Work-rest regimens for work in hot environments: A scoping review.

BACKGROUND: To limit exposures to occupational heat stress, leading occupational health and safety organizations recommend work-rest regimens to prevent core temperature from exceeding 38°C or increasing by ≥1°C. This scoping review aims to map existing knowledge of the effects of work-rest regimens in hot environments and to propose recommendations for future research based on identified gaps. METHODS: We performed a search of 10 databases to retrieve studies focused on work-rest regimens under hot conditions. RESULTS: Forty-nine articles were included, of which 35 were experimental studies. Most studies were conducted in laboratory settings, in North America (71%), on healthy young adults, with 94% of the 642 participants being males. Most studies (66%) employed a protocol duration ≤240 min (222 ± 162 min, range: 37-660) and the time-weighted average wet-bulb globe temperature was 27 ± 4°C (range: 18-34). The work-rest regimens implemented were those proposed by the American Conference of Governmental and Industrial Hygiene (20%), National Institute of Occupational Safety and Health (11%), or the Australian Army (3%). The remaining studies (66%) did not mention how the work-rest regimens were derived. Most studies (89%) focused on physical tasks only. Most studies (94%) reported core temperature, whereas only 22% reported physical and/or mental performance outcomes, respectively. Of the 35 experimental studies included, 77% indicated that core temperature exceeded 38°C. CONCLUSIONS: Although work-rest regimens are widely used, few studies have investigated their physiological effectiveness. These studies were mainly short in duration, involved mostly healthy young males, and rarely considered the effect of work-rest regimens beyond heat strain during physical exertion.

Spiro heterocycles bearing piperidine moiety as potential scaffold for antileishmanial activity: synthesis, biological evaluation, and in silico studies.

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1.

Synthesis, Antioxidant and Antiproliferative Evaluation, Molecular Docking and DFT Studies of Some Novel Coumarin and Fused Coumarin Derivatives.

N'-[(4-Chloro-2-oxo-2H-chromen-3-yl)methylene]-2-cyanoacetohydrazide (3) was synthesized in excellent yield from the condensation of 4-Chloro-2-oxo-2H-chromene-3-carbaldehyde with cyanoacetohydrazide. Compound 3 was utilized as a building block to synthesize novel coumarin and heterocycle-fused coumarin derivatives. The chemical structures of all the new coumarin compounds were identified by spectral analyses. Some of the new coumarins compounds were screened in human cancer cell lines (HEPG-2, MCF-7, HCT-116 and PC-3) to learn about their cytotoxic effects in addition to the study of their DNA damage and antioxidant activity. Three of these compounds exhibited remarkable antioxidant and anti-proliferative activities. Moreover, they have the capability to protect DNA from damage induced by bleomycin. Molecular docking, DFT and molecular electrostatic potential studies were performed on the compounds in vitro.

Nanoswitch-linked immunosorbent assay (NLISA) for fast, sensitive, and specific protein detection.

Protein detection and quantification play critical roles in both basic research and clinical practice. Current detection platforms range from the widely used ELISA to more sophisticated, and more expensive, approaches such as digital ELISA. Despite advances, there remains a need for a method that combines the simplicity and cost-effectiveness of ELISA with the sensitivity and speed of modern approaches in a format suitable for both laboratory and rapid, point-of-care applications. Building on recent developments in DNA structural nanotechnology, we introduce the nanoswitch-linked immunosorbent assay (NLISA), a detection platform based on easily constructed DNA nanodevices that change conformation upon binding to a target protein with the results read out by gel electrophoresis. NLISA is surface-free and includes a kinetic-proofreading step for purification, enabling both enhanced sensitivity and reduced cross-reactivity. We demonstrate femtomolar-level detection of prostate-specific antigen in biological fluids, as well as reduced cross-reactivity between different serotypes of dengue and also between a single-mutation and wild-type protein. NLISA is less expensive, uses less sample volume, is more rapid, and, with no washes, includes fewer hands-on steps than ELISA, while also achieving superior sensitivity. Our approach also has the potential to enable rapid point-of-care assays, as we demonstrate by performing NLISA with an iPad/iPhone camera for imaging.

