Staging and operability of primary lung cancer in Western Cape Province, South Africa.

Background: Lung cancer is the leading cause of cancer-related death globally and in South Africa. Historically, the majority of patients diagnosed with lung cancer are incurable at presentation. Objectives: To assess the tumour, nodes, metastasis (TNM) staging of lung cancer in a centre with access to both positron emission tomography-computed tomography (PET-CT) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) using a structured diagnostic approach and to compare results with a historical cohort from 2009 from the same hospital. Methods: A retrospective descriptive observational study was performed using the registry of a high-volume tertiary hospital's weekly multidisciplinary thoracic oncology meeting (MDT). A structured diagnostic approach was used for staging purposes. All patients with a tissue diagnosis of primary lung cancer and adequate imaging (chest CT and/or PET-CT) who presented at the MDT during the period from 1 January - 31 December 2019 were included. Final staging and tissue diagnoses were documented and compared with a historical cohort from 2009 from the same institution. Results: Adenocarcinoma was the most common subtype (38.8%; n=116). Less than a tenth of patients (6.3%; n=16/254) with non-small cell lung cancer had potentially curable lung cancer (stage IA to IIIA) at presentation, significantly less than the 2009 cohort (14.5%; n=25/173; p=0.007). The most common procedure administered on patients was transthoracic needle aspiration (37.54%; n=112), followed by conventional bronchoscopic needle aspiration or biopsy (20.4%; n=61), and EBUS-TBNA (17.1%; n=51/299). After PET-CT, 19/30 cases were upstaged including 9/18 from potentially resectable to unresectable. Two of these cases were down-staged to potentially resectable following EBUS-TBNA. Conclusion: There was a significant decline in resectable and potentially curable lung cancer at presentation over a 10-year period. PET-CT and EBUS-TBNA improved the accuracy of non-small cell lung cancer staging among patients with resectable and potentially curable lung cancer but have exposed a higher stage profile.

Unaccompanied Clinic Visits: Practical Consequences of a Stressor Imposed by the COVID-19 Pandemic.

One of the restrictive measures of COVID-19 (coronavirus disease 2019) pandemic control is the prohibition of accompanied clinic visits. The specific features of ophthalmological patients imply different degrees of dependency that directly affect their response to such measures. This study aims to assess the effects of unaccompanied medical appointments on outpatients' stress levels and their retention of medical advice. A questionnaire-based survey was conducted at a large ophthalmic clinic in northern Greece during September 2020. Suitable subjects were asked to self-administer a 7-item questionnaire addressing their subjective perception of stress and their ability to fully understand and remember their doctor's instructions, given the fact that they would be alone during the consultation. The analysis was based on 200 patients who completed the survey. Sixty-three patients (31.5%) reported that unaccompanied clinic visits increased their stress, with a median value of 7.5 (mean 6.77 ± .2.7) on a scale from 1 to 10. A large number of the patients (30%) claimed it was difficult to remember the doctor's comments or instructions, and 24.6% indicated that they would not fully understand them if they were to attend the clinic unaccompanied. A marked impact on women and on the elderly (up to threefold) over 70 years of age was identified. This is the first study specifically addressing practical repercussions of unaccompanied clinic visits during the COVID-19 pandemic. A negative effect on patients' emotional status and on counseling effectiveness was demonstrated. Female gender and advanced age were found to be determinants of the highest vulnerability.

Optical coherence tomography biomarkers for visual acuity in patients with idiopathic epiretinal membrane.

PURPOSE: To investigate the correlation between outer and inner retina optical coherence tomography (OCT) biomarkers and visual acuity in patients with idiopathic epiretinal membrane (iERM) and identify which of them may be predictive of visual function. METHODS: A retrospective cross-sectional single-center study was conducted that included patients diagnosed with iERM. Spectral domain OCT images were obtained and assessed qualitatively and quantitatively. The association of OCT parameters with best corrected visual acuity was analyzed. RESULTS: Charts of 97 eyes of 97 patients were reviewed. Central foveal thickness, maximal retinal thickness (MRT), photoreceptor outer segment length, outer foveal thickness, ganglion cell-inner plexiform layer complex thickening, inner retinal thickness and inner retinal layer irregularity index were among the major outcome measures. OCT scans were also assessed for the presence of cotton ball sign, ellipsoid zone disruption, ectopic inner foveal layer, disorganization of retinal inner layers (DRIL), intraretinal fluid, subretinal fluid (SRF) and epimacular membrane rip. Univariate analysis showed statistically significant association between all the aforementioned parameters with worse vision, except for cotton ball sign and SRF. Multivariate analysis found that MRT and severe DRIL were strongly correlated with worse vision (p < 0.001). CONCLUSION: MRT and severe DRIL should be considered as negative prognostic factors for visual acuity.

