A spontaneous coronary artery dissection (SCAD) during the postpartum period is a serious medical emergency and the most important non-atherosclerotic cause of coronary artery disease (CAD) in this population. While conservative management is recommended in most SCAD scenarios, cases complicated by hemodynamic instability or cardiogenic shock are particularly challenging and might be amenable only with invasive percutaneous or cardiothoracic surgical management. Herein, we present a case of a 35-year-old otherwise healthy woman that suffered an intense emotional stress event and was subsequently admitted with crushing chest pain to the emergency department. The initial electrocardiogram showed dynamic changes suggesting anterolateral ST-elevation myocardial infarction. She gave birth to a healthy child 3 months before the current presentation. Diagnostic angiography found no occlusive CAD but instead an extensive intramural hematoma originating from the left main artery dissection and extending to the whole left coronary circulation was observed. Hemodynamic instability and hypotension soon followed, and the patient went into cardiogenic shock. The heart team opted for conservative and supportive intensive care management without surgical or percutaneous intervention. This decision ultimately led to the successful extubation of the patient and the achievement of hemodynamic stability. The patient was eventually safely discharged home without any permanent disability. Spontaneous coronary artery dissection (SCAD) is an important non-atherosclerotic cause of acute coronary syndrome (ACS), especially among younger female patients without traditional cardiovascular risk factors. The latest data show that extra coronary arteriopathies, such as fibromuscular dysplasia, might be associated with a predilection for SCAD . SCAD isAngiographic findings of SCAD are characterized by the presence of false lumen due to intimal disruption  and formation of intramural hematoma due to bleeding originating from vasa vasorum. These changes are often accompanied with periadventitial inflammation with eosinophil predominance . AdvanceIn the acute and subacute setting, most patients with SCAD can be managed conservatively, since the dissected vessel usually self-repairs and spontaneously heals over a few weeks or months. In contrast to this, results of revascularization with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are suboptimal and are often associated with an increased rate of complications and adverse in-hospital events compared to optimal conservative management . HoweverHerein, we present a case of a young woman without cardiovascular risk factors diagnosed with SCAD during the delayed postpartum period whose clinical presentation and symptoms were provoked by intense emotional stress. Furthermore, her SCAD case had several high-risk features, such as the dissection of the left main stem propagating to the whole left coronary artery tree and the onset of hemodynamic instability with progression to cardiogenic shock. Finally, we show how careful selection of conservative management yielded the successful recovery of the patient in this complicated SCAD scenario.A 35-year-old female without known chronic illnesses, allergies, and cardiovascular risk factors was admitted to the emergency department with symptoms of crushing substernal chest pain with propagation to the throat and accompanied with electrocardiographic signs of anterolateral ST-segment elevation myocardial infarction (STEMI) . The important differential diagnosis of STEMI is provided in The patient experienced significant emotional distress due to a family feud shortly before the onset of symptoms and was in a delayed postpartum period, as she gave healthy childbirth 3 months earlier. Physical examination revealed no heart murmurs upon auscultation and no pathological breathing sounds. Furthermore, she was afebrile, with a heart rate of 104 beats per minute, peripheral saturation of 93% on pulse oximetry, and initial arterial blood pressure of 103/73 mmHg. She had normally palpable peripheral pulses on both sides. The patient was immediately transferred to the coronary care unit (CCU) for STEMI pathway, and she was perorally loaded with 300 mg of acetylsalicylic acid and 180 mg of ticagrelor along with 5000 IU of unfractionated heparin intravenously. Her initial laboratory workup revealed slightly elevated D-dimer levels  with high-sensitivity cardiac troponin I (hs-cTnI) and C-reactive protein within normal limits .She was immediately transferred to cath lab from CCU, and an emergent coronary angiography was performed by intubating a right coronary artery (RCA), with the 6F diagnostic catheter showing a dominant high-caliber vessel giving off posterolateral (PL) and posterodescending (PD) branches with normal TIMI-3 flow and no signs of obstructive coronary disease .The catheter was then exchanged, and the left coronary artery (LCA) was later intubated. This revealed a gracile left coronary circulation characterized by the narrow-caliber LM that was prone to spasm and a narrow caliber LAD that featured a slow flow as well as the angiographical picture of an intramural hematoma due to a spontaneous coronary artery dissection (SCAD) originating from the left main stem A. A diffMovies depicting the selective coronary intubation of RCA and LCA are shown in The patient was, therefore, transferred to the cardiosurgical intensive care unit (CICU) for further clinical evaluation and potential provision of extracorporeal membrane oxygenation (ECMO). Her initial hs-cTnI level at admission to CICU was 132,470 ng/L, while her urine output was about 