Herein we report a supramolecular strategy, self-assembling and pH regulated fusion protein to extend the in vivo half-life and tumor targeting ability of a therapeutically important protein trichosanthin (TCS). TCS was genetically fused to the N-terminus of a self-assembling protein, Sup35p prion domain (Sup35), to form a fusion protein of TCS-Sup35 that self-assembled into uniform spherical TCS-Sup35 nanoparticles (TCS-Sup35 NP) rather than classic nanofibrils. Importantly, due to the pH response ability, TCS-Sup35 NP well retained the bioactivity of TCS and possessed a 21.5-fold longer in vivo half-life than native TCS in a mouse model. As a result, in a tumor-bearing mouse model, TCS-Sup35 NP exhibited significantly improved tumor accumulation and antitumor activity without detectable systemic toxicity as compared with native TCS. These findings suggest that self-assembling and pH responding protein fusion may provide a new, simple, general, and effective solution to remarkably improve the pharmacological performance of therapeutic proteins with short circulation half-lives.Frequent injections at high concentrations are often required for many therapeutic proteins due to their short  For ins ability .To increase the tumor targeting and cellular uptake of TCS, an alternative strategy is to develop self-assembled stimuli-responsive TCS nanoparticles that only accumulate in the specific tumor microenvironment, such as a relatively low pH of 5.4–7.0, which is widely used for pH-triggered theragnostic agents delivery . For exaSaccharomyces cerevisiae  plyss competent strain (Invitrogen) separately, and cultured in Terrific Broth (TB) medium containing 100 μg/mL ampicillin at 37°C. When the optical density at 600 nm (OD600) reached 0.5, the culture temperature was lowered to 25°C and then a final concentration of 0.5 mM IPTG was added for expression induction overnight.The gene encoding TCS (GenBank: AY082349.2)and TCS-Sup35 was design in pET-25b (+) separately, and synthesized by Sangon company , so the pET-TCS-H6 and pET- TCS-Sup35-H6 vector were obtained (H6 was 6× histidine tag for protein purification). After the DNA sequencing was verified, those recombinant plasmid pET-TCS-H6 and pET-TCS-Sup35 were transformed into Bacteria were collected and resuspended in lysis buffer  and lysed by sonication. After centrifuged the matrix at 14,000 rpm for 20 min, polyethyleneimine (1% w/v) was added to the supernatant to precipitate nucleic acid. After centrifugation, collect supernatant and filtered with a 0.22 μm membrane, and then using a 5 mL HiTrap HP column  mounted on AKTA purifier to purify the protein with continuous gradient chromatography. Using 10 mM PB, 500 mM NaCl, 10 mM imidazole, pH = 7.4 as the equilibration buffer and 10 mM PB, 500 mM NaCl, 500 mM imidazole, pH = 7.5 as eluent. Peaks containing TCS or TCS-Sup35 were collected, exchanged to storing buffer  via a desalting column. The protein samples were stored at −80°C.The solution buffer was changed to PBS  before use.The purification process was analyzed by SDS-PAGE. Protein concentration was determined by bicinchoninic acid (BCA) assay using a BCA kit (Beyotime Biotech) with directions.2O. CD spectra were recorded in the range from 190 nm to 260 nm on Pistar π-180 (Applied Photophysics Ltd.) instrument. For transmission electron microscopy (TEM), the morphologic and particle size examination of nanoparticles were performed by a Hitachi H-7650B transmission electron microscopy. The samples were diluted to 0.5 mg/mL, deposited onto carbon-coated copper grids for 2 min, stained with 2% (w/v) phosphotungstic acid solution, and air-dried at room temperature prior to imaging. For Critical micelle concentration (CMC), nile red was dissolved in PBS buffer to 1.25 μM. A series of dilutions of TCS-Sup35 from 8.3 μM to 0.03 μM were prepared for CMC measurement at 25 C and mixed with the nile red solution at a volume ratio of 1:1. The fluorescence intensity was determined at excitation/emission wavelengths of 550/630 nm with a SpectraMax M3 Microplate Reader (Molecular Devices).For dynamic light scattering (DLS), protein samples were diluted in pH of PBS, 10% Tween 20, or 10% SDS, followed by filtration with 0.22 μm pore size membranes. Protein number distribution was determined with a Zetasizer Nano-zs90  operating at a laser wavelength of 633 nm and a scattering angle of 90° at 25°C. Data were analyzed by Zetasizer software 6.32. For Circular dichroism (CD), Samples were diluted into a concentration of 0.2 mg/mL in H2 atmosphere at 37 C. Human mammary epithelial cell (MCF-10A) and mouse fibroblast (L929) were cultured with DMEM medium with same condition described above. Cells were seeded in a 96 well plate (Corning) with a density around 5,000 cells/well and serial dilutions  of the samples in fresh medium were added. The wells filled with just media and media-treated cells served as the background and control, respectively, After incubating the plate for 72 h, cell viability was assessed using the MTT assay, as outlined in the Cell Proliferation Assay kit (Promega). Data fitting and IC50 calculation were then performed using Origin 9.0 software and the results were reported as the mean ± standard deviation.Mouse breast cancer cells (4T1) and Mouse melanoma cells (B16) cells were cultured in RPMI-1640 medium with 15% fetal bovine serum (FBS) and 1% penicillin/streptomycin, and kept in a humidified, 5% COFirst, for protein visualization, atto-488 NHS ester (Sigma) was conjugated with TCS and TCS-Sup35 proteins at a molar ratio 1:2 (protein/dye). Then conjugating efficiency was calculated using Nanodrop ND-1000. For confocal, after planting 4T1 cells on Mat-Teck culture dishes  and incubating overnight, 100 ng/mL of protein was added to the cell culture and incubated for 12 h. The nucleus was then stained with Hoechst 33,342  and the plasma membrane was stained with Cell MaskTM Deep Red . Once the incubation was completed in darkness for 5 min, the cells were washed with PBS for 3 times. The cells were then analyzed with a TCS-SP5 confocal laser scanning microscope  with a Plan Apo 639/1.4 (oil HC 9 PL APO l blue) objective.g for 15 min after standing for 30 min at 4°C. The plasma was stored at −80 C for further use. TCS concentration in plasma was determined by ELISA assay under the instruction of ELISA kit (PBL Interferon Source). Pharmacokinetic parameters were analyzed by DAS 3.0 software and fitted with a two-compartment model.Healthy female SPF BALB/c nude mice with an average body weight of about 20 g were randomly divided into 3 groups  and intravenously injected with TCS and TCS-Sup35 at a dose of 1 mg TCS equivalent/kg body weight (BW), and an equivalent volume of PBS, respectively. At selected time points , blood samples (10 μL) were collected via tail vein, centrifuged at 4,000 6 OVCAR-3 cells (0.2 mL) in the right dorsal area. When tumor size reached 100 mm3 (∼4 weeks), the mice were divided into 2 groups (3 mice in each group), and injected intravenously with TCS and TCS-Sup35 at a dosage of 1 mg TCS equivalent/kg BW, respectively. At 5 h after injection, mice were euthanized and major organ  were collected, weighted and homogenized, and then resuspended in corresponding quantity of extraction buffer ). The concentration of TCS in each sample was measured by ELLIA as described previously. Data were presented as percentage of total injected dose (%ID) per gram of tissue.6–8 weeks old female BALB/c nude mice were inoculated subcutaneously with 5 × 103 (∼30 days), the animals were randomized to 3 groups (n = 6–8 per group), and acquired intravenous injections of TCS and TCS-Sup35 at a dosage of 50 μg equivalent TCS per mouse, and PBS at an equivalent volume once every 4 days until the mice of control group (PBS group) were sacrificed. Tumor volumes were measured via digital calipers and calculated with the formula: volume = length ×width2 × 0.5. The mice were weighed on the days of tumor measurements and would be killed if their tumor volume was larger than 500 mm3 or the body weight loss was greater than 15%. Statistical analyses were performed by Origin 9.0 software.Human OVCAR-3 cells were cultured and implanted into female BALB/c nude mice as described above. When tumor size reached 30 mmin vivo toxicity of TCS-Sup35, histomorphology, clinical biochemistry and hematology were examined after the treatment. After treated with PBS, TCS and TCS-Sup35 NP for 28 days, the mice were sacrificed and organs including tumor, heart, kidney and liver were collected, fixed with 4% neutral paraformaldehyde, and embedded in paraffin for histological examination. Tissue sections with a 5 μm thickness mounted onto glass slides were stained with hematoxylin-eosin (H&E) for morphology observation according to standard procedures. The images of all sections were captured with a Nikon Eclipse 90i microscope.To study the On day 28, a Hematology Analyzer (SYSMEX) was used to measure hematological parameters such as white blood cells (WBC), red blood cells (RBC), platelets (PLT), and the concentration of hemoglobin (HGB), and an Automatic Biochemical Analyzer (HITACHI) was employed to analyze serum lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (CRE) and blood urea nitrogen (BUN) in the collected blood sample.The Laboratory Animal Facility at the Henan University of Animal Husbandry and Economy is accredited by AAALAC , and all animal protocols used in this study are approved by the Institutional Animal Care and Use Committee (IACUC).E. coli after isopropyl β-D-1-thiogalactopyranoside (IPTG) induction, followed by purification with immobilized metal affinity chromatography. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that TCS-Sup35 and TCS had expected molecular weights around 34 and 27 kDa, respectively (Dh) of around 55 nm, which was much larger than that of TCS (7 nm)  , suggestS (7 nm) . InteresS (7 nm) . TransmiS (7 nm) . This prS (7 nm) . This reS (7 nm) . MoreoveS (7 nm) . SurprisS (7 nm) . This reS (7 nm) .50) of TCS-Sup35 NP and TCS toward OVCAR-3 were 604 and 947, respectively, and that in 4T1 cells were 615 and 1,130 ng/mL, respectively, indicating that the antiproliferative activity of TCS-Sup35 NP was nearly 1.7 times higher than native TCS. Compared to OVCAR-3 and 4T1 cells, B16 cells were less sensitive to TCS, the IC50 of TCS-Sup35 NP and TCS was 1,092 and 2,364 ng/mL, TCS-Sup35 NP still hold stronger tumor cell cytotoxicity than TCS. This may due to that after the formation of nanoparticle, the internalization ability was increased because more receptor was present on the surface of nanoparticle, thus, more TCS was transported inside tumor cells and the inhibition of tumor cells was also enhanced. This hypothesis was supported by confocal results. From Next, we measured the anti-proliferative activity of TCS-Sup35 NP by using OVCAR-3, 4T1 and B16 cells that are highly sensitive to TCS. From in vivo half-life of TCS by reducing renal clearance due to its enlarged size. To verify this hypothesis, we investigated the pharmacokinetics of TCS-Sup35 NP in a mouse model (1/2β = 17.9 h) of TCS-Sup35 NP was 21.5-fold longer than that (0.83 h) of TCS. Especially, after 24 h, the TCS plasma level of TCS-Sup35 NP  was 632 times higher than that of TCS (285 ng/mL). Moreover, the area under the curve (AUC) increased by 51 times from 0.32 × 106 ng/mL/L*h for TCS to 16.6 × 106 ng/mL/L*h for TCS-Sup35 NP, indicating the significantly improved systemic