Real-World Evaluation of the Safety and Effectiveness of 2.3% Hypertonic Saline Soft Mist Spray for Sino-Nasal Symptoms.

Introduction and aims Mildly hypertonic saline is more effective in relieving symptoms of nasal congestion compared to placebo or isotonic saline. Recently, a unique device, delivering a soft mist of 2.3% hypertonic sea-salt saline (Nasoclear PureHaleTM; Zydus Healthcare Ltd., India) has been introduced in India. The device uses a power-less manual technique to release the saline as a soft mist at 1 ml/min. Methods This is a retrospective, multi-centric, single-arm study to evaluate the safety and effectiveness of 2.3% hypertonic sea-salt saline nasal irrigation delivered through a soft mist device in patients with sino-nasal symptoms. This is an analysis of data of 130 patients collected from the medical records of 11 practicing pediatricians across India. Results The mean age of the patients was 5.23 ± 4.24 years; 63 % were boys and 37% were girls (n = 130). The mean reduction in total nasal symptom score (TNSS) at follow-up from baseline was 6.28 ± 0.18 (median days = 7) (95% CI = 5.92 to 6.64; p<0.0001; mean TNSS at baseline = 7.75 ± 2.01, mean TNSS at follow-up = 1.47± 1.30). Out of 130 patients, 33 patients (25.3%) showed complete improvement in TNSS, 93 patients (71.5%) had ≥ 50% improvement in TNSS while 4 patients (3.07%) showed <50% improvement in TNSS. The effectiveness of the device was rated as excellent (75%-100% improvement) and very good (50%-75% improvement) in 41 and 74 patients, respectively. It was rated as very easy to use and easy to use by 62 patients and 57 patients, respectively. One hundred nineteen patients (91.5%) were compliant with the prescribed frequency of the device and 110 patients (84.6%) were compliant with the prescribed duration of use of the device. No serious adverse events were reported; two patients reported mild side effects - stinging and irritation of the throat. Conclusions The 2.3% hypertonic sea-salt saline nasal irrigation delivered through the soft mist device was found to be well-tolerated and effective in patients with sino-nasal symptoms in real-world clinical settings. Clinical trial number The clinical trial number of this study is CTRI/2022/07/043751.

Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks.

Fibrosis has been characterized as a global health problem and ranks as one of the primary causes of organ dysfunction. Currently, there is no cure for pulmonary fibrosis, and limited therapeutic options are available due to an inadequate understanding of the disease pathogenesis. The absence of advanced in vitro models replicating dynamic temporal changes observed in the tissue with the progression of the disease is a significant impediment in the development of novel antifibrotic treatments, which has motivated research on tissue-mimetic three-dimensional (3D) models. In this review, we summarize emerging trends in preparing advanced lung models to recapitulate biochemical and biomechanical processes associated with lung fibrogenesis. We begin by describing the importance of in vivo studies and highlighting the often poor correlation between preclinical research and clinical outcomes and the limitations of conventional cell culture in accurately simulating the 3D tissue microenvironment. Rapid advancement in biomaterials, biofabrication, biomicrofluidics, and related bioengineering techniques are enabling the preparation of in vitro models to reproduce the epithelium structure and operate as reliable drug screening strategies for precise prediction. Improving and understanding these model systems is necessary to find the cross-talks between growing cells and the stage at which myofibroblasts differentiate. These advanced models allow us to utilize the knowledge and identify, characterize, and hand pick medicines beneficial to the human community. The challenges of the current approaches, along with the opportunities for further research with potential for translation in this field, are presented toward developing novel treatments for pulmonary fibrosis.

A Real-World Observational Study to Evaluate the Safety and Effectiveness of Fluticasone Furoate-Oxymetazoline Fixed Dose Combination Nasal Spray in Patients with Allergic Rhinitis.

