Patients' Demographics and Risk Factors in Voice Disorders: An Umbrella Review of Systematic Reviews.

OBJECTIVES: This study aimed to provide a comprehensive overview of the systematic reviews that focus on the prevalence of voice disorders (VDs), associated risk factors, and the demographic characteristics of patients with dysphonia. An umbrella review was conducted to identify general research themes in voice literature that might guide future research initiatives and contribute to the classification of VDs as a worldwide health concern. STUDY DESIGN: Umbrella review of systematic reviews. METHODS: Pubmed/Medline and Embase were searched for eligible systematic reviews by two authors independently. Extracted data items included the study publication details, study design, characteristics of the target population, sample size, region/country, and incidence and/or prevalence of the VD(s) of interest. RESULTS: Forty systematic reviews were included. Sixteen reported a meta-analysis. Great heterogeneity in methods was found. A total of 277,035 patients across the included studies were included with a prevalence ranging from 0%-90%. The countries represented best were the United States and Brazil, with 13 studies each. Aging, occupational voice use, lifestyle choices, and specific comorbidities, such as obesity or hormonal disorders, seem to be associated with an increased prevalence of dysphonia. CONCLUSIONS: This review underscores the influence of VDs on distinct patient groups and the general population. A variety of modifiable or non-modifiable risk factors, having varied degrees of impact on voice qualities, have been identified. The overall effect of VDs is probably underestimated due to factors, such as sample size, patient selection, underreporting of symptoms, and asymptomatic cases. Employing systematic reviews with consistent methodologies and criteria for diagnosing VDs would enhance the ability to determine the prevalence of VDs and their impact.

The effects of preosteoblast-derived exosomes on macrophages and bone in mice.

The effect of preosteoblast-derived exosomes on bone marrow macrophages (BMMΦ) and calvarial osteoblasts (cOB) was evaluated in vitro, and bone formation studies were performed in vivo in mice. Preosteoblastic MC3T3-E1 clone 4 (MC4) cell-derived exosomes (MC4exo) were characterized with particle tracking, transmission electron microscopy and western blot analysis to validate size, number, shape and phenotypic exosome markers. Exosomes pre-labelled with PKH67 were incubated with BMMΦ and phagocytosis of exosomes was confirmed. To examine the effect of MC4exo on macrophage polarization, BMMΦ were treated with MC4exo and the expression of pro- and anti-inflammatory cytokines was determined by qPCR. MC4exo treatment upregulated mRNA expression of Cd86, Il1ß, Ccl2, Rankl and Nos, and downregulated Cd206, Il10 and Tnfα, suggesting a shift towards pro-inflammatory 'M1-like' macrophage polarization. Combination of RANKL and MC4exo increased osteoclast differentiation of BMMΦ in comparison to RANKL alone as analysed by TRAP staining. MC4exo treatment showed no significant effect on calvarial osteoblast mineralization. For in vivo studies, intratibial inoculation of MC4exo (2 × 109 particles in PBS, n = 12) and vehicle control (PBS only, n = 12) was performed in C57Bl/6 mice (8 weeks, male). Micro-CT analyses of the trabecular and cortical bone compartments were assessed at 4 weeks post-injection. Tibial sections were stained for TRAP activity to determine osteoclast presence and immunofluorescence staining was performed to detect osteocalcin (Ocn), osterix (Osx) and F4/80 expression. Intratibial inoculation of MC4exo increased the diaphyseal bone mineral density and trabecular bone volume fraction due to increased trabecular number. This increase in bone was accompanied by a reduction in bone marrow macrophages and osteoclasts at the experimental endpoint. Together, these findings suggest that preosteoblast-derived exosomes enhanced bone formation by influencing macrophage responses.

Use of portable air purifiers to reduce aerosols in hospital settings and cut down the clinical backlog.