exposure of TCS-Sup35 NP relative to TCS. All these results showed that Sup35 fusion could substantially enhance the pharmacokinetic performance of TCS in a mouse model.The size of TCS-Sup35 NP (55 nm in diameter) was 5.5-fold larger than the cutoff size of kidney filtration (around 10 nm); in contrast, TCS was smaller in size (7 nm) than the cutoff size of renal clearance. These data suggested that TCS-Sup35 NP would enhance the se model . After ase model . The terAs the pH of the tumor micro-environment was around 5–7, we assumed that TCS-Sup 35 NP could target to tumor site through EPR effect and retained there because TCS-Sup 35 NP formed larger size particle at lower pH . To prov3 at ∼30 d post inoculation of cancer cells, mice were randomized into three groups, and treated with PBS, TCS, and TCS-Sup35 NP, respectively, at the same dose of 50 μg TCS equivalent per mouse every 4 days until the tumor size of control groups reached 500 mm3. Tumor growth was slightly inhibited in TCS treatment group as compared to PBS treatment group (3) was 5.3 and 5.5 folds smaller than those in TCS treatment group (465 mm3) and PBS treatment group (485 mm3), respectively (3 on average) that did not grow any more. Hematoxylin-Eosin (H&E) staining further confirmed the anti-tumor efficacy of TCS-Sup35 NP (Encouraged by the significantly improved pharmacokinetics and biodistribution of TCS-Sup35 NP as compared to TCS, we further investigated the anti-tumor efficacy of TCS-Sup35 NP in an ovarian cancer mouse model . After tnt group . In contectively . The outectively . All of Sup35 NP . Not surThe biosafety of TCS-Sup35 NP treatment was further studied. The body weight of mice in all treatment groups remained steady during the treatments. H&E staining indicated that TCS-Sup35 NP and TCS treatments did not induce any significant histological change in major organs such as heart, liver and kidney at 28 d post administration as compared with PBS treatment . The bioin vivo half-life of an important therapeutic protein, TCS, by generating a pH-regulating and self-assembling protein nanoparticle with significant tumor targeting and inhibiting ability. Our results demonstrate that genetic fusion of TCS to Sup35 produces self-assembled TCS-Sup35 NP with uniform spherical morphology, instead of the β-sheet-rich amyloid nanofibrils that were always observed for Sup35 alone and its fusion proteins before. Unlike TCS-HAS or PEGylated-TCS (E. coli with high efficiency, indicating low production cost. Moreover, the bioactivity of TCS-Sup35 NP is much higher than TCS alone, and its internalization ability was vastly enhanced. More interestingly, Sup35 fusion not only substantially prolongs the in vivo half-life of TCS but also markedly improves the biodistribution of TCS in a mouse model. This is because the size of the nanoparticle increases when pH decreases, allowing the nanoparticle to accumulate at the tumor site and enhance the tumor targeting ability and the delivery efficacy of TCS to the tumor site. Consequently, Sup35 fusion remarkably enhances the anti-tumor activity of TCS in a tumor-bearing mouse model without detectable side effects. These findings suggest that Sup35 fusion can offer a supramolecular property to therapeutic proteins, such as interferon alpha/beta/gamma/lambda, erythropoietin, granulocyte colony-stimulating factor, epidermal growth factor, insulin-like growth factor, and glucagon-like peptide-1, to tremendously extend their in vivo half-lives, improve their biodistribution, and thus enhance their therapeutic efficacy. We believe that other self-assembling proteins (in vivo half-life of therapeutic proteins. Therefore, self-assembling protein fusion may provide a new, simple, and effective technology platform to improve the pharmacological properties of therapeutic proteins with short circulation half-lives.In summary, we have presented a novel strategy to extend the ated-TCS , TCS-Supproteins , such as


Crisaborole 2% ointment is a non-steroidal treatment for mild-moderate atopic dermatitis (AD) and may produce fewer adverse effects than topical corticosteroids (TCS). We used PS-OCT to quantify dermal collagen at baseline and after 29 days of treatment with crisaborole and betamethasone valerate (BMV), in 32 subjects. PS-OCT detected a mean increase 1 × 10-6, 95% CI  × 10-6 in dermal birefringence following TCS use , whereas a change of -4 × 10-6, 95% CI  × 10-6 was detected for crisaborole . These results could suggest a differential effect on dermal collagen between the two compounds. PS-OCT may thus find an important role in safety assessment of novel AD treatment’ and larger trials are warranted. The cauPatients with mild-moderate AD are often prescribed TCS to mitigate AD symptoms. TCS have been popular since the 1950’s due to a combination of high efficacy and low cost. Given the chronic and recurring nature of AD, TCS is often used by patients for long periods. Although the efficacy of TCS is high, long-term use of high potency TCS is not recommended due to common side-effects such as skin atrophy and striae formation ,7. OtherHence next-generation therapies, based on non-steroidal compounds, are currently under active development. One such example is crisaborole, a non-steroidal phosphodiesterase 4 (PDE4) inhibitor that has been approved by the FDA in 2016 as a topical anti-inflammatory treatment for patients aged over 2 years of age with mild-moderate AD. Crisaborole blocks the hydrolysis of cyclic adenosine monophosphate (cAMP), thereby degrading the activity of inflammatory cytokines that generate some of the clinical symptoms of AD such as pruritus . CurrentA review study and meta-analysis by Barnes et. al.  found thOptical Coherence Tomography (OCT) has been investigated as a non-invasive tool to perform longitudinal assessments of TCS-induced epidermal thinning . OCT, ofTCS treatment has also been reported to adversely alter collagen metabolism in the dermis, which as a result could also contribute to skin atrophy. Healthy dermal collagen mainly consists of type I and type III fibrillar collagen that are organized in a basket weave-like structure, and a decrease in both types of collagens was reported after TCS treatment . Hence iThe OCT variant used in this study, polarization-sensitive OCT (PS-OCT), is a functional extension of OCT where the polarization state of backscattered light is detected, in addition to the light intensity . PS-OCT Here we use PS-OCT to study changes in the dermal collagen birefringence caused by TCS administration during a controlled clinical trial. We compare the changes with those caused by crisaborole.2.2.1This study is a part of a larger trial called SMART . SMART is an observer-blind randomized within-subject controlled clinical trial to compare the effects of 4 weeks of TCS use to 4 weeks of crisaborole use. A total of 37 AD patients, within the age range of 18-65 years old  with mixed ethnicity were enrolled, of whom 32 completed the entire study. Crisaborole 2% ointment and betamethasone valerate 0.1% cream (BMV) were applied onto subjects’ inner forearm  twice per day for 4 weeks. PS-OCT imaging was performed on day 1 (baseline scans - without treatment applied on) and day 29. The SMART study was reviewed by East Midlands – Derby Research Ethics Committee (REC Reference 20/EM/0006), with NCT number – NCT04194814.2.2The system configuration of the in-house PS-OCT system used in this study largely follows Al-Quasi et. al. . The sysAs shown in 2.3x × The data processing of the obtained volumetric data sets was done in MATLAB . Each volumetric data set has a size . Our semi-automatic algorithm first detects the stratum corneum as a surface edge using sub-pixel edge detection based on the partial area effect , findingQuantifying the birefringence of biological tissue by computing the evolution of Stokes vectors on the Poincare sphere is well established and has been reported previously by Götzinger et. al. ,25. We hHere  and Eq.  becomes:Following Lin et. al. , the pha see Eq. . (3)SˆHere, l. noted , this eqThe phase retardance profile m is then converted to local birefringence Δn by: Because z is the pixel size in air (4 µm), RI is the refractive index of tissue (1.4).Here One problem with such 1D phase unwrapping is that noise fluctuations can cause artifactual phase wraps to be detected and erroneously unwrapped. This causes the phase to increase much faster with depth and an artifactually high birefringence value is then returned. Lin et al. noted this problem when imaging striae  and adopAs Lin et. al.  noted, t3.32 subjects completed the study and are analyzed herein. PS-OCT scans were performed on day 1 and day 29, with 3 repeats for both arms for each subject, yielding a total of 384 volumetric data sets. A descriptive statistical table of the dermal birefringence values is shown in Our finding for TCS (BMV) is in broad agreement with a previous study by Jung et.al. , where 1TCS has been widely used in dermatological therapy for anti-inflammatory purposes since it was introduced in 1952. Despite its effectiveness in reducing inflammatory-related symptoms, adverse effects such as skin atrophy have been reported. While numerous studies reported TCS induces epidermal atrophy and such a parameter dominates the whole skin atrophy, less studies were done focusing on the dermal aspect, it is believed that TCS inhibits collagen synthesis and leads to a loss of dermal extracellular matrix which may explain skin atrophy [The results of this study suggest that there was a structural change in the dermal collagen after using TCS, which was not produced to the same extent when using crisaborole. As noted in the methodology section, the algorithm used in this study quantifies an effective dermal birefringence, by assuming that the birefringence fast axis orientation does not alter strongly with depth. It should be noted that the collagen and elastin fibers in healthy human dermis have been reported to possess a woven mesh-like structure, with a fast axis orientation that changes with depth according to some recent PS-OCT studies ,31. Such3.1We present a novel application of PS-OCT, to assess TCS induced skin atrophy via changes in dermal collagen birefringence rather than epidermal thinning and to compare this with a non-steroidal alternative. While epidermal atrophy is widely reported as a side effect of TCS usage, fewer studies have focused on the effects on dermal collagen. Our detection of an increase in the effective dermal collagen birefringence after application of TCS is consistent with dermal collagen becoming more compacted as result of dermal thinning, although other interpretations may also be compatible with our data. We further find that a non-steroidal alternative to TCS, crisaborole, showed a much smaller change in effective dermal collagen birefringence relative to baseline. Regardless of the precise interpretation that is placed on our effective birefringence values, this observation may provide further evidence that such non-steroidal creams pose less risk of skin atrophy during prolonged atopic dermatitis treatment. To the best of our knowledge, studies reported using PS-OCT to evaluate the effect of anti-inflammatory skin creams on dermal collagen birefringence are limited. PS-OCT may potentially play an important role in assessing the safety of novel topical atopic dermatitis treatments, relative to TCS, and more studies in this area are warranted.