Comparison of postoperative refractive outcome in eyes undergoing combined phacovitrectomy vs cataract surgery following vitrectomy.

BACKGROUND: To investigate the accuracy of preoperative biometry in eyes undergoing combined phacovitrectomy and to compare it with eyes having cataract surgery at a later point in time following vitrectomy. METHODS: Patients with epiretinal membrane or macular hole who underwent combined phacovitrectomy (group 1) or phacoemulsification following pars plana vitrectomy (PPV) (group 2) were included in this retrospective, comparative, interventional case series. The primary outcome measures were the intraocular lens power prediction error (PE) and the percentage of eyes with PE > ± 0.5D in the two groups. Secondary outcome measures included the correlation between epidemiological, clinical, or surgical factors and dioptric shift. In addition, the influence of optical coherence tomography characteristics to the PE was investigated. RESULTS: Group 1 and 2 consisted of 55 and 54 eyes, respectively, for a total of 109 eyes included in the study. The mean absolute PE was 0.59 D (range + 1.4 to - 2.5D) in group 1 and 0.35 (range + 1.0 to - 1.45D) in group 2 (p = 0.01). PE greater than 0.5D was observed in 47% of eyes in group 1 as opposed to 16.6% of eyes in group 2 (p = 0.027). The PE was associated with shallower anterior chamber depth (ACD), increased central macular thickness (> 300 µ), and worse baseline best-corrected visual acuity. Photoreceptor ellipsoid zone or external limiting membrane disruption was not associated with significantly greater postoperative refractive deviations. CONCLUSION: Combined phacovitrectomy may result in greater postoperative refractive prediction error compared to phacoemulsification alone following vitrectomy. Patients with worse vision, greater central macular thickness, and shallow anterior chambers require more caution since they are prone to inaccurate preoperative biometry.

How Successful is Switching from Bevacizumab or Ranibizumab to Aflibercept in Age-Related Macular Degeneration? A Systematic Overview.

Emerging anti-vascular endothelial growth factor (anti-VEGF) therapies for neovascular age-related macular degeneration (nAMD) have revolutionised medical retina practice and the management and eventual outcome of nAMD. Recent research has focused on evaluating and comparing the efficacy of the two most widely employed anti-VEGF agents, bevacizumab and ranibizumab; however, a subgroup of patients with nAMD demonstrates a suboptimal response to standard therapy. We have therefore conducted a review of pertinent studies published until August 2018 which have documented the clinical efficacy when switching to a different anti-VEGF. Evidence on baseline disease characteristics, injection frequency and disease outcome has been obtained for patients treated with ranibizumab 0.5 mg and/or bevacizumab 1.25 mg and were switched to aflibercept 2 mg. Our review identified 45 studies investigating switching to aflibercept. Our review showed a clear anatomical benefit after the switch in terms of central retinal thickness and pigment epithelium detachment characteristics, whereas the functional outcomes were variable. Remarkable heterogeneity was documented among the relevant studies with regard to several factors including the baseline characteristics of the cohorts, the non-response definition and previous treatment protocols. Larger prospective trials with appropriate control arms are therefore required to elucidate the potential benefit when switching between anti-VEGF agents in refractory nAMD.

Update in treatment of uveitic macular edema.