BACKGROUND: Allergic rhinitis (AR) has shown an increasing prevalence leading to a considerable medical and social burden. Nasal congestion is the cardinal symptom of AR, and the upper respiratory tract is most affected by this long-lasting ailment. Intranasal corticosteroids alleviate nasal congestion, along with other symptoms of AR, but their effect is not evident immediately. Oxymetazoline has a rapid onset of action, but its use should be limited to 3-5 days. OBJECTIVE: The study aimed to evaluate the safety and effectiveness of the fixed-dose combination nasal spray containing fluticasone furoate and oxymetazoline hydrochloride (FF + OXY) 27.5/50 mcg once daily in patients with AR in a real-world clinical setting. METHODS: The study was a prospective, open-label, single-arm, multicenter, real-world observational study conducted in patients with AR for a period of 28 days. Patients (n = 388) with a diagnosis of AR were treated with a combination of FF + OXY nasal spray. Total nasal symptom score (TNSS), total ocular symptom score (TOSS) and total symptom score (TSS) were documented at baseline and at the end of study period. The overall effectiveness of treatment with FF + OXY was rated by the investigators as very good/good/satisfactory/poor (4-point Likert scale) for each patient. RESULTS: Treatment with FF + OXY resulted in significant reduction in the TNSS, TOSS and TSS, from 7.18 ± 3.38 at baseline to 0.20 ± 0.84 (p < 0.001), from 2.34 ± 2.29 at baseline to 0.09 ± 0.53 (p < 0.001), from 9.51 ± 4.94 at baseline to 0.29 ± 1.32 (p < 0.001) at 28 days respectively. With respect to effectiveness, the investigators reported very good effectiveness in 52.12% of patients. No serious adverse events were reported. CONCLUSION: The fixed-dose combination of once-daily fluticasone furoate and oxymetazoline hydrochloride nasal spray 27.5/50 mcg was effective in relieving the nasal congestion and reduction of TNSS, TOSS and TSS in patients suffering from AR. The combination was safe and well tolerated with no rebound congestion throughout the treatment period.

Monkeypox virus-infected individuals mount comparable humoral immune responses as Smallpox-vaccinated individuals.

In early 2022, a cluster of monkeypox virus (MPXV) infection (mpox) cases were identified within the UK with no prior travel history to MPXV-endemic regions. Subsequently, case numbers exceeding 80,000 were reported worldwide, primarily affecting gay, bisexual, and other men who have sex with men (GBMSM). Public health agencies worldwide have offered the IMVANEX Smallpox vaccination to these individuals at high-risk to provide protection and limit the spread of MPXV. We have developed a comprehensive array of ELISAs to study poxvirus-induced antibodies, utilising 24 MPXV and 3 Vaccinia virus (VACV) recombinant antigens. Panels of serum samples from individuals with differing Smallpox-vaccine doses and those with prior MPXV infection were tested on these assays, where we observed that one dose of Smallpox vaccination induces a low number of antibodies to a limited number of MPXV antigens but increasing with further vaccination doses. MPXV infection induced similar antibody responses to diverse poxvirus antigens observed in Smallpox-vaccinated individuals. We identify MPXV A27 as a serological marker of MPXV-infection, whilst MPXV M1 (VACV L1) is likely IMVANEX-specific. Here, we demonstrate analogous humoral antigen recognition between both MPXV-infected or Smallpox-vaccinated individuals, with binding to diverse yet core set of poxvirus antigens, providing opportunities for future vaccine (e.g., mRNA) and therapeutic (e.g., mAbs) design.

The clinical presentation of monkeypox: a retrospective case-control study of patients with possible or probable monkeypox in a West London cohort.

OBJECTIVES: Since May 2022, cases of human monkeypox virus (hMPXV) with human-to-human cross-transmission have significantly increased in nonendemic countries. Our aim was to characterize diagnostic features of patients with confirmed and possible monkeypox to guide future risk stratification and to describe a virtual care model. METHODS: We performed a retrospective case-control study of 140 patients assessed and screened for suspected monkeypox; on hMPXV polymerase chain reaction testing, 70 were confirmed positive, and 70 were negative. Data were compared to generate odds ratios of demographic and clinical features. RESULTS: Patients who tested positive were predominantly cis-male (99%) and self-identified as gay, bisexual, and other men who have sex with men (94%). Lymphadenopathy at presentation was associated with a higher likelihood of a positive result (odds ratio [OR] 7.69 [95% confidence interval (CI) 3.58, 16.51]). Patients who tested positive were more likely to have a rash affecting the genital (OR 5.38 [95% CI 2.57, 11.23]) or buttocks/perianal region (OR 3.79 [1.70, 8.45]) than negative controls. A total of 79% of patients were engaged with a virtual ward follow-up. CONCLUSION: These data can inform a risk-based approach to the management of suspected monkeypox in gay, bisexual, and other men who have sex with men populations. Lymphadenopathy at presentation and the location of the rash were more associated with a positive hMPXV result. Health authorities can consider a virtual ward approach in the hMPHXV outbreak.