Metachronous colorectal cancer is relatively rare, occurring in 0.7–3.6% of patients diagnosed with colorectal adenocarcinoma. Cutaneous metastases are similarly a rare presentation, occurring in <6% of metastatic colorectal cancer patients. Even more rare are the cutaneous recurrences at the peristomal site. Clinically, it is difficult to distinguish between metachronous cancer and cutaneous metastases. This paper reports a case of an elderly woman presenting with a slowly progressing peristomal cutaneous lesion 16 years after surgical resection for colorectal cancer. Core punch biopsy revealed a cutaneous localization of an intestinal type of adenocarcinoma. A surgical resection of the peristomal area was carried out whereby a new colostomy was created on the contralateral side. Definite histopathological examination showed a superficially located intestinal type adenocarcinoma with extensive pagetoid spread in the epidermal surface. In conclusion, it is important to remain alert and strive for early detection for cutaneous abnormalities following colorectal cancer. The standard follow-up after colorectal cancer diagnosis spans over a period of 5 years according to Dutch guidelines . These gde novo metaplasia [Metachronous colorectal cancer is a new primary tumor occurring >6 months after the initial colorectal cancer. It is a relatively rare and easily missed presentation, occurring in 0.5–3.6% of all patients diagnosed with a colorectal adenocarcinoma . Varioustaplasia , 5. Metataplasia . In the taplasia , 10–12. Skin abnormalities at the peristomal site could also be a cutaneous metastatic lesion. Cutaneous metastasis occurs in <6% of all colorectal metastatic cancer patients . The varThis case report presents an unusual presentation of a late-occurring metachronous colorectal adenocarcinoma 16 years after initial diagnosis. The purpose of this case report is to raise awareness and to promote early detection of both metachronous adenocarcinoma and cutaneous metastatic lesions at colostomy site.A female patient presented to our hospital with peristomal cutaneous abnormalities see . The patExcept for the colorectal carcinoma and a bladder tumor the medical history of the patient was unremarkable, and the patient was a healthy, non-smoking woman. Initially, the peristomal cutaneous abnormality was classified as a rash and stoma granulomas. However, conservative treatment consisting of ointment and silver nitrate had no effect. A dermatologist was consulted, and further research was initiated.A biopsy taken from the peristomal environment revealed a cutaneous located intestinal type adenocarcinoma of colorectal origin. The subsequently performed positron emission tomography–computed tomography (PET/CT) scan showed physiological intestinal stacking and minimal fluorodeoxyglucose (FDG) stacking surrounding the colostomy site . In addiMultidisciplinary consultation resulted in a colostomy resection plan with margin down to the fascia due to no disease dissemination on the PET/CT scan. In addition, a new colostomy would be placed on the contralateral side. Due to the expected defect size a plastic surgeon was consulted for advice on closure technique.Surgery was performed under general anesthesia. Upon laparoscopic inspection, there were no intra-abdominal abnormalities or signs of peritoneal implants. Adhesiolysis on the colostomy was performed and the descending colon was mobilized until enough length was created to reach the contralateral side. A new colostomy was created, and the fascia was closed with Vicryl and the skin with Monocryl. The colon was opened and attached to the skin with Monocryl transcutaneous sutures. The newly created colostomy was temporarily covered with gauze.Next, the old colostomy location was marked with a 3 cm margin. The area was resected in its entirety down to the fascia, resulting in a total excised area of 11 × 9 × 3 cm . The resThe patient was transported to the surgical ward postoperatively and was hospitalized for 2 days. The examination of the resected preparation by the pathologist confirmed a superficially invasive intestinal adenocarcinoma with extensive pagetoid spread into the epidermis. The lesion seemed to have originated from stomal mucosa at the stoma-cutaneous transition. Further pathological examination revealed superficial infiltration in the dermis (2 mm) . The resOutpatient clinic visits at 13 and 15 days postoperatively showed no abnormalities regarding wound healing. After multidisciplinary consultation only close follow-up was advised. The follow-up will be in accordance with the guidelines for colorectal carcinoma whereby the first check-up showed a CEA value of 1.8 ug/L [de novo metaplasia/dysplasia seem to be the most likely cause in our patient. The lesion was resected, and the standard 5-year follow-up was set in motion.The patient in this report was initially diagnosed with a T4N2M0 colorectal adenocarcinoma for which she received curative treatment. During the 5-year follow-up, according to National Dutch Guidelines, no abnormalities or signs for recurrences and metastases were found. Sixteen years later, she presented with a peristomal cutaneous abnormality which was proven to be a metachronous cutaneous adenocarcinoma originated from stomal mucosa. The rash-like presentation could possibly be attributed to an early presentation with no mass formation yet, compared with the mass formation as is seen in most of the reported cases . From thIn general, the recommendations for follow-up are up to 5 years as 90% of recurrences occur in this period , 22. OurAs metachronous colorectal tumors develop >6 months after a previous colorectal tumor, arguably the same colorectal cancer standard of care and follow-up can be applied . HoweverOne of the most important prognostic factors is the time interval between initial colorectal cancer and a recurrence. Patients with an early recurrence, within 2 years after primary surgery, have a lower patient survival (32 vs 77 months) and a 5-year survival rate (34.7% vs 78.8%) compared with patients with a late recurrence , 26. The


In GIN, the NEG had a significantly lower percentage of correct answers . In TEOAE, the NEG had smaller amplitude values bilaterally  and a smaller inhibitory effect of the efferent pathway . In ABR, the NEG had greater latencies of wave V  and interpeak intervals III-V and I-V in the LE . In LLAEP, the NEG had a smaller P3 amplitude bilaterally . The NEG performed worse than the CG in most of the assessments, suggesting that the auditory function in individuals exposed to occupational noise is impaired, even with normal audiometric thresholds.Recent studies involving guinea pigs have shown that noise can damage the synapses between the inner hair cells and spiral ganglion neurons, even with normal hearing thresholds—which makes it important to investigate this kind of impairment in humans. The aim was to investigate, with multiple audiological assessments, the auditory function of normal hearing workers exposed to occupational noise. Altogether, 60 workers were assessed ; the workers were matched according to age. The following procedures were used: complete audiological assessment; speech recognition threshold in noise (SRTN); speech in noise (SN) in an acoustic field; gaps-in-noise (GIN); transient evoked otoacoustic emissions (TEOAE) and inhibitory effect of the efferent auditory pathway; auditory brainstem response (ABR); and long-latency auditory evoked potentials (LLAEP). No significant difference was found between the groups in SRTN. In SN, the NEG performed worse than the CG in signal-to-noise ratio (SNR) 0 ( Noise-induced hearing loss results from lesions or dysfunctions, especially in the cochlear outer hair cells; these cells were believed to be the structures most vulnerable to noise. Thus, noise exposure that did not cause permanent hearing loss used to be considered safe ,2,3.However, recent studies have demonstrated that the structures most vulnerable to noise following exposure that leads to temporary hearing loss are the synapses between the inner hair cells and the spiral ganglion neurons, even with normal hearing thresholds. This synaptopathy has been demonstrated in guinea pigs and is named hidden hearing loss ,3,4,5.Furthermore, this synaptopathy is specifically located in the fibers that form synapses on the modiolar side of the inner hair cells, whose spontaneous rates are relatively low. They are particularly important in noisy environments because they are more resistant to masking by continuous background noise due to their higher thresholds. Therefore, high spontaneous rate fibers (the pillar side of inner hair cells) are believed to be the ones that contribute the most in quiet environments, but as the background noise increases, low spontaneous rate fibers are particularly important. Hence, in situations of greater auditory demand, with higher background noise, speech intelligibility and temporal auditory processing may be impaired, and it has been suggested that this is a sign of hidden hearing loss ,4,5,6,7.Reduced input, with or without elevated hearing thresholds, may also lead to central plasticity because the input to the auditory nerve decreases, causing a cascade of events that impair the whole auditory pathway . As thisIt is important to highlight that there is no consensus regarding the occurrence of noise-induced synaptopathy in humans. Despite advances in the comparisons between animal and human models, further studies in humans are still needed to establish strong and reliable conclusions, especially regarding the diagnostic tools .The studies on noise-induced hidden hearing loss suggest that humans are less vulnerable to noise damage than smaller mammals. Moreover, animals and humans are exposed to different types of noise. Guinea pigs are usually exposed to continuous noise at the highest possible level; this noise does not cause PTS, but it does cause synaptic losses in a short period of time. Humans, however, do not experience this in real life; instead, they are often exposed to intermittent noise at a much lower level and for a long time, especially when hearing protection devices are used according to the current security standards ,10,11.Considerable attention has been given to experiments on specific mice strains to identify candidate assays using non-invasive measures that could potentially identify hidden hearing loss in humans. Nonetheless, there is still no consensus on which part of the neurophysiological evidence observed in animal models would also be evident in humans; this underlies the cause of the difficulties in speech intelligibility experienced by subjects with normal audiograms after occupational noise exposure .Therefore, it is highly important to investigate the feasibility and inclusion of multiple assessments  to monitor workers exposed to noise. Hearing thresholds are normal in cases of hidden hearing loss, and these workers may present subtle auditory impairments, such as difficulty in following a conversation in noisy environments. Moreover, this type of impairment must be confirmed in humans, due to its possible practical consequences, including occupational regulations regarding noise exposure limits.Our study hypothesizes that workers exposed to noise, even while wearing hearing protection, may have an unnoticed auditory impairment, which can be detected with multiple peripheral and central auditory assessments. The noise-exposure and control groups were matched according to age and underwent multiple audiological procedures