[Pseudotumoral calcinosis of the wrist compressing the radial nerve in systemic sclerosis]. / Compression du nerf radial au poignet par une calcinose pseudo-tumorale au cours d'une sclérodermie systémique.

BACKGROUND: Pseudotumoral calcinosis, a rare complication of systemic scleroderma, is characterized by the presence in extra-articular tissue, but rarely intra-articular tissue, of large masses made up of hydroxyapatite crystals. PATIENTS AND METHODS: We report an original case of intra- and extra-articular pseudotumoral calcinosis of the wrist diagnosed in a patient followed for mild systemic scleroderma. The calcinosis was revealed in a highly unusual way via ductal syndrome secondary to compression of the radial nerve in the wrist. Surgical treatment resulted in marked clinical and functional improvement. COMMENT: Although subcutaneous calcinoses are a fairly common complication of systemic scleroderma, the pseudo-tumoral form remains extremely rare. It may be complicated by pain, recurrent infection, and functional restriction, but literature contains only very rare reports of its revelation via ductal syndrome.

Discovery of a novel DNA binding agent via design and synthesis of new thiazole hybrids and fused 1,2,4-triazines as potential antitumor agents: Computational, spectrometric and in silico studies.

New series of furan-thiazole hybrids (3a-f), thiazolo[2,3-c]-1,2,4-triazines (4a-f), their bioisosteres 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazines (8a-d) and 1,2,4-triazino[4,3-b]-1,2,4-triazines (13a-e) were designed, synthesized and evaluated for their in vitro antitumor activities at the National Cancer Institute (NCI, USA). Among the synthesized compounds, 3d was found to exhibit promising broad spectrum antitumor activity (GI50 MG-MID = 14.22 µM) in a five-dose assay against the full panel NCI-cancer cell lines. 3d displayed higher antitumor activity against most tested cancer cell lines than 5-FU as reference. COMPARE analysis and molecular electrostatic potential computational study revealed that 3d probably exerts its antitumor properties through DNA binding similar to Clomesone. Further DNA binding studies using fluorescent terbium (Tb+3) probe revealed increased fluroresence of DNA-3d-Tb+3 mixture due to damage of the double-stranded DNA. Also, UV-vis absorption study was conducted which showed hyperchromic shift in DNA absorption confirming 3d-induced DNA damage. The assessed potency of 3d-induced DNA damage of calf thymus DNA showed a concentration as low as 2.04 ng/mL for a detectable DNA damage. Moreover, in silico calculation of physicochemical properties and druglikeness were in compliance to Lipinski's rule.

Synthesis, modeling and biological evaluation of some pyrazolo[3,4-d]pyrimidinones and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones as anti-inflammatory agents.

New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity.

DNA nanoswitches: a quantitative platform for gel-based biomolecular interaction analysis.

We introduce a nanoscale experimental platform that enables kinetic and equilibrium measurements of a wide range of molecular interactions using a gel electrophoresis readout. Programmable, self-assembled DNA nanoswitches serve both as templates for positioning molecules and as sensitive, quantitative reporters of molecular association and dissociation. We demonstrated this low-cost, versatile, 'lab-on-a-molecule' system by characterizing ten different interactions, including a complex four-body interaction with five discernible states.

Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidines as anti-inflammatory agents.