Neurobrucellosis: the great mimicker.

Neurobrucellosis is caused by bacteria of the genus Brucella and is responsible for several clinical manifestations, making diagnosis challenging. The most common route of infection is through the consumption of unpasteurized or raw dairy products such as fresh milk, butter, and cheese. As neurological complications can develop chronically, they are frequently misdiagnosed as other infections, such as tuberculosis. This report reviews the clinical manifestations, diagnostic approach, treatment, and prognosis of neurobrucellosis, illustrating a case of chronic intracranial hypertension and meningoencephalitis secondary to brucellosis. The clinical presentation of brucellosis can mimic several systemic diseases, resulting in diagnostic delays and clinical complications. A high degree of suspicion is required, and neurobrucellosis should always be considered in the differential diagnosis of chronic meningitis.

Antiviral metabolite 3'-deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19.

BACKGROUND: There is a critical need for rapid viral infection diagnostics to enable prompt case identification in pandemic settings and support targeted antimicrobial prescribing. METHODS: Using untargeted high-resolution liquid chromatography coupled with mass spectrometry, we compared the admission serum metabolome of emergency department patients with viral infections (including COVID-19), bacterial infections, inflammatory conditions, and healthy controls. Sera from an independent cohort of emergency department patients admitted with viral or bacterial infections underwent profiling to validate findings. Associations between whole-blood gene expression and the identified metabolite of interest were examined. FINDINGS: 3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum. When comparing 60 viral with 101 non-viral cases in the discovery cohort, ddhC was the most significantly differentially abundant metabolite, generating an area under the receiver operating characteristic curve (AUC) of 0.954 (95% CI: 0.923-0.986). In the validation cohort, ddhC was again the most significantly differentially abundant metabolite when comparing 40 viral with 40 bacterial cases, generating an AUC of 0.81 (95% CI 0.708-0.915). Transcripts of viperin and CMPK2, enzymes responsible for ddhCTP synthesis, were among the five genes most highly correlated with ddhC abundance. CONCLUSIONS: The antiviral precursor molecule ddhC is detectable in serum and an accurate marker for acute viral infection. Interferon-inducible genes viperin and CMPK2 are implicated in ddhC production in vivo. These findings highlight a future diagnostic role for ddhC in viral diagnosis, pandemic preparedness, and acute infection management. FUNDING: NIHR Imperial BRC; UKRI.

Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study.

BACKGROUND: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department. METHODS: Individuals (aged ≥18 years) presenting with suspected infection to an emergency department at a major teaching hospital in the UK were prospectively recruited as part of the Bioresource in Adult Infectious Diseases (BioAID) discovery cohort. Whole-blood RNA sequencing was done on samples from participants with subsequently confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes that met additional filtering criteria were subjected to feature selection to derive the most parsimonious discriminating signature. We validated the signature via RT-qPCR in a prospective validation cohort of participants who presented to an emergency department with undifferentiated fever, and a second case-control validation cohort of emergency department participants with PCR-positive COVID-19 or bacterial infection. We assessed signature performance by calculating the area under receiver operating characteristic curves (AUROCs), sensitivities, and specificities. FINDINGS: A three-gene transcript signature, comprising HERC6, IGF1R, and NAGK, was derived from the discovery cohort of 56 participants with bacterial infections and 27 with viral infections. In the validation cohort of 200 participants, the signature differentiated bacterial from viral infections with an AUROC of 0·976 (95% CI 0·919-1·000), sensitivity of 97·3% (85·8-99·9), and specificity of 100% (63·1-100). The AUROC for C-reactive protein (CRP) was 0·833 (0·694-0·944) and for leukocyte count was 0·938 (0·840-0·986). The signature achieved higher net benefit in decision curve analysis than either CRP or leukocyte count for discriminating viral infections from all other infections. In the second validation analysis, which included SARS-CoV-2-positive participants, the signature discriminated 35 bacterial infections from 34 SARS-CoV-2-positive COVID-19 infections with AUROC of 0·953 (0·893-0·992), sensitivity 88·6%, and specificity of 94·1%. INTERPRETATION: This novel three-gene signature discriminates viral infections, including COVID-19, from other emergency infection presentations in adults, outperforming both leukocyte count and CRP, thus potentially providing substantial clinical utility in managing acute presentations with infection. FUNDING: National Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.