to assess different portions of the peripheral and central auditory pathways.This observational cross-sectional study was approved by the institution’s Ethics Committee under number 2.435.259/2017. The participants were informed in advance about the study, and those who agreed with it signed an informed consent form.Altogether, 60 male individuals participated in the study; they were divided into two groups and were matched according to age (≤2 years): the noise-exposure group (NEG), comprising 30 individuals exposed to occupational noise, with a mean age of 35.6 ± 7.09 years , and the control group (CG), comprising 30 individuals not exposed to occupational noise, with a mean age of 35.37 ± 7.56 years .The inclusion criteria for the study participants were as follows: age between 18 and 50 years; normal hearing thresholds (<25 dBHL at 250 to 8000 Hz); absence of changes in the external auditory meatus; no exposure to chemical products; absence of tinnitus; not undergoing chemotherapy or radiotherapy; not taking any ototoxic drugs; exposure to occupational noise for at least 5 years (NEG); no exposure to occupational noise (CG); and no exposure to non-occupational noise (both groups). Both groups’ conventional and high-frequency audiometry results can be found in The workers were selected based on the university’s Environmental Risks Prevention Program, which describes the risks to which each worker is exposed in their workday. The NEG comprised individuals who worked in maintenance at the university, and the CG comprised individuals who worked in other university departments without noise . The NEG participants had been exposed to intermittent noise  during their 8 h workday for a mean of 8.6 years (SD: 6.1 years) in which they had been in that position (exposure). All of them used hearing protection during their workday.The tests described below were reproduced in a sound booth with a two-channel audiometer .−Sentence recognition threshold in noise (SRTN) was assessed with a list of sentences in Portuguese (LSP) —a list o−Speech recognition in noise (SN) was assessed with monosyllables, using an acoustic field system with three loudspeakers. Pink noise was presented in channel 1, which was connected to the loudspeakers on the participants’ right and left sides, 85 cm away from them and at a 90° azimuth. Speech stimuli were presented in channel 2, which was connected to the central loudspeaker, placed 100 cm away from them and at a 0° azimuth. The study used recorded monosyllables ,15 as st−Temporal resolution was assessed with the gaps-in-noise test (GIN)—the GIN test  was used−An analysis of the transient evoked otoacoustic emissions (TEOAE) and the inhibitory effect of the efferent auditory pathway was conducted. Nonlinear stimuli were presented at 80 dBSPL to assess responses at 1 kHz, 1.4 kHz, 2 kHz, 2.8 kHz, and 4 kHz and at the total response amplitude . They were considered present when the SNR was ≥3 dBSPL at three consecutive frequencies . The par−Amplitudes and latencies were assessed with auditory brainstem response (ABR)—electrodes were positioned on the vertex (Cz), forehead (FPz), and left (M1) and right mastoid (M2), with impedance values below 5 kiloohms (kΩ). The integrity of the auditory pathways was assessed, first in the right ear, then in the left one, with click stimuli presented through insert headphones at 80 dBnHL . This protocol used a presentation rate of 19 clicks per second, each one lasting 0.1 ms, totaling 2000 stimuli . Two col−Amplitudes and latencies were assessed with LLAEP; initially, the skin was cleaned with abrasive paste at the places where the electrodes were positioned: vertex (Cz), on the right (M2) and left (M1) mastoids, and on the forehead (Fpz). The electrode impedance values should be below 5 kOhms. Tone-burst stimuli were presented monaurally at 75 dBnHL, at a rate of 1.1 stimuli per second, totaling 300 stimuli; 15% were rare stimuli presented at 2000 Hz, while 85% were frequent stimuli presented at 1000 Hz . The analysis window lasted 512 ms, and the high-pass and low-pass filters were from 1 to 30 Hz. The subjects were instructed to pay attention to the rare stimuli and mentally count every time they perceived them. In the tracing that resulted from subtracting the rare stimuli from the frequent ones (waveform subtraction), the P3 component was identified and analyzed regarding its latency and amplitude values (N2-P3). As for the tracing that corresponded to the frequent stimuli, the P1, N1, P2, and N2 components were identified and analyzed regarding their latency and amplitude values (P1-N1 and P2-N2) .p ≤ 0.05).The data were analyzed using descriptive measures  and inferential statistical tests . The odds ratio (OR) and its confidence interval (CI) were also calculated for some tests. The significance level was set at 5% . No statistically significant difference was found between the groups in the SRTN assessment. In the SN test, the NEG had a lower percentage of recognition in both SNRs, with a significant difference in SNR 0   .In the GIN test, the gap detection threshold was higher in the NEG than the CG , though with no significant difference. The percentage of correct answers was significantly lower in the NEG (64.1%). In general, the NEG performed worse as it had more individuals with abnormal GIN test results (43.3%) . The OR p-value 0.048 in the RE; p-value 0.045 in the LE). Likewise, in the qualitative assessment the NEG had more individuals without responses than the CG (30% in the RE and 23.33% in the LE), with a significant difference in the RE .Regarding TEOAE , the NEGp-values: 0.015 and 0.009)  . Furtherp-value 0.017) and interpeak intervals III-V and I-V  in the LE   .The noise-exposed individuals in this study performed worse than the non-exposed ones in most of the assessments. The NEG performed worse than the CG in the speech-in-noise and GIN tests and had smaller TEOAE amplitudes, smaller inhibitory effects of the efferent system, increased ABR latencies in wave V and interpeak intervals I-V and III-V, and decreased P3 amplitudes.Previous studies have suggested that the supraliminal effects of noise-induced hidden hearing loss can be perceived through auditory perception ,6,23,24.This study assessed speech intelligibility in noise with SRTN (using earphones) and SN tests (presenting monosyllables in an acoustic field). However, the two groups performed differently only in SN, in SNR 0. Our hypothesis for these findings, with regard to the fact there was a difference between the groups in only one test, is that the SN test poses a more adverse condition for the auditory system; this makes clearer the NEG’s greater difficulty in listening to speech in noise. This difference in performance between normal hearing individuals exposed to occupational noise and those not exposed agrees with some of the previous studies in the literature, which, though using different methodologies, also verified worse assessment results in noise-exposed individuals ,26,27.Kumar et al.  assessedAnother study, using a free-field system to emit monosyllables  and pink noise at different SNRs , compared a group exposed to occupational noise with a non-exposed group, both with normal hearing. They verified that the non-exposed group performed better in all situations, suggesting that this difference between the groups could be due to deficits in the auditory pathway caused by their history of noise exposure .Nonetheless, other previous studies did not find any association between the history of noise exposure and worse performances in speech in noise and/or temporal processing tests ,29. ThisIn temporal resolution assessment with the GIN test, the NEG had a higher gap detection threshold than the CG . Consequently, they had a significantly lower percentage of correct answers (64.1%). It is important to highlight that the normal GIN threshold in adults is 5 ms or lower. The NEG performed significantly worse in this sample as it had fewer individuals in the normal range (43.3%). This indicates that the NEG had worse temporal resolution—and therefore worse auditory temporal processing—than the CG. Moreover, a 3.0 OR of having abnormal GIN test results was found by comparing individuals exposed to occupational noise with those not exposed, which suggests that this test, when used to investigate noise-induced hidden hearing loss, effectively identifies individuals at a higher risk of changes in auditory temporal processing.The studies by Kumar et al.  and LibeCochlear functioning was assessed with TEOAE, according to which the NEG had lower total amplitude values and more individuals without responses. The inhibitory effect of the RE efferent pathway was assessed in the individuals with TEOAE responses. The NEG had a greater absence of this inhibitory effect and a lower percentage of inhibition. Moreover, an 8.1 OR of absent inhibitory effects of the efferent pathway was found by comparing the individuals exposed to occupational noise with those not exposed to occupational noise. This suggests that this procedure, when used to investigate noise-induced hidden hearing loss, effectively identifies those individuals at a higher risk of changes in the efferent auditory pathway.The studies assessing normal hearing individuals exposed to noise and those not exposed to noise also found a greater absence of otoacoustic emissions in the exposed group ,31. ThisSome researchers highlight the importance of studying not only otoacoustic emission amplitudes but also the olivocochlear efferent auditory pathway, which was believed to be responsible for protecting hair cells from noise exposure. However, since the vulnerability of the synapses between hair cells and the auditory nerve was discovered, some studies have highlighted the protective role of the efferent system against synaptopathy ,36.In studies that assessed the inhibitory effect of the efferent auditory pathway with TEOAE suppression, the researchers found increased synaptopathy in noise-exposed guinea pigs  and old Concerning the electrophysiological assessments performed in this study, the NEG had increased latencies in wave V and interpeak intervals III-V and I-V.A recent study conducted in 56 normal hearing adults divided into groups at low and high risk of hidden hearing loss and matched according to age found similarly increased interpeak results. The authors found increased values in interpeak intervals I–III and I–V in the group at high risk, suggesting delayed central neural conduction, which may be a consequence of hearing impairments more distally present in the auditory system. The authors also found different V/I amplitude ratios from those in the present study as the high-risk group had a higher mean value. These findings were explained as being due to a central gain control mechanism, which compensated for the reduced input. On the other hand, the authors question the clinical usefulness of the V/I amplitude ratio as it has great variability .The study by Nam et al.  comparedConcerning LLAEP, the NEG in this study had smaller P3 amplitudes in both ears. Previous research on the P3 component using verbal and nonverbal stimuli in workers exposed to occupational noise and those not exposed verified that the exposed ones had greater P3 latency values with both stimuli than those not exposed to occupational noise .Brattico et al.  assessedA more recent study used magnetoencephalography to record cortical responses to speech stimuli with a multi-talker background noise. It verified that normal hearing individuals with speech intelligibility difficulties in noise had less cortical speech tracking than the control group . These p−Speech recognition in noise, as poor performances in difficult listening conditions are the most common signs of hidden hearing loss ,26,27,42−Auditory temporal processing assessment, which may indicate the status of auditory processing abilities in adverse listening conditions ,27.