New pyrazolo[3,4-d]pyrimidines substituted with various functionalities or attached to a substituted pyrazole ring through different linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity using in vitro COX-1/COX-2 inhibition assay and in vivo formalin induced paw edema and cotton pellet-induced granuloma assays. Results revealed that compounds 17b and 18 possessed COX-1/COX-2 selectivity indices higher than diclofenac sodium and celecoxib. However, compounds 16a,b exhibited selectivity indices higher than diclofenac sodium and nearly equivalent to celecoxib, whereas, 9b displayed selectivity index comparable to diclofenac sodium. In vivo anti-inflammatory data showed that compounds 9b, 16a, 18 displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, the pyrazolyl derivatives 9b, 16b and 17b displayed anti-inflammatory activity about 2-2.5-fold that of diclofenac sodium and nearly 8-10.5-fold that of celecoxib in the cotton pellet-induced granuloma assay. The ulcerogenic effect of the active compounds was also investigated and results revealed that compounds 16a, 17a,b and 18 showed good gastrointestinal safety profile. Based on this, compounds 16a and 18 were considered as safe and effective leads in managing acute inflammation, while, 17b was prominent in controlling chronic inflammation.

Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidine derivatives bearing thiazolidinone moiety as anti-inflammatory agents.

Two new series of pyrazolo[3,4-d]pyrimidine bearing thiazolidinone moiety were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro (COX-1 and COX-2) inhibitory assay. Compounds that showed promising COX-2 selectivity were further subjected to in vivo anti-inflammatory screening applying formalin induced paw edema (acute model) and cotton-pellet induced granuloma (chronic model) assays using celecoxib and diclofenac sodium as reference drugs. The histopathological and ulcerogenic potential were also determined. In vivo anti-inflammatory data showed that compounds 2, 6, 7d displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, compounds 2, 3d, 3e, 7b and 7d displayed anti-inflammatory activity greater than or nearly equivalent to diclofenac sodium in the cotton pellet-induced granuloma assay. Moreover, most of the tested compounds revealed good gastrointestinal safety profile. Collectively, compounds 2 and 7d were considered as promising candidates in managing both acute and chronic inflammation with safe gastrointestinal margin.

Development of an International Elective in an Emergency Medicine Residency.

BACKGROUND: There is a continued interest in global emergency medicine (EM) training, research, and clinical program development. There are many opportunities for "voluntourism" in medicine, but many of these experiences do not have standard goals and objectives. OBJECTIVE: This article describes a rotation for EM residents from the United States to have a structured learning experience focusing on emergency medical settings in the prehospital phase (something often lacking in U.S. programs). DISCUSSION: The authors discuss the structure of the training program, including goals, objectives, and core competencies. First-hand accounts of the training experience are also presented. CONCLUSIONS: Global training experiences can have clear benefits. Students go to places to "learn," but can also "teach" at the same time. Setting goals and objectives helps to assure that students are gaining specific core competencies as part of the experience. Other global rotations would benefit from having a defined structure.

Synthesis and Characterization of Some New Coumarins with in Vitro Antitumor and Antioxidant Activity and High Protective Effects against DNA Damage.

Coumarins are naturally occurring oxygen heterocyclic compounds having multifarious medicinal properties, hence used as lead compounds for designing new potent analogs. The chromene butenoic acid 3 and the benzochromene butenoic acid 4 which are derived from the reaction of glyoxalic acid with 3-acetylcoumarin and 3-acetylbenzocoumarin, respectively, were reacted with different nitrogen and carbon nucleophiles to give new heterocyclic compounds. The structures of the prepared compounds were elucidated by IR, ¹H-NMR, and mass spectroscopy. Some of the newly prepared compounds were tested in vitro against a panel of four human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, human prostate cancer PC3, and mammary gland breast MCF-7. Also they were tested as antioxidants. Almost all of the tested compounds showed satisfactory activity.

Comparison of visual outcomes after variable spot scanning ablation versus wavefront-optimized myopic LASIK.