500 mL. Advanced critical care measures were continued, with mechanical ventilation and the concomitant placement of arterial line, central venous catheter, and pulmonary catheter. She was placed on levosimendan and noradrenaline drip, while supportive treatment included analgesia and sedation in continuous infusion with stress ulcer prophylaxis and broad-spectrum antibiotic administration. The patient remained hemodynamically stable, and on the next day she was successfully weaned from mechanical ventilation and was able to achieve adequate oxygen saturation on ambient air. Similarly, after vasopressor and inotrope support was discontinued, she was able to sustain normal hemodynamics. Her hs-cTnI value at discharge from CICU was 29,821 ng/L. She was then transferred to the post-intensive care unit, with peroral therapy including amoxicillin-clavulanate, pantoprazole, acetylsalicylic acid, clopidogrel, bisoprolol, atorvastatin, furosemide, and bromocriptine with the administration of subcutaneous enoxaparin in prophylactic antithrombotic dose.The patient’s follow-up chest X-ray was performed, which showed no acute infiltrates and was otherwise normal, except for the small residual pleural effusion in the right costodiaphragmatic recess. Upon stabilization of her clinical condition and 11 days after the index event, a follow-up coronary angiography was performed, which showed normal LM, LAD, and RCA with established TIMI-3 flow, while there was an intermediate 50% stenosis found in the circumflex artery for which a decision was made to treat conservatively. In-hospital transthoracic echocardiographic examination prior to discharge showed an ischemic remodeling of the left ventricle (LV) with residual distal septal, anteroapical, and apical hypokinesia with grade 2 diastolic dysfunction and normal systolic function of the right ventricle. The LV ejection fraction (LVEF) was mildly reduced (45% to 50%). No septal shunting was observed, and valvular function was normal.The total length of the patient’s hospital stay was 17 days, and she was discharged in a stable clinical condition. Her treatment at discharge consisted of acetylsalicylic acid (100 mg OD), clopidogrel (75 mg OD for the next 12 months), pantoprazole (20 mg OD), atorvastatin (80 mg OD), and bisoprolol (1.25 mg OD). In the last outpatient follow-up visit, her cardiac systolic function improved to >50%; however, no repeat angiographies were later performed at our institution. Similarly, details on further fibromuscular dysplasia work-up were unavailable in our records.From the pathophysiological perspective, SCAD is largely caused by underlying non-atherosclerotic systemic arteriopathies, such as fibromuscular dysplasia (FMD), while it is often precipitated by emotional or physical stressors and circumstances, such as labor and delivery . PathohiA Canadian SCAD cohort study encompassing 22 centers in North America showed that women experiencing SCAD during peripartum have worse in-hospital outcomes and more severe/complex lesions than their non-peripartum counterparts, while emotional and physical stress were reported as precipitants in 50.3% and 28.9% of cases, respectively . The vasIn this case report, an otherwise healthy female presented with SCAD precipitated by intense emotional stress during the late postpartum period (6 weeks to 12 months), with the dissection originating from the left main stem and complicated by cardiogenic shock. Although high-risk features, such as the presence of hemodynamic instability, involvement of the left main stem, or proximal LAD or extensive length of the lesion, might be legitimate triggers for percutaneous or surgical revascularization, herein we showed how conservative management of such complex clinical conditions yielded a favorable outcome without further neurological or cardiovascular sequelae. Of importance, even with technically successful PCI, important complications such as the extension of dissection might occur in 25% to 60% of cases, with long-term patency of the vessel achieved in only about a third of all such cases . SimilarRecent data suggest that conservative management in SCAD should prevail in most cases, as such an approach has been associated with lower target vessel revascularization rates and non-inferior clinical outcomes compared to invasive management ,18. It sFinally, patients with SCAD, predominantly women, should be advised to perform further work-up for associated conditions or factors. These include FMD, as recent studies implicate the close genetic association between these two entities, while other vascular territories should also be investigated as per clinical indication since SCAD is associated with a high prevalence of extracoronary dissections, inherited arteriopathies, connective tissue disorders, and aneurysms ,19,20.SCAD is an important nonatherosclerotic cause of ACS in women of childbearing age without traditional cardiovascular risk factors and should raise clinical suspicion particularly if the patient’s history has a context of intense psychophysical stress that occurs during pregnancy or in the postpartum period. Here, we reported a case in which SCAD extending from the left main stem further complicated by hemodynamic instability and cardiogenic shock was successfully managed conservatively in a female patient during the late postpartum period by utilizing a multidisciplinary “heart team” approach. These sorts of patients should be carefully monitored through regular cardiology referrals, and a low threshold for genetic testing and exclusion of other vascular abnormalities should be individually employed by adhering to postulates of precision medicine.