Macular edema (ME) represents the most common cause for visual loss among uveitis patients. The management of uveitic macular edema (UME) may be challenging, due to its often recalcitrant nature. Corticosteroids remain the mainstay of treatment, through their capability of effectively controlling inflammation and the associated ME. Topical steroids may be effective in milder cases of UME, particularly in edema associated with anterior uveitis. Posterior sub-Tenon and orbital floor steroids, as well as intravitreal steroids often induce rapid regression of UME, although this may be followed by recurrence of the pathology. Intra-vitreal corticosteroid implants provide sustained release of steroids facilitating regression of ME with less frequent injections. Topical nonsteroidal anti-inflammatory drugs may provide a safe alternative or adjuvant therapy to topical steroids in mild UME, predominantly in cases with underlying anterior uveitis. Immunomodulators including methotrexate, mycophenolate mofetil, tacrolimus, azathioprine, and cyclosporine, as well as biologic agents, notably the anti-tumor necrosis factor-α monoclonal antibodies adalimumab and infliximab, may accomplish the control of inflammation and associated ME in refractory cases, or enable the tapering of steroids. Newer biotherapies have demonstrated promising outcomes and may be considered in persisting cases of UME.

Robust Hydrophobic and Hydrophilic Polymer Fibers Sensitized by Inorganic and Hybrid Lead Halide Perovskite Nanocrystal Emitters.

Advances in the technology and processing of flexible optical materials have paved the way toward the integration of semiconductor emitters and polymers into functional light emitting fabrics. Lead halide perovskite nanocrystals appear as highly suitable optical sensitizers for such polymer fiber emitters due to their ease of fabrication, versatile solution-processing and highly efficient, tunable, and narrow emission across the visible spectrum. A beneficial byproduct of the nanocrystal incorporation into the polymer matrix is that it provides a facile and low-cost method to chemically and structurally stabilize the perovskite nanocrystals under ambient conditions. Herein, we demonstrate two types of robust fiber composites based on electrospun hydrophobic poly(methyl methacrylate) (PMMA) or hydrophilic polyvinylpyrrolidone (PVP) fibrous membranes sensitized by green-emitting all-inorganic CsPbBr3 or hybrid organic-inorganic FAPbBr3 nanocrystals. We perform a systematic investigation on the influence of the nanocrystal-polymer relative content on the structural and optical properties of the fiber nanocomposites and we find that within a wide content range, the nanocrystals retain their narrow and high quantum yield emission upon incorporation into the polymer fibers. Quenching of the radiative recombination at the higher/lower bound of the nanocrystal:polymer mass ratio probed is discussed in terms of nanocrystal clustering/ligand desorption due to dilution effects, respectively. The nanocomposite's optical stability over an extended exposure in air and upon immersion in water is also discussed. The studies confirm the demonstration of robust and bright polymer-fiber emitters with promising applications in backlighting for LCD displays and textile-based light emitting devices.

Valsalva retinopathy associated with intranasal cocaine abuse: A case report.

INTRODUCTION: The purpose of this report is to describe a case of Valsalva retinopathy in an intranasal cocaine user. CASE REPORT: A 49-year-old male presented with a history of sudden loss of vision and inferior visual field defect in his left eye. Clinical evaluation of the affected eye showed best corrected visual acuity of 20/25 and fundus examination revealed a preretinal hemorrhage superior to the disk with multiple intraretinal hemorrhages in and around the posterior pole. On further questioning, the patient revealed intranasal cocaine use the day before the onset of his visual symptoms. Blood tests were requested to exclude blood dyscrasias or predisposition to vascular occlusive disorders and no further treatment measures were taken. The patient was reviewed a month later when his hemorrhages had completely resolved and his visual acuity had improved to 20/20. His blood results were within normal limits. CONCLUSION: Although never been reported before, Valsalva retinopathy can be associated with intranasal cocaine abuse and should be considered in the differential diagnosis of visual reduction in such population.

A Review of Minimally Invasive Strabismus Surgery (MISS): Is This the Way Forward?

Minimally invasive surgery is rapidly becoming the norm in medicine, as it often leads to better outcomes and earlier rehabilitation. This article reviews the principles and different techniques employed to perform minimally invasive strabismus surgery (MISS). In these techniques, strabismus surgery is performed through keyhole openings, thus reducing the risk of postoperative corneal complications, minimizing postoperative discomfort, and better preserving muscle function. MISS can be used to perform all types of strabismus surgery, namely rectus muscle recessions, resections, plications, reoperations, retroequatorial myopexy, transpositions, oblique muscle recessions, or plications even in the presence of limited motility. Of note, ocular alignment outcomes with MISS versus more traditional techniques have not been compared in randomized trials. Consequently, more controlled evidence is still needed to better delineate the future role and value of MISS in clinical management.

Twenty-four hour efficacy of glaucoma medications.

