditional practitioners (naturopaths)., Design: A descriptive study in which 1509 general medical practitioners in private practice in Queensland were invited to respond to a mailed questionnaire. The sample represented 50% of all such practitioners in Queensland., Results: A 52% response rate was obtained with 784 (638 male, 142 female general practitioners) questionnaires returned. Respondents' ages ranged from 27 to 79 yr. The respondents' years in practice ranged from 1 to 55 yr. The survey showed that attitudes and referral patterns were distinctly different depending on the nontraditional practitioner group in question., Conclusion: The survey results confirm that general medical practitioners are highly unlikely to have professional dealings with chiropractors and osteopaths, including referral of patients to said providers, even if the patient requests such a referral, and that general medical practitioners are much more likely to have professional dealings with physiotherapists than with any of the other nontraditional groups considered.

Neuroblastoma is one of the more common pediatric cancers. Although there have undoubtedly been major advances in therapy over recent decades, there is still room for significant improvements in outcome to be made. Neuroblastoma is a disease with a variable outlook, encompassing a spectrum-from patients with disease which may undergo spontaneous regression, through those who may be cured with limited treatment, to others whose disease is refractory even to the most aggressive management strategies. Great progress has been made toward understanding the basic biology of the disease, which allows reliable allocation of individual patients to good, intermediate, or poor prognostic groups and aids selection of appropriate therapeutic approaches. Unfortunately, attempts to improve the outcome of patients with adverse prognostic factors have been less effective. This paper reviews the clinical and biological features of neuroblastoma which determine outcome, and outlines current management policies. Some experimental approaches involving translational research which seek to exploit the unique biology of neuroblastoma are discussed. Although currently unproven, such new treatments are undergoing clinical evaluation and may yet offer new hope for patients with this enigmatic disease.

We retrospectively analysed serial pulmonary function tests in 14 HIV infected patients receiving either bleomycin and vincristine or liposomal doxorubicin therapy (Doxil) for AIDS related Kaposi's sarcoma. There was a significant reduction in the carbon monoxide transfer coefficient in bleomycin treated patients compared with patients treated with Doxil. No other significant changes in pulmonary function, including the carbon monoxide diffusing capacity, were observed. These preliminary findings suggest that HIV infected patients with Kaposi's sarcoma, who are receiving bleomycin, may be at risk of accelerated pulmonary dysfunction. A larger prospective study should be performed to enable further investigation.

High grade non-Hodgkin's lymphoma accounts for only 5%-10% of all non-Hodgkin's lymphoma. Infection with the human immunodeficiency virus increases the risk of developing high grade, usually B-cell, lymphoma, which has been noted to occur more commonly in homosexual men. These lymphomas often have unusual clinical presentations. We report five cases of high grade non-Hodgkin's lymphoma in HIV negative homosexual men who presented to our hospital in a 13-month period. As a major centre for the treatment of the acquired immune deficiency syndrome, there may be a self-selected homosexual population attending for medical care, and thus a bias in the relative incidence of lymphoma seen in this group.

Sixteen patients with advanced AIDS-related Kaposi's sarcoma received liposomal doxorubicin (Doxil, Liposome Technology, Menlo Park, California) at 20 mg/m2 every 2 or 3 weeks in an open label study, and were evaluated for efficacy and toxicity. Eleven patients achieved a partial remission and five had stable disease. The median time to achieve a maximum response was two cycles (range 1-3) and the median duration of response was 14 weeks (range 6-30). Myelosuppression was the commonest adverse event; one patient was withdrawn because of neutropenia. Other adverse events were uncommon and mild. Liposomal doxorubicin is an effective and safe single agent treatment for advanced AIDs-related Kaposi's sarcoma.

Twenty-four-hour pH monitoring of the esophagus is frequently performed to assess gastroesophageal reflux. We performed a prospective study to determine if results obtained from stationary and ambulatory pH recording systems are comparable. Two groups of patients were studied. Group I consisted of 12 patients monitored simultaneously by both a stationary and an ambulatory pH recording system, each system having a separate pH and reference electrode. In group II, in order to eliminate electrode variability, 10 patients were monitored simultaneously with both systems and a common single pH and reference electrode. In group I, significant correlations were found in six reflux parameters measured and in the 24-hr composite score (r greater than or equal to 0.8722). However, in three of the 12 patients, marked discrepancies were noted in the composite score calculated by the stationary and ambulatory recording systems. Small variations in the pH level recorded by different pH electrodes may have accounted for the discrepancies. In group II, where electrode variability was eliminated, a better correlation was noted between all parameters measured (r greater than or equal to 0.991), and no discrepancies were noted between calculated composite scores. We concluded that the stationary and ambulatory recording systems tested are comparable in measuring 24-hr esophageal pH.