Guillain-Barré syndrome during the Zika virus outbreak in Northeast Brazil: An observational cohort study.

OBJECTIVE: To determine the clinical phenotype of Guillain-Barré syndrome (GBS) after Zika virus (ZIKV) infection, the anti-glycolipid antibody signature, and the role of other circulating arthropod-borne viruses, we describe a cohort of GBS patients identified during ZIKV and chikungunya virus (CHIKV) outbreaks in Northeast Brazil. METHODS: We prospectively recruited GBS patients from a regional neurology center in Northeast Brazil between December 2014 and February 2017. Serum and CSF were tested for ZIKV, CHIKV, and dengue virus (DENV), by RT-PCR and antibodies, and serum was tested for GBS-associated antibodies to glycolipids. RESULTS: Seventy-one patients were identified. Forty-eight (68%) had laboratory evidence of a recent arbovirus infection; 25 (52%) ZIKV, 8 (17%) CHIKV, 1 (2%) DENV, and 14 (29%) ZIKV and CHIKV. Most patients with a recent arbovirus infection had motor and sensory symptoms (72%), a demyelinating electrophysiological subtype (67%) and a facial palsy (58%). Patients with a recent infection with ZIKV and CHIKV had a longer hospital admission and more frequent mechanical ventilation compared to the other patients. No specific anti-glycolipid antibody signature was identified in association with arbovirus infection, although significant antibody titres to GM1, GalC, LM1, and GalNAc-GD1a were found infrequently. CONCLUSION: A large proportion of cases had laboratory evidence of a recent infection with ZIKV or CHIKV, and recent infection with both viruses was found in almost one third of patients. Most patients with a recent arbovirus infection had a sensorimotor, demyelinating GBS. We did not find a specific anti-glycolipid antibody signature in association with arbovirus-related GBS.

Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study.