Current medical therapy of glaucoma aims to attain a meaningful and consistent reduction of intraocular pressure (IOP) to a predetermined level of target IOP, which will commensurate with either stability, or delayed progression of visual loss. Glaucoma is a 24-h disease and the damaging effect of elevated IOP is continuous. Therefore, it is reasonable that we should endeavor to identify the true efficacy of currently available and future antiglaucoma medications throughout the 24-h period. This review chapter deals first with the concept and value of diurnal and 24-h pressure monitoring. It then evaluates existing evidence on the 24-h efficacy of medical therapy options. Unfortunately, significant gaps exist in our present understanding of the short-term and particularly the long-term 24-h efficacy of most antiglaucoma medications. More long-term controlled evidence is needed in the future to improve our understanding of the 24-h efficacy of current medical glaucoma therapy, the ideal 24-h target pressure and the precise impact of IOP characteristics upon the different stages of the various forms of glaucoma.

Persistent Subretinal Fluid After Successful Full-Thickness Macular Hole Surgery: Prognostic Factors, Morphological Features and Implications on Functional Recovery.

INTRODUCTION: The present study aimed to identify preoperative factors that predispose the development of subretinal fluid (SRF) following successful macular hole (MH) surgery. METHODS: Thirty-four eyes of 33 consecutive patients that underwent pars plana vitrectomy for idiopathic full-thickness MH surgery were included in this retrospective study. Best corrected visual acuity (BCVA), and spectral domain-optical coherence tomography (OCT) images were evaluated pre- and postoperatively in all cases. Patient's demographic characteristics, stage of MH, measurements of base diameter and minimum aperture diameter of the MH, preoperative foveal vitreomacular traction and selected intra-operative parameters were correlated with the development of postoperative SRF. RESULTS: Postoperative SRF was observed in 15 cases (48%). Total absorption of SRF was observed in 73% of affected eyes and was most commonly seen between the third and the fifth postoperative month. One patient developed lamellar hole leading to full-thickness MH. Postoperative BCVA was similar between the eyes that did and the eyes that did not develop postoperative SRF (0.31 ± 0.2 vs 0.35 ± 0.2; p ≥ 0.05). Development of postoperative SRF was significantly associated with the presence of preoperative foveal vitreomacular traction (p = 0.048), stage II MH (p = 0.017) and smaller size of the closest distance between the MH edges (p = 0.046). CONCLUSIONS: Postoperative SRF is a common occurrence following successful MH surgery. Meticulous evaluation of preoperative clinical and OCT findings may disclose risk factors associated with this condition. Based on our observations, idiopathic holes of early stage appear to be at a higher risk of developing postoperative SRF. This could be a point of interest with the advancing use of enzymatic proteolysis.

Neoarchean carbonate-associated sulfate records positive Δ³³S anomalies.

Mass-independent fractionation of sulfur isotopes (reported as Δ(33)S) recorded in Archean sedimentary rocks helps to constrain the composition of Earth's early atmosphere and the timing of the rise of oxygen ~2.4 billion years ago. Although current hypotheses predict uniformly negative Δ(33)S for Archean seawater sulfate, this remains untested through the vast majority of Archean time. We applied x-ray absorption spectroscopy to investigate the low sulfate content of particularly well-preserved Neoarchean carbonates and mass spectrometry to measure their Δ(33)S signatures. We report unexpected, large, widespread positive Δ(33)S values from stratigraphic sections capturing over 70 million years and diverse depositional environments. Combined with the pyrite record, these results show that sulfate does not carry the expected negative Δ(33)S from sulfur mass-independent fractionation in the Neoarchean atmosphere.

Evoked pressure curves from the external anal sphincter following transcranial magnetic stimulation in healthy volunteers and patients with faecal incontinence.