−Assessment of the inhibitory effect of the efferent auditory pathway, which provides indications of the efferent system protection from synaptopathy ,36.−ABR, assessing V/I wave amplitude ratio to help identify hidden hearing loss ,43.−LLAEP, to assess possible changes more rostrally in the auditory system ,39.Our study hypothesized that workers exposed to noise performed worse in peripheral and central assessments. In summary, this study found abnormal results in various audiological battery tests for individuals exposed to occupational noise, even with normal hearing thresholds. Hence, we suggest using the following procedures along with conventional audiometry to assess noise-induced damage early:The strengths of this study include the sample selected with extremely strict inclusion and exclusion criteria—including study and control groups matched according to age, which made it possible to control this variable as much as possible. Moreover, the study used an extensive battery of tests to assess the whole peripheral and central auditory systems and to identify which procedures were more suitable to assess noise-exposed individuals at higher risk of developing hidden hearing loss. Our findings suggest that the current noise regulation laws may not be enough to effectively protect workers exposed to occupational noise, and we verified that the exposed workers performed worse in auditory assessments than those who had not been exposed. Thus, hidden hearing loss can be a ubiquitous and neglected health problem. It is also possible that hearing protection devices are not being used properly or are not providing adequate attenuation ,45 sinceIt is important to consider the fact that some of our results were different from those obtained in previous studies—which may be due to different study populations (different levels and types of noise and duration of exposure) and the different procedures used, as well as other methodological differences. Furthermore, different results in human studies may be due to the lower susceptibility of human auditory structures to adverse noise exposure effects than that of guinea pigs. Valero et al. (2017)  describeThe limitations of the study include its cross-sectional design, which prevents inferences on the causality of the changes that were found, as well as the sample size and the relatively long exposure period. Future longitudinal studies may have larger samples and divide them into different groups according to their exposure time, allowing for additional comparisons.Despite the normal hearing thresholds verified with conventional audiometry, the NEG performed worse than the CG in most of the audiological assessments conducted in this study.Therefore, it is suggested that the auditory function of normal hearing individuals exposed to occupational noise may be impaired. This highlights the importance of including complementary assessments in the battery of tests for noise-exposed individuals and of conducting further studies to investigate hidden hearing loss in this population.


Athletes completed a body composition assessment using air displacement plethysmography and RMR using indirect calorimetry. Assessments were completed in a fasted state and after refraining from intense physical activity > 24 h prior to testing. Data were collected during the 2016–2019 seasons. Men had a higher RMR compared to women ; however, when adjusted for body mass (p = 0.064) and fat-free mass (p = 0.084), the observed differences were not significant. Height, body mass, body mass index, fat-free mass, and fat mass were positively associated with RMR in both men and women athletes . Body mass ) was the strongest predictor of RMR. Men athletes have a higher absolute RMR compared to their women counterparts, which is influenced by greater body mass and fat-free mass. Body mass is the strongest predictor of RMR in both men and women athletes.The purpose of this study was to examine sex differences in resting metabolic rate (RMR) and associations between measured RMR and body composition parameters in athletes. One-hundred and ninety collegiate men (n = 98; age: 20.1 ± 1.6 yr.; body mass: 92.7 ± 17.5 kg; height: 181.6 ± 6.2 cm, body mass index: 28.0 ± 4.7 kg/m For athletes to ensure adequate energy intake for optimal performance, recovery, and health, maintaining energy balance is essential. In order to establish individualized energy recommendations for athletes, the total daily energy expenditure must be determined. Resting metabolic rate (RMR) accounts for nearly 60–70% of total daily energy expenditure; thus, determining RMR serves as an essential part of identifying an athlete’s energy requirement. RMR is largely influenced by body size and body composition as metabolic activity may vary across different tissue compartments, thereby influencing energy expenditure ,2,3. FurFurther evaluation of sex differences in RMR among athlete populations is necessary to enable individualized energy prescription regarding nutritional recommendations for sports performance and overall health. This would allow for the development of sex-specific nutritional recommendations and provide additional insight as to how body size and composition may influence metabolic activity and the resulting energy requirement of athletes. This may help to identify appropriate RMR prediction equations when the option of directly measuring RMR is not readily available. Therefore, the primary aim of the current study was to examine sex differences in RMR among a large mixed cohort of athletes as a follow-up to our original study. A secondary aim was to examine predictors of RMR.2) and women  volunteered to participate in this study. All athletes were screened for health contraindications by the sports medicine staff as part of the team’s normal standard of care. Inclusion criteria included being medically cleared to participate on the team. Exclusion criteria included currently being treated for or diagnosed with a cardiac, respiratory, circulatory, autoimmune, musculoskeletal, metabolic, hematological, neurological, or endocrine disorder or disease. Male athletes competing in baseball: n = 8; cross country: n = 5; football: n = 62; track and field: n = 6; and wrestling: n = 17, with an average weekly training volume of 7.7 ± 4.7 h per week, and female athletes competing in cross country: n = 9; diving: n = 2; soccer: n = 43; swimming: n = 4; track: n = 23; volleyball: n = 9; and tennis: n = 2, with an average weekly training volume of 9.4 ± 3.1 h per week, participated in the current study. Interested athletes were informed of the risks associated with the study, and they provided their written informed consent prior to participation. All procedures involving human subjects were conducted in accordance with the requirements of the Declaration of Helsinki and approved by an Institutional Review Board. Trained research personnel conducted all study data collection according to standard laboratory practices.One-hundred and ninety collegiate men . During a single morning of testing between the hours of 0600 and 1000 with each testing session lasting approximately 1 h, the athletes completed a body composition assessment and RMR test in a climate-controlled laboratory setting (temperature range: 22–24 °C and relative humidity range: 37–44%). Participants reported to the laboratory in a fasted (>12 h) state and were advised to consume 0.5 L of water upon waking, but no later than within 1 h. of testing. Participants were also asked to refrain from strenuous activity <24 h prior to testing. This included strength training activities, conditioning, and sport-specific practice sessions greater than 50% effort.® physicians scale and stadiometer. Participants then completed a body composition assessment via air displacement plethysmography . Calibration procedures were completed in accordance with the manufacturer guidelines using a calibration cylinder of a standard volume (49.55 L) and an empty chamber prior to testing for the day. Participants wore tight-fitting clothing, removed all jewelry, and wore a swim cap prior to entering the testing chamber. Thoracic gas volumes were predicted using manufacturer default settings. Fat mass and fat-free mass (FFM) were determined based on the participant’s body mass and measured body volume using the Brozek equation [Height and body mass were assessed with a Secaequation . Test to2 L/min) did not vary by more than 5%.Indirect calorimetry  was used for RMR measurement. Participants were instructed to remain motionless in a supine position on an examination table. A clear, hard plastic hood and soft, clear plastic drape was then placed over the participant’s neck, head, and shoulders to determine resting oxygen uptake and energy expenditure. Participants were instructed to remain awake throughout the duration of testing. Data were recorded after the first ten minutes of testing during a five-minute period in which criterion variables  best predicted RMR in men and women. Slope was calculated to determine the observed changes in RMR per 1 unit increase in body mass and fat-free mass. The standard error of estimate (SEE) was determined to help evaluate the fit of the regression model for the measured RMR values. Normality was assessed via a visual inspection of normal Q-Q plots and skewness/kurtosis values. Homoscedasticity was assessed with Levene’s Test of Equality of Error Variances. Statistical analyses were conducted using the IBM SPSS Statistics for Windows . Strength of correlation coefficients was classified as trivial (|r| < 0.10), weak (0.10 ≤ |r| < 0.30), moderate (0.30 ≤ |r| < 0.50), strong (0.50 ≤ |r| < 0.70), very strong (0.70 ≤ |r| < 0.90), and nearly perfect (r ≥ 0.90) .p < 0.001)  .p < 0.001). When adjusted for body mass (p = 0.064) and fat-free mass (p = 0.084), the observed differences were no longer significant , and there was a moderate relationship between height and RMR (r = 0.40). In men, body mass (β = 0.784) was the strongest predictor of RMR , body mass index (r = 0.72), and RMR. Fat-free mass, body fat percentage, and fat mass were strongly associated with RMR in men , fat-free mass (r = 0.77), and RMR. Body mass index and fat mass were strongly associated with RMR in women (r = 0.69), and there was a moderate relationship between height, body fat percentage, and RMR (r = 0.48–0.49). In women, body mass (β = 0.832) was the strongest predictor of RMR .The primary aim of the current study was to examine sex differences in RMR among a large mixed cohort of men and women collegiate athletes. To the best of our knowledge, this is the largest study to date evaluating sex-specific differences in RMR among collegiate athletes. The main findings from the current study indicate that men athletes have a higher RMR, which is largely influenced by their larger body stature, specifically greater body mass when compared to their female counterparts. On average, males had a 50% higher RMR compared to females. However, when RMR was normalized to body mass and fat-free mass, the differences in RMR were no longer significant . This isA secondary aim of the current study was to identify predictors