PURPOSE: To compare the refractive and visual outcomes of variable spot scanning ablation versus the wavefront-optimized ablation for myopia and myopic astigmatism. METHODS: Fifty patients with myopia who underwent LASIK (100 eyes) were divided into two equal groups. Myopic correction performed using the variable spot scanning (VSS) ablation with the VISX STAR S4/IR platform (Abbott Medical Optics, Inc., Santa Ana, CA) (VSS group) and wavefront-optimized (WFO) ablation profile with the WaveLight Allegretto Wave Eye-Q platform (Alcon Laboratories, Inc., Fort Worth, TX) (WFO group). Manifest refraction, uncorrected distance visual acuity, and corrected distance visual acuity were obtained preoperatively and 1 day and 1 and 3 months postoperatively. Wavefront measurement and contrast sensitivity testing were done preoperatively and 3 months postoperatively. RESULTS: Postoperative mean refractive spherical equivalent was -0.14 ± 0.2 diopters for the VSS group and -0.15 ± 0.28 diopters for the WFO group. Forty-eight eyes of the VSS group and 47 eyes of the WFO group were within ±0.5 diopters. Postoperative mean corrected distance visual acuity was 1.05 ± 0.13 for the VSS group and 1.06 ± 0.12 for the WFO group. The postoperative uncorrected distance visual acuity was 1.01 ± 0.16 for the VSS group and 1.01 ± 0.11 for the WFO group. The safety index was 1.12 for the VSS group and 1.06 for the WFO group, whereas the efficacy index was 1.07 for the VSS group and 1.01 for the WFO group. The mean induced positive spherical aberration was 0.041 ± 0.046 µm for the VSS group and 0.195 ± 0.171 µm for the WFO group (P < .001). Mesopic contrast sensitivity testing showed no statistically significant differences between groups at all tested spatial frequencies. CONCLUSIONS: Both VSS and WFO treatments showed similar refractive and visual outcomes. Both induced significant positive spherical aberration, significantly more with WFO.

Wavefront-Guided Laser Treatment Using a High-Resolution Aberrometer to Measure Irregular Corneas: A Pilot Study.

PURPOSE: To evaluate in a pilot study the visual, refractive, corneal topographic, and aberrometric changes after wavefront-guided LASIK or photorefractive keratectomy (PRK) using a high-resolution aberrometer to calculate the treatment for aberrated eyes. METHODS: Twenty aberrated eyes of 18 patients undergoing wavefront-guided LASIK or PRK using the VISX STARS4IR excimer laser and the iDesign aberrometer (Abbott Medical Optics, Inc., Santa Ana, CA) were enrolled in this prospective study. Three groups were differentiated: keratoconus post-CXL group including 11 keratoconic eyes (10 patients), post-LASIK group including 5 eyes (5 patients) with previous decentered LASIK treatments, and post-RK group including 4 eyes (3 patients) with previous radial keratotomy. Visual, refractive, contrast sensitivity, corneal topographic, and ocular aberrometric changes were evaluated during a 6-month follow-up. RESULTS: An improvement in uncorrected (UDVA) and corrected visual acuity (CDVA) associated with a reduction in the spherical equivalent was observed in the three groups, but was only statistically significant in the keratoconus post-CXL and post-LASIK groups (P ≤ .04). All eyes gained one or more lines of CDVA after surgery. Improvements in contrast sensitivity were observed in the three groups, but they were only statistically significant in the keratoconus post-CXL and post-LASIK groups (P ≤ .04). Regarding aberrations, a reduction was observed in trefoil aberrations in the keratoconus post-CXL group (P = .05) and significant reductions in higher-order and primary coma aberrations in the post-LASIK group (P = .04). CONCLUSIONS: Wavefront-guided laser enhancements using the evaluated platform seem to be safe and effective to restore the visual function in aberrated eyes.

Protocol for sortase-mediated construction of DNA-protein hybrids and functional nanostructures.