Carbon monoxide has been recognized relatively recently as signaling molecule, and only very few dedicated natural CO sensor proteins have been identified so far. These include in particular heme-based transcription factors: the bacterial sensor proteins CooA and RcoM. In these 6-coordinated systems, exchange between an internal protein residue and CO as a heme ligand in the sensor domain affects the properties of the DNA-binding domain. Using light to dissociate heme-ligand bonds can in principle initiate this switching process. We review the efforts to use this method to investigate early processes in ligand switching and signaling, with an emphasis on the CO-“trappingˮ properties of the heme cavity. These features are unusual for most heme proteins, but common for heme-based CO sensors. This coIn the present mini-review we will mainly focus on the two unambiguously identified bacterial systems. As mentioned above, in these heme-based sensor proteins, CO interacts with the heme iron and its binding to the heme Fe(II) complex changes the heme coordination state. Establishing the intra-protein pathway in which heme coordination changes lead to functional changes in the remote DNA-binding effector domain is of high interest. For the structurally best characterized sensor CooA, this has been studied for instance using structural modeling , structu2) or internal amino acid residues can be followed.In principle, time-resolved spectroscopic or structural methods may allow characterizing functional switching intermediates and pathways following dissociation of the heme-ligand axial bond upon light absorption by the heme. Although this photochemical phenomenon does not correspond to any solidly documented functional property, it is widely used to provoke heme-ligand dissociation using short light pulses, down to the femtosecond timescale, during time-resolved optical spectroscopy experiments . In thisIn non-sensor heme-proteins like myoglobin and hemoglobin, photo-dissociated CO [photochemical quantum yield close to unity ] initialRhodospirillum rubrum, where it activates the transcription of genes required for the anaerobic oxidation of CO to CO2  CO binding to the CooA dimer occurs with modest affinity, with Km values in the order of 1 μM . ExcitatThe very high CO geminate recombination yield complicates the use of flash photolysis to study the switching mechanism directly (see below). Notwithstanding this limitation, the kinetics can give more indirect information on allosteric interactions allowing switching. The heterogeneity in the rebinding kinetics has been ascribed to conformational heterogeneity of the heme pocket . BindingWhereas time-resolved experiments on ultrafast timescales necessarily are performed under low excitation conditions (<< 1 excitation/heme), on longer time scales longer and intense excitation pulses can be used that allow multiple excitations . Under Burkholderia xenovorans that is capable of oxidizing carbon monoxide , pointing at bidirectional allosteric interactions between the two domains .Furthermore, upon addition of DNA to full-length RcoM-2, a very small but sizeable acceleration of the rebinding occurred, a qualitatively similar effect as observed in CooA (see above), and also ascribed to a rigidification of the heme domain . Yet, veTo date, no attempts to study processes occurring on longer time scales after CO dissociation from RcoM proteins have been reported, presumably related to the prohibitively low escape rate of CO. Efforts to understand the molecular switching mechanism, which might be studied in real time on the timescale >∼100 ms by mixing techniques starting from the fully reduced system , must fucor (CO resistance) gene is strongly implicated in the sensitivity of mycobacteria for CO  CO sensors. First, the product of the a for CO  and therhis heme . Stronglhis heme , but witel SUR2A   can hardly escape the heme pocket. On the molecular level, this property is unusual for CO, as its binding to heme requires near-perpendicular orientation of the heme-CO system. Thus dissociated CO is expected to have very limited conformational freedom in the heme pockets of these sensors. Further transient infrared and ultimately transient crystallographic studies may clarify the molecular mechanisms underlying this property. On the functional level, these properties help to reduce effective CO dissociation rates and therewith adapt the response time of the sensor to physiologically relevant times, smoothening out the effect of fast environmental fluctuations . In thissor FixL  and the sor FixL .