of RMR. The results demonstrated that body mass was the strongest predictor of RMR for both male and female athletes, which is in agreement with our initial findings  and thosThe mean RMR values of the male athletes included in the current study 2595 ± 433 kcals) are higher than those previously reported in male endurance 1868 ± 239 kcals) , highly 9 kcals ,3 kcals aThis study is not without limitations. The current study was conducted in collegiate athletes; therefore, it is unknown if sex differences in RMR would exist, along with similar relationships between body composition and RMR, in untrained or overweight populations. Menstrual status was not standardized across female athletes during the data collection process. A detailed training load was not collected prior to testing. This information could have help evaluate relationships between acute and chronic workloads and how prior activity may influence RMR. Additionally, energy availability and dietary intake were not accounted for in the days and weeks prior to testing. Lastly, hormone levels were not evaluated, specifically catecholamine or sex hormone concentrations, which have been shown to influence RMR .In NCAA Division III athletes, men have a higher absolute RMR than women. However, when normalized to body mass and fat-free mass, there are no differences in RMR between men and women, suggesting that male athletes tend to have a higher RMR because of their greater body mass. Additionally, body mass was the strongest predictor of RMR in both men and women athletes. Therefore, larger athletes have higher metabolic requirements than their smaller counterparts. These findings may help direct nutritional recommendations for athletes to help them meet their energy requirements. An emphasis should be place on a higher energy intake for larger athletes to ensure adequate energy availability to support their physiological requirements and demands of their sport activity.


The most common management option for hearing loss is hearing aids. In addition to devices, patients require information and support, including maintenance and troubleshooting. Mobile health  technologies can support hearing aid management, acclimatization, and use. This study developed an mHealth acclimatization and support program for first-time hearing aid users and subsequently implemented and pilot-tested the feasibility of the program. The program was facilitated by community health workers (CHWs) in low-income communities in South Africa.This study aimed to evaluate the feasibility of an mHealth acclimatization and support program supported by CHWs in low-income communities.An application-based acclimatization and support was adapted and translated for use in low- and middle-income countries. This program was delivered in the form of 20 different voice notes accompanied by graphical illustrations via WhatsApp or 20 different SMS text messages. The program was provided to first-time hearing aid users immediately after a community-based hearing aid fitting in March 2021 in 2 low-income communities in the Western Cape, South Africa. The 20 messages were sent over a period of 45 days. Participants were contacted telephonically on days 8, 20, and 43 of the program and via open-ended paper-based questionnaires translated to isiXhosa 45 days and 6 months after the program started to obtain information on their experiences, perceptions, and accessibility of the program. Their responses were analyzed using inductive thematic analysis.A total of 19 participants fitted with hearing aids received the mHealth acclimatization and support program. Most participants  received the program via WhatsApp, with 21% (4/19) of them receiving it via SMS text message. Participants described the program as helpful, supportive, informative, sufficient, and clear at both follow-ups. A total of 14 participants reported that they were still using their hearing aids at the 6-month follow-up. Three participants indicated that not all their questions about hearing aids were answered, and 5 others had minor hearing aid issues. This included feedback (n=1), battery performance (n=1), physical fit (n=2), and issues with hearing aid accessories (n=1). However, CHWs successfully addressed all these issues. There were no notable differences in responses between the participants who received the program via WhatsApp compared with those who received it through SMS text message. Most participants receiving WhatsApp messages reported that the voice notes were easier to understand, but the graphical illustrations supplemented the voice notes well.An mHealth acclimatization and support program is feasible and potentially assists hearing aid acclimatization and use for first-time users in low-income communities. Scalable mHealth support options can facilitate increased access and improve outcomes of hearing care. Hearing loss is one of the most prevalent impairments , with esIn recent years, there has been a drive to develop innovative person-centered service-delivery models to make hearing aids more accessible and affordable ,13-15. HConsequently, the World Health Organization recommends adopting task shifting as a strategy to move ear and hearing services to community health care workers (CHWs) in order to improve the accessibility and availability of hearing services and hearing aids in these contexts . CHWs wiSeveral studies have used alternative methods to improve the quality and retention of the education and training provided to hearing aid users after fitting to address the factors contributing to nonuse. These methods included home education programs delivered via DVD or videotape recording , web-basInnovative mHealth support programs can provide a potential strategy to facilitate acclimatization, continued or consistent use, and benefit from hearing aids . The comInstitutional review board approval was granted by the Research Ethics Committee, Faculty of Humanities, University of Pretoria (HUM030/0621). Participants were provided with detailed information about the study in their home language, and written informed consent was obtained from all participants before data collection commenced. Participants could keep their hearing aids free of charge once the study ended. Study data were deidentified to ensure privacy and confidentiality.This study formed part of a community-based service-delivery model previously reported by Frisby et al . This stAn application-based acclimatization and support program developed by a web-based direct-to-consumer hearing aid provider in the United States (Lexie Hearing) was adapted and translated to isiXhosa for this project through a collaboration with a local nongovernmental organization . The program, originally developed by audiologists for in-app delivery at Lexie Hearing, consisted of 20 unique messages in English, covering various aspects of hearing aid acclimatization and support. The content was adapted for delivery through WhatsApp voice notes or standard SMS text messages.This program aims to improve the use of hearing aids by providing basic information on how a hearing aid works, optimal use and care, troubleshooting, and motivational support  48,49].,49.48,49The 20 unique English messages were translated and adapted to isiXhosa, the home language in the target communities. Two CHWs, employed by the NGO partner, whose first language is isiXhosa, and are fluent in English, were recruited to assist with the translations. The CHWs worked independently to translate the messages and then produced a consolidated isiXhosa translation. The original English and isiXhosa versions of the first 7 messages were sent to a certified isiXhosa linguist. The linguist compared the translations and suggested edits. The CHWs then reviewed these edits to ensure clarity according to the prevailing dialect used in the communities. On the basis of the high accuracy of their translations, CHWs translated the remaining messages without assistance from the linguist.The content of the 20 messages was used to create 20 voice notes sent via WhatsApp or 20 SMS text messages if WhatsApp was unavailable. Voice notes were used to ensure comprehension regardless of the users’ literacy level, and voice notes also have an option of increasing the volume if needed. The voice notes ranged from 10 to 93 seconds and were accompanied by graphical illustrations with textual explanations in English to summarize the information provided .The 20 unique messages were sent over a period of 45 days, with all participants receiving the same messages on the same days. Week 1, the primary focus for acclimatization, included 8 messages. Messages in subsequent weeks were spread to include two in weeks 2 and 3, three in weeks 4 and 5, and two in week 6 .Community members of 2 low-income communities received a CBR service providing hearing aids to adults previously reported by Frisby et al . These cEligible participants met the following inclusion criteria: (1) age of ≥18 years, (2) bilateral hearing loss (pure tone average ≥26 dB hearing loss  with thrThe hearing aid fittings took place during a second home visit while the audiologists observed (observation was purely for data collection purposes). The audiologists were not involved in providing the program or collecting the data. These digital hearing aids were fit via Bluetooth through a smartphone according to a standard hearing aid fitting algorithm  using participant hearing thresholds. The hearing aids were behind-the-ear (Lexie Lumen), slim tube, non-custom mold devices with 16 channels, wide-dynamic-range compression technology, feedback reduction, Bluetooth connectivity and programming, digital noise reduction, and a directional microphone array ,48. OnceParticipants were enrolled in the mHealth acclimatization and support program. CHWs were supplied with project smartphones (Android) and were responsible for sending the messages to participants. Participants who did not have access to WhatsApp received the program through SMS text messages. Participants were provided with the CHWs’ contact details and could contact the CHWs if they experienced any difficulties. Participants accessing WhatsApp received graphical illustrations with textual explanations accompanied by a voice note .Participants completed a nonstandardized, closed-ended questionnaire before initiating the acclimatization and support program to determine their competence in operating a mobile phone . SubsequCHWs conducted home visits 45 days and 6 months after the acclimatization and support program started. Participants completed a nonstandardized, open-ended questionnaire  at both Raw data were recorded in an Excel 2016 (Microsoft Corp) spreadsheet and imported for statistical analysis into the SPSS software . Observational descriptive analysis, including mean, frequency counts, and SDs, were determined for quantitative statistics such as participant age, gender, and degree of hearing loss. Qualitative open-ended questionnaire responses were analyzed using inductive thematic analysis with a semantic approach . To ensuIn total, 20 messages were adapted and developed from the Lexie Hearing application  years. Females accounted for 78.9% of participants. Participant hearing status and competence in operating a mobile phone are reported in Overall, 14, 7, and 15 participants could be contacted during phone calls 1, 2, and 3, respectively, and all reported using the program . Most participants who could be contacted for phone calls 1, 2, and 3  were satisfied with the hearing aids and program. Four participants