Recent methods in DNA nanotechnology are enabling the creation of intricate nanostructures through the use of programmable, bottom-up self-assembly. However, structures consisting only of DNA are limited in their ability to act on other biomolecules. Proteins, on the other hand, perform a variety of functions on biological materials, but directed control of the self-assembly process remains a challenge. While DNA-protein hybrids have the potential to provide the best-of-both-worlds, they can be difficult to create as many of the conventional techniques for linking proteins to DNA render proteins dysfunctional. We present here a sortase-based protocol for covalently coupling proteins to DNA with minimal disturbance to protein function. To accomplish this we have developed a two-step process. First, a small synthetic peptide is bioorthogonally and covalently coupled to a DNA oligo using click chemistry. Next, the DNA-peptide chimera is covalently linked to a protein of interest under protein-compatible conditions using the enzyme sortase. Our protocol allows for the simple coupling and purification of a functional DNA-protein hybrid. We use this technique to form oligos bearing cadherin-23 and protocadherin-15 protein fragments. Upon incorporation into a linear M13 scaffold, these protein-DNA hybrids serve as the gate to a binary nanoswitch. The outlined protocol is reliable and modular, facilitating the construction of libraries of oligos and proteins that can be combined to form functional DNA-protein nanostructures. These structures will enable a new class of functional nanostructures, which could be used for therapeutic and industrial processes.

The clinical challenges of akathisia.

Akathisia is one of the most vexing problems in neuropsychiatry. Although it is one of the most common side effects of antipsychotic medications, it is often difficult to describe by patients, and is difficult to diagnose and treat by practitioners. Akathisia is usually grouped with extrapyramidal movement disorders (ie, movement disorders that originate outside the pyramidal or corticospinal tracts and generally involve the basal ganglia). Yet, it can present as a purely subjective clinical complaint, without overt movement abnormalities. It has been subtyped into acute, subacute, chronic, tardive, withdrawal-related, and "pseudo" forms, although the distinction between many of these is unclear. It is therefore not surprising that akathisia is generally either underdiagnosed or misdiagnosed, which is a serious problem because it can lead to such adverse outcomes as poor adherence to medications, exacerbation of psychiatric symptoms, and, in some cases, aggression, violence, and suicide. In this article, we will attempt to address some of the confusion surrounding the condition, its relationship to other disorders, and differential diagnosis, as well as treatment alternatives.

Novel 2-Acetamido-2-ylidene-4-imidazole Derivatives (El-Saghier Reaction): Green Synthesis, Biological Assessment, and Molecular Docking.

El-Saghier reaction is the novel, general, and green reaction of various amines with ethyl cyanoacetate and ethyl glycinate hydrochloride. A new series of imidazolidin-4-ones and bis-N-(alkyl/aryl) imidazolidin-4-ones was synthesized in a sequential, one-pot procedure under neat conditions for 2 h at 70 °C. Excellent high yields (90-98%) were achieved in a short period of time while avoiding issues related to the hazardous solvents utilized (cost, safety, and pollution). The spectrum analyses and elemental data of the newly synthesized compounds helped us to clarify their structures. The obtained compounds were tested for antibacterial activity in vitro and compared to the standard antibiotic chloramphenicol as the standard, measuring the inhibition zone (nm) and activity index (%). With an antibacterial percentage value of 80.0 against Escherichia coli, N,N'-(propane-1,3-diyl) bis(2-(4-oxo-4,5-dihydro-1H-imidazole-2-yl) acetamide) proved to be the most effective. Antimicrobial activity was confirmed by a molecular docking investigation to investigate how chemicals bind to the bacterial FabH-CoA complex in E. coli (PDB ID: 1HNJ).