The mechanism of telomere elongation in T cells is not clear. A recent study revealed that memory CD4Maintaining telomere length is important for preventing T cells from undergoing senescence . Upon anNature Cell Biology by Lanna and colleagues [+ T cells  were able to elongate their telomeres by acquiring telomeres from vesicles following immunological synapse formation in the presence of an antigen pool . Telomere elongation was independent of telomerase, which was confirmed by the use of telomerase-deficient T cells. Using DNA labeling and telomere tracking, the researchers found that the release of telomere vesicles and telomeric DNA-containing vesicles from APCs depended on TCR-mediated activation of APCs and calcium flux in donor APCs. Surprisingly, fluorescently labeled telomeric DNA from APC was captured by recipient T cells via vesicle transfer. However, telomere extension in T cells did not require TCR/MHC II activation. These findings suggest a new mechanism involving telomere vesicle transfer from donor APCs to T cells that maintains their telomere length and protects them from senescence.In a recent study published in lleagues , CD4+ T To reveal the mechanism by which the APC donor cells transferred telomeres to recipient T cells, the investigators examined the content of the telomere vesicles. The telomere vesicles contained a critical telomere trimming factor, TZAP. The expression and activation of TZAP in APCs were found to be increased upon ionomycin activation or after immune synapse formation. TZAP was necessary for cleavage of telomeric repeat sequences and subsequent encapsulation into vesicles for transfer to T cells Fig. , as vesiLanna and colleagues showed that telomere transfer also had protective effects against T-cell aging. The researchers found that functional telomere vesicles containing TZAP and Rad51 from activated APCs prevented T cells from undergoing senescence in vitro. T cells with ultrashort telomeres became senescent, whereas those that acquired telomeres from activated APCs. Furthermore, telomere transfer preserved T-cell senescent memory, which was strongly reduced in senescent cells. Moreover, naive T cells were induced to differentiate into stem-like T cells and central memory T cells. However, not all T cells had a high capacity to acquire telomeres from activated APCs.+ T cells acquired telomeres from APCs primed with OVA. The researchers confirmed that Rad51 was required for telomere vesicle transfer and telomere recombination in T cells. After long-term vaccination, CD4+ T cells acquiring telomeres expanded more than those that did not acquire telomeres or when Rad51 was depleted. This implies that telomere transfer promotes strengthening of immunological memory. To examine the immune defense potential of these memory cells, mice were challenged with FLUAD influenza vaccination, and the CD4+ T-cell memory response was measured. Telomere transfer to T cells protected mice from long-term influenza challenge rather than acute influenza infection, confirming that telomere transfer in T cells induces chromosome extension to provide long-lasting immune protection.The researchers investigated the telomere vesicle transfer system in vivo via OT-II ovalbumin antigen-specific challenge in mice. In animals injected with OVA, CD4In conclusion, telomere shortening is a feature of senescent T cells that leads to defects in proliferation and effector functions. The findings from this work provide a new mechanism of T-cell telomere elongation involving telomere transfer from APCs, which can prevent T-cell senescence without telomerase. However, it is a mystery why only some rare types of T cells have a high capacity to acquire telomere vesicles. Further studies are needed to reveal the mechanisms of telomere release and vesicle transfer to T cells. Moreover, future research should focus on whether the control and regulation of functional telomere release and acquisition can rescue additional types of immune cells from aging.


Flexible electronic textiles are the future of wearable technology with a diverse application potential inspired by the Internet of Things (IoT) to improve all aspects of wearer life by replacing traditional bulky, rigid, and uncomfortable wearable electronics. The inherently prominent characteristics exhibited by textile substrates make them ideal candidates for designing user-friendly wearable electronic textiles for high-end variant applications. Textile substrates  combined with nanostructured electroactive materials provide a universal pathway for the researcher to construct advanced wearable electronics compatible with the human body and other circumstances. However, e-textiles are found to be vulnerable to physical deformation induced during repeated wash and wear. Thus, e-textiles need to be robust enough to withstand such challenges involved in designing a reliable product and require more attention for substantial advancement in stability and washability. As a step toward reliable devices, we present this comprehensive review of the state-of-the-art advances in substrate geometries, modification, fabrication, and standardized washing strategies to predict a roadmap toward sustainability. Furthermore, current challenges, opportunities, and future aspects of durable e-textiles development are envisioned to provide a conclusive pathway for researchers to conduct