SARS-CoV-2 has severely affected capacity in the National Health Service (NHS), and waiting lists are markedly increasing due to downtime of up to 50 min between patient consultations/procedures, to reduce the risk of infection. Ventilation accelerates this air cleaning, but retroactively installing built-in mechanical ventilation is often cost-prohibitive. We investigated the effect of using portable air cleaners (PAC), a low-energy and low-cost alternative, to reduce the concentration of aerosols in typical patient consultation/procedure environments. The experimental setup consisted of an aerosol generator, which mimicked the subject affected by SARS-CoV-19, and an aerosol detector, representing a subject who could potentially contract SARS-CoV-19. Experiments of aerosol dispersion and clearing were undertaken in situ in a variety of rooms with two different types of PAC in various combinations and positions. Correct use of PAC can reduce the clearance half-life of aerosols by 82% compared to the same indoor-environment without any ventilation, and at a broadly equivalent rate to built-in mechanical ventilation. In addition, the highest level of aerosol concentration measured when using PAC remains at least 46% lower than that when no mitigation is used, even if the PAC's operation is impeded due to placement under a table. The use of PAC leads to significant reductions in the level of aerosol concentration, associated with transmission of droplet-based airborne diseases. This could enable NHS departments to reduce the downtime between consultations/procedures.

Adjustment of Health-Care Service Delivery Among Phoniatricians and ENT Specialists During the COVID-19 Pandemic, A UEP Survey.

BACKGROUND: Applying measures that prioritize staff safety, while protecting patient safety and care, represents a challenge during the current pandemic. Many documents of recommendations toward safe practice have been developed for this purpose. OBJECTIVE: To assess adjustments that have been undertaken by phoniatricians and otolaryngologists in the delivery of health-care services during the pandemic in order to reduce staff exposure to COVID-19 and improve safety. STUDY DESIGN: Cross-sectional. METHODS: An online self-administered survey was used during the first wave of the COVID-19 pandemic in June 2020 to collect data related to demographics of participants, their sources of information, administrative alterations, and changes they adopted when meeting patients for a consultation/procedure/surgery. RESULTS: The eligible 154 responses were grouped into 4 groups based on country of residence. Alterations to service delivery amongst the different groups were compared. CONCLUSIONS: The majority of participants were following the suggested recommendations to service delivery adjustments, with some inconsistencies in practice across countries.

Rehearsal Sound Exposure and Choir Singers' Hearing: A Pilot Field Study.

Exposure to high- and moderate-intensity sound is inevitable for professional singers during their working day, the majority of which is spent in rehearsal, preparing for a performance. The impact of self-produced sound exposure on singers' hearing within the rehearsal setting has not been examined. OBJECTIVES: This original pilot field study investigates the feasibility of data collection and hypothesis testing of singers' hearing within the rehearsal environment. METHODS: 18 professional choir singers are examined for hearing threshold changes following routine rehearsal sound exposure. Pure Tone Audiometry is measured before, immediately after, and approximately 24 hours after rehearsal. RESULTS: This study does not identify definitive Temporary Threshold Shift in this population under these conditions. That said, mean temporary threshold shift was found 3.61 dB higher than the recovery threshold shift in the right ear at 3000 Hz (P = 0.06), and this may be important to look at for future studies. CONCLUSIONS: Methodological challenges of this field study include dynamic experimental conditions intrinsic to the rehearsal process, environmental and musical influence on Pure Tone Audiometry results and estimation of sound intensity exposure.

Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization.

The clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow (BM) macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment in their cellular response to hypoxia. Here, we show that BM macrophage efferocytosis increased hypoxia inducible factor-1alpha (HIF-1α) and STAT3 phosphorylation (p-STAT3 at Tyr705) under normoxic conditions, while inhibitors of p-STAT3 reduced HIF-1α. Efferocytosis promoted HIF-1α stabilization, reduced its ubiquitination, and induced HIF-1α and p-STAT3 nuclear translocation. HIF-1α stabilization in efferocytic BM macrophages resulted in enhanced expression of pro-inflammatory cytokine MIF, whereas BM macrophages with inactive HIF-1α reduced MIF expression upon efferocytosis. Stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in BM macrophages. Furthermore, BM macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by BM macrophages triggers p-STAT3/HIF-1α/MIF signaling to promote further inflammation in the bone tumor microenvironment where a significant number of apoptotic cancer cells are present.

Severe distinct dysautonomia in RFC1-related disease associated with Parkinsonism.