AIM: The hypothesis was tested that evoked pressure curves (EPCs) after transcranial magnetic stimulation (TMS) would provide additional neuropathophysiological information on the descending pathways to the external anal sphincter (EAS) in patients with faecal incontinence (FI). METHOD: Twenty-five healthy subjects and 69 patients with FI were investigated. TMS was applied to the vertex, and EPCs were recorded with a probe placed through the EAS. TMS was performed with the EAS at rest and during contraction (facilitated responses). At least three responses were recorded for each modality. Clinical data and anorectal manometric, electrophysiological perineal and transanal ultrasound recordings were compared with respect to the EPC results. RESULTS: There was no statistically significant difference between the EPCs of healthy subjects and FI patients. Twenty-three per cent of the FI patients had abnormal EPC latencies, with significantly lower voluntary contraction amplitudes (P = 0.03) and significantly higher rectal sensation (P = 0.04) than the other group. We found no significant difference between FI patients with and without abnormal EPC latencies in terms of clinical characteristics and electrophysiological and endoanal ultrasound parameters. There was no difference in the identified causes of the FI between the two groups. CONCLUSION: As abnormal EPC latencies were found in 23% of FI patients with no known central neurological disease, abnormal EPC latencies might reveal undetected lesions of descending pathways in patients with FI.

Oropharyngeal dysphagia in amyotrophic lateral sclerosis alters quality of life.

Dysphagia is one of the most important complications encountered in amyotrophic lateral sclerosis (ALS). Our aim was to determine whether oropharyngeal dysphagia impacted the quality of life (QoL) of patients with ALS. Thirty consecutive patients were recruited (31-82 years, 18 men). Swallowing function was evaluated using a standardised videofluoroscopic barium swallow. All the patients completed a specific questionnaire on quality of life in dysphagia (SWAL-QoL) immediately after the videofluoroscopy. The results of dysphagia outcome severity scale separated 14 patients with oropharyngeal dysphagia and 16 with normal swallowing function. There was no difference in the average age, weight and body mass index of the two groups (dysphagic patients: 68 ± 11 kg versus non-dysphagic patients: 69 ± 14 kg). Most of the dysphagic patients had a bulbar affection based on their Norris scores which determine the importance of cranial nerves illness (20 ± 8), significantly lower than those of the non-dysphagic patients (35 ± 5) (P < 0·0001). There was no difference in the neurological peripheral symptoms evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale scores (dysphagic patients: 26 ± 7 versus non-dysphagic patients: 27 ± 8) (ns). The swallowing quality of life questionnaire revealed that the dysphagic patients had significant burden (P < 0·001). They were affected by the necessity to applied a food selection (P < 0·01), by the increase in eating duration (P < 0·05) and described a decrease in eating desire (P < 0·05). They complained of fear regarding the risk of dysphagia (P < 0·05). They also described difficulties with oral communication (P < 0·001). All of those complained about dysphagia which impacted directly mental health (P < 0·05) and social life (P < 0·05). In conclusion, oropharyngeal dysphagia is a common symptom accompanying ALS, which alters the patient's QoL, especially social health.

Clinical screening of oropharyngeal dysphagia in patients with ALS.

OBJECTIVE: It is a major issue to diagnose and detect oropharyngeal dysphagia in the early stage of ALS in order to avoid pulmonary and nutritional complications. The aim of this study was to validate a simple clinical test, the Volume-Viscosity Swallow Test (V-VST), to detect oropharyngeal dysphagia in this population. PATIENTS AND METHODS: Twenty patients were included in this study (mean age: 66.1 ± 8.13, six women). All patients had their swallowing function assessed by videofluoroscopy and V-VST. RESULTS: Among these 20 patients, 15 presented oropharyngeal dysphagia, diagnosed by videofluoroscopy, and five had normal swallowing. Norris score was lower in patients with oropharyngeal dysphagia compared to the patients with normal swallowing (27 ± 6 versus 36 ± 2; P=0.003). Among the 15 patients with oropharyngeal dysphagia, 14 had abnormal V-VST, and only one had normal V-VST. The sensibility of V-VST to detect oropharyngeal dysphagia in these patients with ALS was of 93%, and the specificity was of 80% (P=0.007). There was no significant difference between the two populations for ALSFRS score (22 ± 6 versus 20 ± 6) and body mass index (BMI) (26 ± 6 versus 26 ± 6 kg/m(2)). CONCLUSION: The V-VST presented good sensibility and specificity. It may be interesting to use it systematically for the detection of oropharyngeal dysphagia in ALS, after confirming these results on a wider patient sample.

Long-term follow-up of inflammatory cystoid macular edema.