had a complaint regarding the hearing aids during the 3 phone calls. This included feedback (n=1), pain (n=1), hearing aids falling out (n=1), hearing aids not working, and confusion regarding the drying kit (n=1). How these hearing aid issues were addressed is reported in Overall, 17 participants took part in the 45-day follow-up and 16 in the 6-month follow-up. All participants reported making use of the program and felt a general sense of support provided by the program. Most participants  relied on others in their homes to receive the information as they did not own phones or could not operate a phone independently. Of these participants, 64% (7/11) relied on their children, 18% (2/11) on their spouses, and 18% (2/11) on grandchildren. Participant responses to open-ended questions asked at the follow-up visits are reported in All participants (n=17) reported feeling well supported and that messages were easy to understand. Most participants  reported that the program messages covered all questions about their hearing aid. A total of 7 participants reported difficulties performing specific tasks with the hearing aids, including difficulties putting on the hearing aid on (n=3), cleaning the hearing aid (n=3), and changing the batteries (n=1). These reported difficulties were covered by the program messages, and these participants reported that the information provided in the program made these tasks easier. Only 3 of 17 (18%) participants reported that the acclimatization and support program did not answer all their questions . Almost half  of participants reported that they reviewed the program messages several times. Two participants reported that although they did not experience any difficulties, they reviewed all messages as a general reminder of the concepts covered.Among the 16 participants who participated in the 6-month follow-up visit , 14 repoThis study implemented and evaluated an mHealth acclimatization and support program for first-time hearing aid users in low-income communities, facilitated by CHWs. The mHealth program aimed to improve first-time hearing aid users’ usage of their hearing aids by providing basic information covering how a hearing aid works, optimal use and care, troubleshooting, and motivational support. The feasibility of the mHealth acclimatization and support program in this study could be ascribed to several factors, including the accessible information with text developed with lower reading grade levels and accessibility of the platforms used to distribute the program. The readability level of information is critical for ensuring accessible health literacy ,58. To eUsing an mHealth platform is relevant because nearly 5.7 billion individuals globally are predicted to have access to mobile phones by 2025, of which approximately 84% will be smartphones . AlthougThe positive reports by participants in this study, indicating an experience of being supported by the program, compare well with other studies ,37,38. FThis study demonstrates that mHealth technologies facilitated by CHWs in low-income communities can support the rehabilitation process of hearing aid users and improve hearing aid use. This study also determined that audiologists are not required in the field during the implementation of such a program and that audiologist-led training and remote support via teleaudiology is sufficient. Although the overall responses were positive, it may be beneficial for future studies to consider incorporating additional information on hearing loss and its permanency, the lifespan of hearing aids, how each hearing aid is personalized for the user, usage of a drying kit, and how to replace domes or tubing.CHWs were assigned several participants and had to track when to send the messages to each participant. Although no errors were reported in this study, this is a barrier to scaling the intervention. Future studies and implementations should employ automated programs to allow for improved scalability and a reduced chance of human error. The graphical illustrations sent via WhatsApp contained textual explanations that were in English. Future research should consider providing all information in participants’ home language. This study did not perform user testing on the graphical illustrations before implementation, which will be useful in future to ensure the appropriateness and clarity of the images, messages, and font style and size. Future research should consider using a pre-post measurement of practical skills needed to use and maintain hearing aids to investigate postintervention changes. Future studies should investigate how cognitive functioning and literacy levels could influence the benefit of such an intervention. This study had a small sample size, and female participants were overrepresented. Furthermore, objective measures were not included to determine if participants accessed the program or hearing aid use. This study made use of observational descriptive analysis for the quantitative data; future research on larger sample sizes will allow inferential statistics. Most importantly, owing to the feasibility nature of this study, the results should be seen as preliminary. Controlled studies are needed to evaluate the outcome and the effect size of such programs. A cost-effectiveness study is needed to determine the usability of such a program in a real-world context.An mHealth acclimatization and support program for first-time hearing aid users supported by CHWs was adapted for use in LMICs and implemented successfully. Feedback from the hearing aid users was positive, with all participants feeling well supported, and most were still making use of their hearing aids 6 months later. Making use of a real-world sample of participants illustrated that an mHealth acclimatization and support program provided in the home language of the users is feasible and can assist self-management of first-time hearing aid users in LMICs. These results demonstrate the potential for self-management of hearing aids from first-time hearing aid users’ homes. This is particularly relevant in LMICs where, owing to a lack of resources and professionals, opportunities for in-person interactions with hearing health care professionals may be limited. Scalable mHealth support options can facilitate increased access and quality in hearing care. Future research should consider randomized controlled trials to compare hearing aid self-management outcomes with and without the support program.


Systematic review and pooled analysis of randomized controlled trials in Countries of the Gulf Cooperation Council (GCC).Methods and quality assessmentAlraddadi et al describe variations in characteristics of randomized controlled trials conducted in the Gulf Cooperation Council (GCC) countries, and critically appraising the quality of design, conduct and analysis of the trials. a systematically comprehensive electronic search of articles published between 1990 and 2018 and indexed in several databases were carried out. The proportion of adequately generated random sequence methods has increased yearly, and this increase accounted for a relatively large proportion over the latter half of the studied period, in contrast to the proportion of allocation concealment and blinding. The randomization methods have gained more attention over the last 3 decadessee page 345 The impact of viability assessment using cardiac MRI and echocardiogram on the outcome of revascularization in patients with multi-vessels coronary artery disease and moderate to severe ischemic cardiomyopathyAlzahrani et al investigate he influence of viability assessment in the management of patients with ischemic cardiomyopathy (ICM). All patients with ICM with moderate to severely reduced left ventricular ejection fraction (LVEF) who underwent viability assessment using cardiac magnetic resonance imaging (MRI) and echocardiogram as modalities of imaging were included. Posttreatment LVEF improved by 5% in the viable group compared to the nonviable group. Patients with viable myocardium had better outcomes in which LVEF significantly improved posttreatment.see page 373Potential barriers to the daily use of hearing aids in childrenYousef et al identify factors affecting hearing aid usage of 59 children ranging from 6 months to 6 years. Patients with moderate to profound sensorineural hearing loss with complete data-logging information stored in the hearing aid programming file from January 2020 until June 2021 were included. The average daily hearing aid usage was 5.5 hour (h) after 3 months, 7 h after 6 months; and 8.7± 4.7 h as reported by parents. Patient age was positively correlated with data logging at 3 months and 6 months. We found that children’s age, gender, severity of hearing loss, residential location, and parents’ educational level had a significant effect on daily hearing aid usage.see page 406


Gene expression programming (GEP) is one of the most prominent algorithms in function mining. In order to obtain a more accurate function model in configuration parameters-execution efficiency (CP-EE) of map-reduce job in the high-speed railway catenary monitoring system, this paper proposes a novel algorithm, called GEP based on multi-strategy (MS-GEP). Compared to traditional GEP, the proposed algorithm can escape premature convergence and jump out of local optimum. First, an adaptive mutation rate is designed according to the evolutionary generations, population diversity, and individual fitness values. A manual intervention strategy is then proposed to determine whether the algorithm enters the dilemma of local optimum based on the generations of population evolutionary stagnation. Finally, the average quality of the population is changed by randomly replacing individuals, and the ancestral population is traced to change the evolutionary direction. The experimental results on the benchmarks of function mining show that the proposed MS-GEP has better solution quality and higher population diversity than other GEP algorithms. Furthermore, the proposed MS-GEP has higher accuracy on the function model of CP-EE of high-speed railway catenary monitoring system than other commonly used algorithms in the field of function mining. The real-time nature of map-reduce job execution in high-speed railway catenary monitoring software systems  is a keyRecently, several attempts have been made to extensively study the optimization of the big data job configuration parameters. Consequently, several authors proposed many models for the execution efficiency of the big data job using AI methods. Vidhyasagar et al.  searchedGene expression programming (GEP)  is an evTherefore, this paper proposes a GEP algorithm based on multi-strategy (MS-GEP) for CP-EE of the map-reduce job function mining model construction in the catenary monitoring system of high-speed railway and some shortcomings of GEP algorithm. The proposed MS-GEP can obtain a more accurate function model using the GEP algorithm optimized by the adaptive mutation rate based on population information entropy and manual intervention strategy to guide the population evolution. The main contributions of this paper are summarized as follows:(1) We propose an adaptive mutation rate setting based on the population information entropy that can maintain the diversity of the population by taking it into consideration.(2) We propose a manual intervention strategy since the traditional GEP fails to converge to a better solution due to converging prematurely or falling into the local optimum.