advanced studies. Wearable technologies have created a universal platform for innovation and advancement towards the 4th industrial revolution in versatile areas to connect the virtual world with reality. Wearable electronics can facilitate human quality of life in all possible aspects by properly monitoring different actions in real time . HoweverTo date, many high-performance e-textiles with improved performance are reported ,105,106,So far, various review articles have been published ,118,119 E-textiles are the traditional textiles of different hierarchies embedded with multifunctional nanomaterials to be utilized in different areas, for instance, human motion monitoring, i.e., joints bending, walking, running, facial expression, vocal vibration, pulse, breathing, laughing, etc. a, healthFiber is the first phase of the textile hierarchy which serves as the basic construction block of e-textiles, conductivity at the fiber level facilitates seamless integration of electronic function for the next generation of miniature devices. Nanomaterials with fiber components are expected to exhibit strong adhesion at the molecular level with improved electrical properties, mechanical properties , durability , comfort, etc. Fiber materials can be made of natural  or synthetic resources. Synthetic fibers  are manufactured from polymer solution following different electrospinning processes. Traditional cellulosic textile fiber can be functionalized in the typical yarn manufacturing phase (sliver/roving) and subsequently spun into yarn.0 < 1.3) in resistance for 8 consecutive wash cycles while the CNT-coated cotton yarn was vulnerable and could barely satisfy such circumstances  via the dip-coating technique. The roving modified ring-spun yarn can withstand repeated bending (180°) of 100 cycles with nominal resistance change (<10%), optimum stability for abrasion (up to 400 cycles), and displayed washability with minimal changes (R/Rmstances a 147]. . 0 < 1.3mstances b 148]..0 < 1.3)The functional protein fibers  are mostly produced by electrospinning (dry/wet/bio-mimetic) processes, which are accused of damaging the micro and nanostructures of the fiber. Thus, directly modified silkworm spinning is admired for keeping the inherent properties of the fiber intact. Wang et al. developed a functional native silk fiber via the continuous force-reeling and dip-coating technique  directly from Antheraea pernyi (A. pernyi) silkworms (known as Chinese Oak Tussah silkworms and having a similar primary structure to spider silk ). The fuFibrous materials are highly flexible to retain any shape as desired at the pre-stage of e-textiles development. Distinctive fiber architecture often offers better performance than regular configuration. A recent study reported a 3D helical fiber-shaped sensor with improved sensing performance (<1% detection limit), superior stability , and washability  than regular fiber-shaped triboelectric nanogenerators (TENG). The helical fiber was obtained from the multiaxial winding of two core-shell braided fibers  followed by alternative winding on a stretchable fiber substrate d 152]. . 152]. TFibers of all categories in the form of aqueous suspension synchronized with nanomaterials are of great interest and are produced through electrospinning, printing, and other solution-based methods for the development of e-textiles with long-lasting stability and durability. Liao et al. developed large-scale continuous fiber (~1500 km) lithium-ion batteries using the solution-extrusion method that displayed excellent stability  and durability (<10% loss of capacity) against different hostile events, i.e., water immersion, heavy pressure, washing, and hammer strike f 154]. . 154]. CIn general, yarn is a continuous assembly of fibers or filaments twisted/bonded together for improved mechanical properties, i.e., strength, flexibility, etc. Electronically active yarn can be constructed in different ways, i.e., by converting conductive fibers/filaments into yarn, imparting functionality at the yarn stage, and synthetic spinning of polymeric solution with conductive filler. The conductive yarn plays an important role in the architecture of the wearable system by interconnecting different units within the system and facilitates the fabrication of mass-scale electronic devices in the form of fabric or garments. The conductive yarn must be robust enough to withstand different physical, chemical, mechanical, and other hostile stimuli involved in daily use. The combination of nanomaterials at the yarn level expedites functionality-induced performance enhancement because of the increased contact surface area.OC) ~ 34.5 V, short circuit current (ISC) ~ 60 nA, short circuit charge (QSC) ~ 12 nC) was superior to that of other TENGs  and showed better cyclic stability up to 3000 contact separation cycles [−1) and durability. A thermoelectric energy harvester was designed by sewing the electronic yarn into a multilayered fabric. No resistance changes were observed for the device after repeated bending (1000 cycles) and machine washing  leads to notable changes)  made of textiles (fabric made of Ag-coated nylon yarn) with differently coated triboelectric material (Polydimethylsiloxane-PDMS). It was observed that yarn-coated TENG outperforms other TENGs  in output due to higher triboelectric contact surface area. The electrical output of the yarn-coated TENG  