Biallelic repeat expansions in replication factor C subunit 1 (RFC1) have recently been found to cause cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Additional features that have been described include Parkinsonism and a multiple system atrophy (MSA)-like syndrome. CANVAS can include features of dysautonomia, but they are much milder than typically seen in MSA. We report a detailed autonomic phenotype of multisystem RFC1-related disease presenting initially as CANVAS. Our patient presented aged 61 with a sensory ataxic neuropathy who rapidly developed widespread autonomic failure and Parkinsonism. The autonomic profile was of a mixed pre- and post-ganglionic syndrome with progressive involvement of sympathetic and parasympathetic cardiovascular and sudomotor function. The Parkinsonism did not respond to levodopa. We present a patient with CANVAS and biallelic RFC1 expansions who developed Parkinsonism with severe autonomic involvement similar to that seen in classical MSA. The link between MSA and CANVAS remains uncertain.

'Malregulative' Rather Than 'Functional' Dysphonia: A New Etiological Terminology Framework for Phonation Disorders-A Position Paper by the Union of European Phoniatricians (UEP).

Practitioners in the field of voice are often faced with patients who are 'dysphonic', but who do not have identifiable abnormalities of the vocal tract structures or any neural or hormonal alteration affecting the phonatory function. For lack of better nomenclature describing the origin of the disorder, this group of patients has been labeled as having 'non-organic' or 'functional' dysphonia. 'Non-organic' only states what the dysphonia is not, and 'functional' does not have any etiological implication. Hence 'functional disorder' as a determination of the origin is at best vague, imprecise and often misleading. In truth, the terms "functional" and 'non-organic' are by now so muddled and confused in everyday clinical usage and parlance that it is unclear what they mean in any given clinical setting or for any particular clinical case. Thus, the UEP Voice Committee (VC) has come to the conclusion that it is best to adopt a new term that is clearly defined, universally agreed to, and indicative of a different and more useful perspective. We have reviewed the literature relating to terminology of these phonatory disorders. We now propose replacement of the phrase 'functional dysphonia' with 'malregulative dysphonia', since the indication of faulty regulation represents an etiological connotation. We also propose a restructuring of the etiological terminology of phonation disorders. We believe this to be a biologically clearer framework for the labeling of 'non-organic' phonatory disorders, and hope that its routine use will allow for more clarity of presentation and discussion in the future.

Spatiotemporal droplet dispersion measurements demonstrate face masks reduce risks from singing.

COVID-19 has restricted singing in communal worship. We sought to understand variations in droplet transmission and the impact of wearing face masks. Using rapid laser planar imaging, we measured droplets while participants exhaled, said 'hello' or 'snake', sang a note or 'Happy Birthday', with and without surgical face masks. We measured mean velocity magnitude (MVM), time averaged droplet number (TADN) and maximum droplet number (MDN). Multilevel regression models were used. In 20 participants, sound intensity was 71 dB for speaking and 85 dB for singing (p < 0.001). MVM was similar for all tasks with no clear hierarchy between vocal tasks or people and > 85% reduction wearing face masks. Droplet transmission varied widely, particularly for singing. Masks decreased TADN by 99% (p < 0.001) and MDN by 98% (p < 0.001) for singing and 86-97% for other tasks. Masks reduced variance by up to 48%. When wearing a mask, neither singing task transmitted more droplets than exhaling. In conclusion, wide variation exists for droplet production. This significantly reduced when wearing face masks. Singing during religious worship wearing a face mask appears as safe as exhaling or talking. This has implications for UK public health guidance during the COVID-19 pandemic.

Unique Pro-Inflammatory Response of Macrophages during Apoptotic Cancer Cell Clearance.

The clearance of apoptotic cells by macrophages (efferocytosis) is crucial to maintain normal tissue homeostasis; however, efferocytosis of cancer cells frequently results in inflammation and immunosuppression. Recently, we demonstrated that efferocytosis of apoptotic prostate cancer cells by bone marrow-derived macrophages induced a pro-inflammatory response that accelerated metastatic tumor growth in bone. To evaluate the microenvironmental impact of macrophages and their efferocytic function, we compared peritoneal macrophages (P-MΦ) versus bone marrow-derived macrophages (BM-MΦs) using an efferocytosis in vitro model. The capability to engulf apoptotic prostate cells was similar in BM-MΦs and P-MΦs. Ex vivo analysis of BM-MΦs showed an M2-like phenotype compared with a predominantly M1-like phenotype in P-MΦs. A distinct gene and protein expression profile of pro-inflammatory cytokines was found in BM-MΦs as compared with P-MΦs engulfing apoptotic prostate cancer cells. Importantly, the reprogramming of BM-MΦs toward an M1-like phenotype mitigated their inflammatory cytokine expression profile. In conclusion, BM-MΦs and P-MΦs are both capable of efferocytosing apoptotic prostate cancer cells; however, BM-MΦs exert increased inflammatory cytokine expression that is dependent upon the M2 polarization stage of macrophages. These findings suggest that bone marrow macrophage efferocytosis of apoptotic cancer cells maintains a unique pro-inflammatory microenvironment that may support a fertile niche for cancer growth. Finally, bone marrow macrophage reprogramming towards M1-type by interferon-γ (IFN-γ) induced a significant reduction in the efferocytosis-mediated pro-inflammatory signature.