PURPOSE: To determine the long-term functional and anatomical outcome of idiopathic uveitic cystoid macular edema (UCME). METHODS: A longitudinal retrospective study was undertaken of the medical records of patients with UCME. All individuals were examined in the uveitis Service at the Moorfields Eye Hospital. The main outcome measures were change in visual acuity and anatomical outcome of UCME at diverse time points. RESULTS: A total of 109 eyes (92 patients) with UCME were included in the analysis. Mean follow-up was 60 ± 45 months (median, 48 months). Mean logarithm of the minimum angle of resolution visual acuity 1 month after the intervention improved significantly (P < 0.001) by 0.21 ± 0.27 and maintained at similar levels throughout the follow-up period. Visual acuity at the final follow-up improved in 75 eyes (69%), was deteriorated in 21 eyes (19%), and remained unchanged in 13 eyes (12%). Younger age and better visual acuity at baseline were associated with more favorable visual outcome (P < 0.001). Optical coherence tomography documentation of improvement or total resolution of UCME was observed in 84 eyes (77%) at the final follow-up. CONCLUSION: Cystoid macular edema is a major complication in uveitis. Current management provides satisfactory long-term results for the majority of those individuals. Visual acuity 1 month after the intervention is usually indicative of the final functional outcome.

Pseudovasculitis associated with vitreoretinal traction.

PURPOSE: The purpose of this study was to report a case of vitreoretinal traction masqueraded as retinal vasculitis. METHODS: An 81-year-old woman with exudative age-related macular degeneration was treated with intravitreal injections of ranibizumab. During routine follow-up, angiographic evidence of focal, segmental, retinal vasculitis, involving both arteries and veins, was noticed in the fellow eye. Clinical examination revealed no sign of ocular inflammation in either eye. RESULTS: Spectralis optical coherence tomography revealed partial posterior vitreous detachment with multiple areas of persisting vitreoretinal adhesion. Focal vasculitis on fluorescein angiography showed absolute correspondence with sites of vitreoretinal traction on optical coherence tomography. Patient was managed by observation and 6 months later, despite persisting fluorescein leak, she was still asymptomatic with no evidence of anterior chamber or vitreous activity. CONCLUSION: This is an exceptional case of pseudovasculitis associated with mechanical traction, representing a variant of vitreomacular traction syndrome. Clinicians should be aware of this unusual manifestation, which may mimic true vasculitis associated with uveitis.

Terrestrial gamma-ray flashes as powerful particle accelerators.

Strong electric discharges associated with thunderstorms can produce terrestrial gamma-ray flashes (TGFs), i.e., intense bursts of x rays and γ rays lasting a few milliseconds or less. We present in this Letter new TGF timing and spectral data based on the observations of the Italian Space Agency AGILE satellite. We determine that the TGF emission above 10 MeV has a significant power-law spectral component reaching energies up to 100 MeV. These results challenge TGF theoretical models based on runaway electron acceleration. The TGF discharge electric field accelerates particles over the large distances for which maximal voltages of hundreds of megavolts can be established. The combination of huge potentials and large electric fields in TGFs can efficiently accelerate particles in large numbers, and we reconsider here the photon spectrum and the neutron production by photonuclear reactions in the atmosphere.

Management of neurogenic bowel dysfunction.

There are several modalities for treating neurogenic bowel dysfunction (NBD), including conservative treatments (diet, medications, biofeedback, transanal irrigation, massage, electrical stimulation, anal plug). When conservative treatments fail, clinicians can choose from a variety of therapeutic options, including colostomies, Malone anterograde continence enemas, sacral anterior root stimulator implantations, graciloplasties, and artificial bowel sphincters. We reviewed the various treatments for constipation and/or fecal incontinence in patients with NBD and propose over-reaching stepwise algorithms for the management of NBD. Our review included English language articles, randomized controlled studies, cohort studies, case-control studies, and retrospective studies (if necessary) that assessed the management of NBD. Our literature search identified 577 articles, of which 79 met our inclusion criteria. There is little evidence for the success of conservative but non-pharmacological treatments. There is strong evidence for the success of pharmacological interventions (i.e., prokinetic agents) in the treatment of chronic constipation. While surgical interventions may be considered, there is little evidence of their effectiveness. Bowel management programs for patients with neurologic diseases require a multi-faceted approach. While a range of medical and surgical treatments are available, there is little evidence for their effectiveness, with the exception of pharmacological interventions.