b 157]..OC) ~ 34The core-sheath yarn structure holds great promise toward durability by combining nanoparticles in the core securely and preventing it from decay. Zeng et al. developed a highly durable wearable strain sensor based on a spandex dip-coated CNT core and cotton fiber sheath yarn. The sensor showed promising stability under 20% cyclic stress and ultrasonic washability  against water, acid, and alkali solution . The selPre-stretching of the yarn (in case of stretchable substrate) prior to nanomaterial incorporation leads to the formation of a wrinkled surface, which allows the electroconductive properties to be more stable against mechanical deformation by a gradual release of the surface wrinkles upon stretching. Zhang et al. developed an underwater wireless charging patch made of pre-stretched polyurethane filament spray-coated with multi-walled carbon nanotubes (MWCNT), silver nanowire (AgNW), and styrene-(ethylene-butylene)-styrene (SEB), respectively. The device could withstand more than 100,000 stretching cycles under 50% strain and displayed good washability (up to ten cycles without significant resistance change) e 162]..162].−2. Furthermore, the yarn could withstand ten repeated washing cycles without a significant change in RMS power output. The slight resistance change observed in between five and ten washing cycles may be due to the small amount of water residue inside or slight damage due to washing  spun into a continuous filament directly or the spinning of functional nanofiber around a conductive filament. A unique triboelectric yarn was manufactured via electrospinning of Poly(vinylidene fluoride) (PVDF) nanofiber around a CNT filament. The device showed phenomenal stability  without a decrease in RMS (root mean square) power output; instead, a 33% increase in energy harvesting capability was observed with a peak power density of 20.7 μW cm washing f. Howeve washing g 164]..−2. FurtDifferent yarn-shaped e-textiles and their endurance properties are presented in Fabric is the final phase of the textile hierarchy that enables mass-scale development of the e-textile component by either integrating it as an individual functional unit in the clothing or converting it into a complete wearable garment. Washable electronic fabrics can be obtained in many ways, such as by knitting or weaving the electroconductive yarn, by electrospinning an electronic nanofiber mat/film (nonwoven), or by direct incorporation of nanomaterials with them, etc. Satharasinghe et al. revealed that the washability assessment of photodiode-embedded yarns in both the e-yarn and the fabric form showed distinctive performance. For the e-yarn, the first failure was observed after 5 washing cycles and only 20% of them survived 25 washing cycles, while the fabric remained unaffected up to 15 cycles and 60% of them fully functioned after 25 cycles . The e-yThe type, structure, and composition of the fabric affect not only the mechanical performance but also its operational longevity when combined with nanoparticles. Salavagione et al. demonstrated that different types of woven fabrics  have variant washability when coated with graphene/elastomer composite ink via hand printing. Although all samples showed stable performance (no change in resistance) against repeated folding (1000 cycles), in the case of washing, surprisingly, nylon and acrylic fabric had superiority  over others (significant loss of resistance) . In a di−2 at 10 MΩ load) /silver nanowires (AgNWs) that revealed long-term cyclic stability (86% capacitance retention) under 10,000 operation cycles and exceptional aqueous wash durability (100 times) within acceptable relative resistance change (40% increase) up to 80 cycles and remained stable afterward a 179]. . 179]. FMΩ load) b. Such oMΩ load) c. The apQi et al. developed a wearable e-textiles pressure sensor by plain weaving of CNT embedded electrospun nanofiber yarn. The device had superior stability with insignifcant resistance change against 10,000 operation cycles under 0.1 N pressure. Besides, no obvious change in electrical response was observed after 1 h of continuous water washing d 182]. . 182]. TOC, ISC) (−2) 3.5 times higher than that of the planar substrate (PET) based supercapacitor /polyethylene (PE) fiber-based 3D nonwoven fabric coated with multi-walled carbon nanotubes (MWCNT). The sensor showed excellent operational stability against 5000 compression/release cycles with a constant relative resistance change (RCR) pattern. The initial slight drop in RCR may be attributed to slight plastic deformation of the fiber under pressure. Furthermore, the pressure sensor could withstand 40 h of vigorous washing with an acceptable change in RCR (8.4%) f 185]. . 185]. DOC, ISC) g 186]. . OC, ISCapacitor h 187]..OC, ISC)Different fabric-shaped e-textiles and their endurance properties are presented in The wearable electronic system may involve the integration of different multifunctional, stimuli-responsive electronic textile components interconnected with other circuit elements for operation a. IntercEom et al. demonstrated highly conductive (1300 S/cm) and stretchable ionic liquid/poly (vinylidene fluoride-co-hexafluoropropylene) modified dry spun CNT fibers for interconnections in wearable e-textiles. A commercial sewing machine was used to design a variety of patterns on a fabric. The linear interconnection pattern showed the lowest electrical resistance (88.9 Ω) while an increasing trend was observed for more complex patterns, respectively. The CNT fiber showed optimal durability under 30 min of domestic washing with a slight loss of conductivity (1015 S/cm). The fiber interconnection with the serpentine pattern also displayed excellent cyclic stability under 50% strain for 1000 stretch-release cycles with only a 2.9% variation in relative resistance b 200]. . 