(3) The experimental results on the benchmark dataset show that the proposed MS-GEP outperforms the other GEP algorithms.(4) In the function mining experiments of map-reduce job CP-EE of the high-speed railway catenary monitoring system, the evaluation index of the proposed MS-GEP outperforms other commonly used function mining algorithms.The remainder of this paper is organized as follows. Section 2 introduces the relevant fundamentals. Section 3 presents details of the proposed MS-GEP. Section 4 shows the experimental and analysis results. Finally, Section 5 presents the conclusion and future research.GEP encodes individuals as fixed-length linear strings and then represents them as nonlinear entities of different lengths and shapes. GEP improves the functional complexity loss of individuals caused by fixed-length linear strings during evolution using GA and also optimizes the limited variation of individuals caused by nonlinear entities of different lengths and shapes during evolution using GP. Additionally, GEP has a flexible genetic structure to avoid wasting many resources to check the survival of individuals in GA and GP.GEP consists of individual coding methods, individual fitness evaluation function, initial populations and genetic operations. The genetic operations consist of selection, mutation, inversion, insertion, gene transformation, and gene recombination. The standard GEP algorithm flow is shown as follows: (1) Creating initial population and parameters setting. (2) Chromosome decoding. (3) Evaluating fitness. (4) Determining whether the end condition is satisfied. If it is satisfied, the process is terminated; otherwise, the next step is executed. (5) Saving the best individuals. (6) Individual selection algorithm. (7) Genetic operation. (8) Forming a new population and return to (2).Lt, where Lh is the gene head length and n is the maximum number of operations of a single function in the function set.Individuals in GEP are called chromosomes. A chromosome can be composed of one or more genes. The combination of gene head and tail forms a gene. The head is made up of a function set and a terminal set, whereas the tail is only made up of a terminal set. F = {+, −, *, /} and the terminal set be T = {x, y}. The length of the gene head is 3. The chromosome consists of two genes. The gene tail length can be obtained as 4 according to xxyy” and “* *y/xxx.” The expression tree is read from top to bottom, left to right to become algebraic. x2 + y2” and “xy,” respectively. Gene 1 and gene 2 are linked by default with a plus sign. The K-expressions and expression tree can be converted to algebraic expressions as “x2 + y2 + xy.”The expressions of chromosomes are divided into expression trees and K-expressions. For example, let the function set be In GEP, the mutation operation is more effective than the remaining genetic operations in the population evolution . TherefoPi is the probability of chromosomes that appear in each region and n is the population size. The step for calculating Pi is as follows:Population information entropy is used to show the magnitude of contemporary population diversity, as shown in fmin, the individual maximum fitness is fmax, and the population size is K. Divide fmin and fmax into K regions; each region interval is given in Step 1. The current population individual minimum fitness is β)fmin + (w1)θ, (1 − β)fmin + wθ), where w = 1, 2, ⋯, K.Each interval is then 26], backR2 is closer, RF is more discrete than MS-GEP for predictions with target values of 45 or less. This difference may account for the slightly lower R2 of RF than MS-GEP.We compared R2, indicating that the model established by MS-GEP is reliable. The three indexes of MS-GEP are better than RF, so the model of map-reduce job CP-EE established by MS-GEP is better than that of the RF. As presented in This paper proposed a new algorithm, i.e., MS-GEP, based on the shortcomings of the standard GEP algorithm. Based on the theoretical analysis, we set the adaptive mutation rate based on the population information entropy, individual fitness, and evolutionary generations. Inspired by manual intervention in biological evolution, we create a manual intervention strategy to guide the population evolution. The results show that the proposed MS-GEP improves population diversity, avoids premature convergence, and fall into local optimum.Benchmark tests have shown that the proposed MS-GEP has better solution quality and higher stability than NMO-SARA, GEP and FF-GEP in most cases. In the experiments of high-speed railway map-reduce job configuration parameters function mining, the proposed MS-GEP still outperforms other commonly used algorithms in constructing complex functions in each evaluation index when a specific function model is available, indicating its effectiveness in solving real-world problems.However, we also recognized that map-reduce job configuration parameters are characterized by nonlinearity and high noise, which may have some impact on model performance. In future research, we will aim to reduce these disturbances more comprehensively and effectively to further improve the accuracy and robustness of the model. In addition, we will also explore the application of MS-GEP to other fields to expand its application scope.


Between early challenges and lasting opportunities, a deaf virologist reflects on how the pandemic transformed his access to academic spaces. On Wednesday March 11, 2020, the governor of New York announced that all in-person classes were to be suspended at my university until the end of the semester. As the news spread, my colleagues speculated that the shutdown might last a few weeks or months. To me it felt more significant, not unlike the aftermath of 9/11 when we realized that the world had irrevocably changed. As a virologist, I had some idea about what was to come; as a deaf individual, I did not fully comprehend what this would entail for me.Ever since the COVID-19 outbreak had reached New York City in late February, I had been checking the newspapers every morning to get the latest number of cases and plot them. With the case rate doubling every 2.5 days, and vaccine production 12–18 months away at best, I knew that it was impossibly optimistic to expect normality to return within a few months. The world was going to be sheltering in place for the foreseeable future, masking, meeting remotely and social distancing. My ability to communicate with others was already tenuous. I felt as if it was about to be severed.Born profoundly hearing impaired, I was fitted with hearing aids as a child and raised in the ‘oral world’. For many like me, hearing isn’t the problem; the problem is to make sense of the sounds. Picture yourself in a foreign country where you have only a rudimentary understanding of the language. Conversations, television programmes, what a service employee is trying to tell you… everything is incomprehensible except for a few words. If it’s quiet and you concentrate, you can partially piece things together. That’s my baseline; in hearing tests, my word recognition score is around 60%. In ideal situations, I can usually puzzle out what someone is saying by relying heavily on lipreading, context and non-verbal cues. If it’s noisy or these cues are not available, I understand nothing.Barely a few days after the governor’s announcement, all my teaching and work meetings were taking place online. This quickly represented a challenge, as electronic or amplified speech sounds heavily distorted when re-amplified by my cochlear implant and hearing aid. Even when speakers had their webcam turned on and I could lipread, it was nearly impossible for me to understand what they were saying.Real-time captioning, which would help solve my problems, was rarely supported by communications platforms at the time. To my dismay, I discovered that it was missing from the learning management system that my college used for teaching. Thankfully, I found an adequate substitute in Google Meet and I was able to continue communicating with my students. I had less success with some colleagues, who insisted on using their preferred platforms even though they lacked live captioning.Online conferences and symposia were another challenge. When I alerted organizers that their software was not providing captions, most gamely tried to accommodate my needs but struggled to navigate technology issues. We once sat in an awkward, embarrassed silence for 20 minutes as the host of a Diversity, Equity, and Inclusion committee meeting attempted to find how to turn on captioning. I had been invited to talk about the challenges faced by deaf individuals; I think this real-time demonstration was possibly more effective than anything I could have planned to say. Not everybody was so cooperative, however. Some organizers did not respond to my requests or claimed that accommodations weren’t possible. One asked me to not “make life more complicated” for them — ironically, they were putting together a series of seminars about improving access to research for underrepresented minorities.After a few of these incidents, I reached out to human resources for assistance. It took four months of persistent emailing before I was presented with a solution: I could schedule a live transcriptionist for meetings, as long as I provided notice 24 hours in advance. As it turned out, this ‘solution’ had several problems. Transcriptionists were slower and less accurate than automatic captioning, and only available during business hours. It was also a logistical challenge to get them into conferences, especially those with registration fees.Fortunately, after a few months, most platforms started to incorporate live transcription into their software. With this, my whole world changed again. Meetings and conferences had always been difficult for me as I would struggle to locate the speaker, focus on their face, and figure out what they were saying before someone else chimed in. Online, it was easy to see everyone clearly and to follow the conversation with lipreading and captioning. With remote communication becoming mainstream, I can now participate in meetings and conferences to a greater extent than in the past.These technological improvements don’t mean that I no longer rely on the kindness and cooperation of others. For example, I still reach out to conference organizers in advance to ensure that captioning will be provided, because it’s usually not turned on by default. Hearing loss is often an invisible disability, and hosts may not realise that attendees – including their colleagues – could have hearing difficulties. They may assume that people will request the accommodations they need, but many are embarrassed to ask or don’t want to ‘be a bother’. It’s better to provide these adjustments proactively and mindfully.The pace of change can sometimes feel frustratingly slow, yet I often say that there has never been a better time to be deaf. The hearing aids I had as a child were primitive compared to the engineering marvels that carefully curate sounds for my ears today. When captioned media began its long, slow rollout in the 1990s, a new world opened for me, one where I could finally share my friends’ enthusiasm for the latest movies and dramas. Now the era of mainstreaming remote meetings has ushered in another sea change for me.Sparks of Change column, where people around the world share moments that illustrate how research culture is or should be changing. Have an interesting story to tell? See what we’re looking for and the best ways to get in touch here.This article is a