Venous thromboembolism risk and prophylaxis in the acute hospital care setting: report from the ENDORSE study in Egypt.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of hospital-related deaths worldwide. However, the proportion of patients at risk of VTE who receive appropriate prophylaxis in Egypt is unknown. The ENDORSE study in Egypt is part of a global initiative to uncover the incidence of high-risk surgical and medical patients and determine what proportion of these patients receive appropriate VTE prophylaxis. METHODS: Ten Egyptian hospitals participated in this observational study, enrolling all surgical and medical patients that met the study criteria. This resulted in a cohort of 1,008 patients in acute care facilities who underwent a retrospective chart review. Each patient's VTE risk status and the presence or absence of appropriate prophylactic care was assessed according to the American College of Chest Physicians (ACCP) guidelines 2004. RESULTS: Of the 1,008 patients enrolled, 395 (39.2%) were found to be at high-risk for VTE. Overall, 227 surgical patients were at high-risk, although only 80 (35.2%) received ACCP-recommended prophylaxis. Similarly, 55/268 (32.75%) of high-risk medical patients received appropriate VTE prophylaxis. Low molecular weight heparin was the most commonly used anticoagulant, while mechanical prophylactic use was quite low (1.5%) in high-risk patients. CONCLUSIONS: In Egypt, more than one-third of all patients hospitalized for surgery or acute medical conditions are at high risk for developing VTE. However, only a small fraction of these patients receive appropriate VTE prophylaxis. Corrective measures are necessary for preventing VTE morbidity and mortality in these high risk patients.

Development of a Cardiac Anesthesia Tool (CAT) to Predict Intensive Care Unit (ICU) Admission for Pediatric Cardiac Patients Undergoing Non-cardiac Surgery: A Retrospective Cohort Study.

Background and aim: of the work: Pediatric cardiac patients often undergo non-cardiac surgical procedures and many of these patients would require intensive care unit admission, but can we predict the need for ICU admission in pediatric cardiac patients undergoing non-cardiac procedures. Numerous preoperative and intraoperative variables were strongly associated with ICU admission. Given the variations in the underlying cardiac physiology and the diversity of noncardiac surgical procedures along with the scarce predictive clinical tools, we aimed to develop a simple and practical tool to predict the need for ICU admission in pediatric cardiac patients undergoing non-cardiac procedures. Material and methods: This is a retrospective study, where all files of pediatric cardiac patients who underwent noncardiac surgical procedures from January 1, 2015, to December 31, 2019, were reviewed. We retrieved details of the preoperative and intraoperative variables including age, weight, comorbid conditions, and underlying cardiac physiology. The primary outcome was the need for ICU admission. We performed multiple logistic regression analyses and analyses of the area under receiver operating characteristics (ROC) curves to develop a predictive tool. Results: In total, 519 patients were included. The mean age and weight were 4.6 ± 3.4 year and 16 ± 13 Kg respectively. A small proportion (n = 90, 17%) required ICU admission. Statistically, there was strong association between each of American society of anesthesiologist's physical status (ASA-PS) class III and IV, difficult intubation, operative time more than 2 hours, requirement of transfusion and the failure of a deliberately planned extubation and ICU admission. Additional analysis was done to develop a Cardiac Anesthesia Tool (CAT) based on the weight of each variable derived from the regression coefficient. The CAT list is composed of the ASA-PS, operative time, and requirement of transfusion, difficult intubation and the failure of deliberately planned extubation. The minimum score is zero and the maximum is eight. The probability of ICU admission is proportional to the score. Conclusion: CAT is a practical and simple clinical tool to predict the need for ICU admission based on simple additive score. We propose using this tool for pediatric cardiac patients undergoing non-cardiac procedure.

Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection.

The conversion of auditory and vestibular stimuli into electrical signals is initiated by force transmitted to a mechanotransduction channel through the tip link, a double stranded protein filament held together by two adhesion bonds in the middle. Although thought to form a relatively static structure, the dynamics of the tip-link connection has not been measured. Here, we biophysically characterize the strength of the tip-link connection at single-molecule resolution. We show that a single tip-link bond is more mechanically stable relative to classic cadherins, and our data indicate that the double stranded tip-link connection is stabilized by single strand rebinding facilitated by strong cis-dimerization domains. The measured lifetime of seconds suggests the tip-link is far more dynamic than previously thought. We also show how Ca2+ alters tip-link lifetime through elastic modulation and reveal the mechanical phenotype of a hereditary deafness mutation. Together, these data show how the tip link is likely to function during mechanical stimuli.