200]. KKomolafe et al. reported filament circuits containing LEDs and other components along with connection wires attached by using anisotropic conductive paste and stencil printed solder paste, respectively. The joint between the track and the bond pad was the main failure point in bending for both filleted and unfilleted filaments and could withstand similar bending cycles (62) before failure. However, glob-top encapsulation of the filaments significantly improved bending resistance and survived twice the number of cycles of the unencapsulated filaments. The filament circuits were later successfully incorporated inside a narrow pocket within the fabric during the weaving process to assess durability against repeated bending and washing. The encapsulated filaments embedded in the fabric survived 1500 repeated 90° bending cycles at a bending radius of 1 cm. The glob-top encapsulation resulted in improved durability but could not provide full protection for a prolonged duration, as the failure point migrates toward unencapsulated areas of the filaments. Therefore, encapsulation of the entire filament could provide a reliable performance output upon mechanical stress. The unencapsulated filament showed poor washability and after only five cycles interfacial crack and dendritic stress on the circuit were noticed. Moreover, the fully encapsulated filament with thermally molded Kapton within the fabric survived up to 45 domestic washing cycles f 204]. . 204]. KInterconnections are an integral part of the wearable e-textile assembly to satisfy the customer’s reliability in data acquisition and analysis. Thus, the interconnection lines must be flawless and exhibit the same degree of robustness as the whole wearable system. Flexible interconnect materials, connection patterns, and joining techniques all must be in synchronization to achieve the highest possible endurance throughout the entire life cycle of the wearable garments.Although different textile structures with variant incorporation techniques with a wide range of nanomaterial selection windows have been investigated, poor durability of the e-textiles is still challenging and may be linked with the mismatch of properties between the substrate and electroactive materials. Thus, to retain the functionality even in a hostile environment, the researcher often adopts different durability enhancement strategies to be employed in various stages, i.e., pre-treatment, during the process, post-treatment, etc. The following section of the article briefly describes numerous techniques aimed at the development of durable e-textiles.3+ (0 (%) ~ 0%) and washing  < 10%) while the fabric without PDA was vulnerable to such actions (2O showed higher conductivity (~2.7 times) than the original substrate. The fabric was highly washable and could withstand repeated washing with optimal antibacterial performance (90% for S. aureus and 88% for E. coli) even after 40 cycles  and washability  due to the strong molecular interactions of the coating materials with the yarn , an amphiphilic bioprotein often termed ‘universal glue’, offers a promising pathway to enhance the durability of e-textiles by attaching different organic and inorganic materials to the substrate via hydrophobic and hydrophilic interactions . Zhou etthe yarn g 215]. . 0 ~ 2.12/C2H5/2H5OH/H2O) surface modification technique of silk fabric before coating it with RGO to develop flexible supercapacitor electrodes. Pretreatment with ternary solvent significantly improved the RGO loading on the substrate and showed 1.69 times lower sheet resistance (Ω) than without ternary solvent modification. In addition, the electrode maintained excellent capacitance retention (148%) at 10,000 charge-discharge cycles (0 ~ 2.5) and retained a 95% current interception rate for 200 repeated operations (voltage on-off). Furthermore, the superior washability  of the device can be attributed to increased adhesion due to the presence of the TA/APTES anchor layer between the fabric surface and Cu molecules /multi-walled carbon nanotube (MWCNT) ink. The excellent stability (0.8% resistance after 1000 bending cycles) and washability (only 2.1% increase in resistance after 20 wash cycles) of the electrode are attributed to increased adhesion due to the abundance of carbonyl and amino functional groups present in the TPU polymer matrix, which initiates direct bonding of MWCNT molecules with the polyamide fabric surface . Li et aPlasma-induced surface modification of textile substrates can substantially enhance the adhesion of functional nanomaterials for higher conductivity and endurance. Deogaonkar (2020) demonstrated that dielectric barrier discharge-atmospheric pressure plasma  pretreatment of the polyester cotton blend fabric significantly improved the binding strength of the Polypyrrole (PPy) coating with the substrate, resulting in a higher conductivity (75 Ω/Sq.) than that of the untreated fabric (210 Ω/Sq.). The surface resistivity of the modified sample experienced a minor increase  after 2500 abrasion cycles, while the unmodified fabric was not competent  k 222]. . 