BACKGROUND: Since 2015, the arthropod-borne viruses (arboviruses) Zika and chikungunya have spread across the Americas causing outbreaks, accompanied by increases in immune-mediated and infectious neurological disease. The spectrum of neurological manifestations linked to these viruses, and the importance of dual infection, are not known fully. We aimed to investigate whether neurological presentations differed according to the infecting arbovirus, and whether patients with dual infection had a different disease spectrum or severity. METHODS: We report a prospective observational study done during epidemics of Zika and chikungunya viruses in Recife, Pernambuco, a dengue-endemic area of Brazil. We recruited adults aged 18 years or older referred to Hospital da Restauração, a secondary-level and tertiary-level hospital, with suspected acute neurological disease and a history of suspected arboviral infection. We looked for evidence of Zika, chikungunya, or dengue infection by viral RNA or specific IgM antibodies in serum or CSF. We grouped patients according to their arbovirus laboratory diagnosis and then compared demographic and clinical characteristics. FINDINGS: Between Dec 4, 2014, and Dec 4, 2016, 1410 patients were admitted to the hospital neurology service; 201 (14%) had symptoms consistent with arbovirus infection and sufficient samples for diagnostic testing and were included in the study. The median age was 48 years (IQR 34-60), and 106 (53%) were women. 148 (74%) of 201 patients had laboratory evidence of arboviral infection. 98 (49%) of them had a single viral infection (41 [20%] had Zika, 55 [27%] had chikungunya, and two [1%] had dengue infection), whereas 50 (25%) had evidence of dual infection, mostly with Zika and chikungunya viruses (46 [23%] patients). Patients positive for arbovirus infection presented with a broad range of CNS and peripheral nervous system (PNS) disease. Chikungunya infection was more often associated with CNS disease (26 [47%] of 55 patients with chikungunya infection vs six [15%] of 41 with Zika infection; p=0·0008), especially myelitis (12 [22%] patients). Zika infection was more often associated with PNS disease (26 [63%] of 41 patients with Zika infection vs nine [16%] of 55 with chikungunya infection; p≤0·0001), particularly Guillain-Barré syndrome (25 [61%] patients). Patients with Guillain-Barré syndrome who had Zika and chikungunya dual infection had more aggressive disease, requiring intensive care support and longer hospital stays, than those with mono-infection (median 24 days [IQR 20-30] vs 17 days [10-20]; p=0·0028). Eight (17%) of 46 patients with Zika and chikungunya dual infection had a stroke or transient ischaemic attack, compared with five (6%) of 96 patients with Zika or chikungunya mono-infection (p=0·047). INTERPRETATION: There is a wide and overlapping spectrum of neurological manifestations caused by Zika or chikungunya mono-infection and by dual infections. The possible increased risk of acute cerebrovascular disease in patients with dual infection merits further investigation. FUNDING: Fundação do Amparo a Ciência e Tecnologia de Pernambuco (FACEPE), EU's Horizon 2020 research and innovation programme, National Institute for Health Research. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Diagnostic performance of a point-of-care saliva urea nitrogen dipstick to screen for kidney disease in low-resource settings where serum creatinine is unavailable.

BACKGROUND: Kidney disease is prevalent in low-resource settings worldwide, but tests for its diagnosis are often unavailable. The saliva urea nitrogen (SUN) dipstick is a laboratory and electricity independent tool, which may be used for the detection of kidney disease. We investigated the feasibility and performance of its use in diagnosing kidney disease in community settings in Africa. METHODS: Adult patients at increased risk of kidney disease presenting to three community health centres, a rural district hospital and a central hospital in Malawi were recruited between October 2016 and September 2017. Patients underwent concurrent SUN and creatinine testing at enrolment, and at 1 week, 1 month, 3 months and 6 months thereafter. RESULTS: Of 710 patients who presented at increased risk of kidney disease, 655 (92.3%) underwent SUN testing at enrolment, and were included (aged 38 (29-52) years, 367 (56%) female and 333 (50.8%) with HIV). Kidney disease was present in 482 (73.6%) patients and 1479 SUN measurements were made overall. Estimated glomerular filtration rate (eGFR) correlated with SUN (r=-0.39; p<0.0001). The area under the receiver operating characteristics curve was 0.61 for presenting SUN to detect acute or chronic kidney disease, and 0.87 to detect severe (eGFR <15 mL/min/1.73 m2) kidney disease (p<0.0001; sensitivity 82.3%, specificity 81.8%, test accuracy 81.8%). In-hospital mortality was greater if enrolment SUN was elevated (>test pad #1) compared with patients with non-elevated SUN (p<0.0001; HR 3.3 (95% CI 1.7 to 6.1). CONCLUSIONS: SUN, measured by dipstick, is feasible and may be used to screen for kidney disease in low resource settings where creatinine tests are unavailable.

Interamerican Society of Cardiology (IASC) position statement: Chlorthalidone vs. thiazide-type diuretics.

The Interamerican Society of Cardiology (IASC) Position Statement for hypertension management in Latin America is a practical and useful review of five different hypertension guidelines. Though, thiazide diuretics have been recommended as firstline option, the position statement needs to highlight differences within the thiazide class. Chlorthalidone is structurally and pharmacokinetically distinct from thiazide-type iuretics like hydrochlorothiazide with a longer half-life and 24-h anti-hypertensive effect. It has been shown to reduce cardiovascular morbidity and mortality in several landmark studies evaluating anti-hypertensives.