Assessment and Management of Preoperative Anxiety.

BACKGROUND: Preoperative anxiety has the potential to alter the dynamics of an elective procedure and has been shown to detrimentally affect patients both cognitively and physiologically. If mismanaged, it can lead to essential procedures being postponed or canceled, delay postoperative recovery, and increase patients' requirements for medical intervention postoperatively. These outcomes have harmful implications both clinically and economically. Our primary objective was to evaluate the levels of anxiety patients experience immediately before elective otorhinolaryngologic procedures. Our secondary outcome was to assess the subjects' views on potential management strategies to tackle their anxiety. METHODS: This is an observational cross-sectional project evaluating 53 patients who were selected consecutively from a list of elective otorhinolaryngologic procedures. All procedures were to be completed under general anesthetic, and all patients had received the same preoperative assessment preparation. 29 male and 24 female patients were included, aged between 19 and 76 years (mean 45). The Spielberger State-Trait Anxiety Inventory was used to assess preoperative anxiety directly before the otorhinolaryngologic procedure. The Service Improvement questionnaire was used to assess whether patients would favor the introduction of anxiety-reduction measures. RESULTS: There was neither a significant increase in patient anxiety levels preoperatively (P = 0.37) nor a significant increase in anxiety levels preoperatively when results were stratified according to patient gender and age (P = 0.45 and P = 0.27). 54% of the patients felt that their anxiety would have been reduced if they had read a procedural information leaflet, and 22% felt it would have been reduced if they had received preoperative behavioral training. 17% of the patients wanted more information from the surgical team. However, 12% of the patients would have liked less information from the surgical team preoperatively. CONCLUSIONS: Patients did not have a significant increase in their anxiety levels preoperatively. On the basis of our findings, we will work to improve the information we provide to patients preoperatively and to identify patient subgroups that require additional preoperative support.

Molecular Correlates of In Vitro Responses to Dacomitinib and Afatinib in Bladder Cancer.

BACKGROUND: The HER family of proteins (EGFR, HER2, HER3 and HER4) have long been thought to be therapeutic targets for bladder cancer, but previous clinical trials targeting these proteins have been disappointing. Second generation agents may be more effective. OBJECTIVE: The aim of this study was to evaluate responses to two second-generation irreversible tyrosine kinase inhibitors, dacomitinib and afatinib, in bladder cancer cell lines. METHODS: Cell lines were characterized by targeted next generation DNA sequencing, RNA sequencing, western blotting and flow cytometry. Cell survival responses to dacomitinib or afatinib were determined using (3-[4,5-dimethylthioazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) or [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and phenazine methosylfate (PMS) cell survival assays. RESULTS: Only two cell lines of 12 tested were sensitive to afatinib. Sensitivity to afatinib was significantly associated with mutation in either HER2 or HER3 (p < 0.05). The two cell lines sensitive to afatinib were also responsive to dacomitinib ralong with an additional 4 other cell lines out of 16 tested. No characteristic was associated with dacomitinib sensitivity. Molecular profiling demonstrated that only two genes were high in both afatinib and dacomitinib sensitive cells. Further rhigher expression of RAS pathway genes was noted for dacomitinib responsive cells. CONCLUSIONS: This study confirms that cell line screening can be useful in pre-clinical evaluation of targeted small molecule inhibitors and suggests that compounds with similar structure(s) and target(s) may have distinct sensitivity profiles. Further rcombinational targeting of additional molecularly relevant pathways may be important in enhancing responses to HER targeted agents in bladder cancer.