222]. The encapsulation of the e-textiles is commonly adopted to elevate endurance behavior and is performed mainly in the post-treatment phase. The thin layer of different encapsulating material provides versatile protection for the conductive pattern to be firmly anchored to the substrate and remains unaffected or less affected by the mechanical stress involved in daily use. It has been well established that the encapsulation of e-textiles provides better performance in terms of stability, flexibility, durability, washability, etc.Islam et al. constructed highly conductive (49 Ω/cm) and durable e-textiles by screen printing cotton fabric with graphene ink followed by fine encapsulation of the conductive pattern with PU-based encapsulant (PE773). The thin PE773 layer ensures the graphene ink adheres firmly to the substrate surface and protects it from the different hostile stimuli involved in regular wash and wear. The electrical resistance of the encapsulated fabric maintained acceptable changes  for ten home laundry cycles, while the bare printed fabric suffered a ten times increase in resistance (49 Ω/cm to 734.0 Ω/cm) for the same amount of washing. The original surface morphology of the encapsulated fabric was retained during wash cycles, but substantial damage and removal of the graphene flake were observed for the bared fabric. In addition, the encapsulated sample showed excellent repeatability in bending (forward direction) and compression (backward direction) compared to the unencapsulated sample. The excellent stability of the device (supercapacitor) was further confirmed by higher capacitance retention (95%) after 10,000 cycles of operation (charge-discharge) a 235]..235].0 ~ 10 for 190 min ultrasonic wash) of the encapsulated sensor compared to that of the unencapsulated yarn  validates the need for encapsulation to retain the electrical functionalities of e-textiles for the long term  encapsulated Spandex/Poly  (PVA)/MXene (SPMP) intelligent fiber connected with a waterproof electronic system for the wireless monitoring of underwater hand gestures. The resistance of the encapsulated device remained almost unchanged for ten washing cycles, while the unencapsulated sample became nonconductive (about 1 GΩ) only after six washing cycles. The excellent underwater reliability of the PDMS coating was confirmed by no change in resistance for 1 h of water immersion compared to bare fiber (20% increase in resistance) for the same period. Furthermore, the encapsulated fiber showed excellent durability and maintained an unchanged resistance profile for 500 stretch-release cycles compared to the unencapsulated fiber, which could hardly withstand such cyclic deformations b 236]. . 236]. Tong term d 238]..0 ~ 10 f0 (%) ~ 1.6%) for periodic operations (50 cycles) in water and air. The absence of an encapsulation layer resulted in a greater variation in resistance (ΔR/R0 ~ 300%) for the same level of underwater/air operations  integrated onto fabric via the embroidery technique followed by encapsulation with Ecoflex and TPU laminating. The Ecoflex-coated supercapacitors suffered the moderate loss of capacitance, but the lamination of TPU as an additional protection layer over Ecoflex-coated samples ensured superior washability with no obvious change in capacitance after 20 machine washing cycles. The encapsulated device could maintain 97% capacitance retention after 10,000 charge/discharge cycles and 9 h of underwater operations (1000 charge/discharge cycles). Additionally, the sample displayed remarkable stability (94% capacitance retention) when bending 4000 times e 239]. . 239]. Ierations f 162]. . 0 (%) ~erations g 240]..0 (%) ~ A typical washing cycle involves mechanical rotation or agitation of e-textiles loaded inside a domestic laundry machine in an aqueous environment containing cleaning chemicals (detergent) and the ballistic workload for a designated period at a certain temperature followed by rinsing, drum spinning, and drying. Damages or loss of functionality of e-textiles in washing could be associated with the following stresses: mechanical action  induced stress, temperature-induced thermal stress, washing media  induced stress, chemical stress , and drying stress (in case of machine drying), etc. The degree of damage in washing greatly depends on the magnitude of these stresses involved in different built-in washing programs, namely cotton, silk, delicate, delicate short, express, and wool, present in commercially available household washing machines. Besides, researchers often follow laboratory washing techniques  that are commonly used for the fastness assessment in the clothing industry. Although it is recommended to follow a specific wash protocol based on the composition  of the clothing substrate, retaining the functional properties of the e-textiles under any washing is very crucial for end-user reliability. It is expected that different washing procedures will have a distinctive impact on substrate properties, making the perception of the washability of e-textiles ambiguous among researchers. The limited number of standard washing protocols forced the researcher to adopt different available or customized methods with varying parameters to define the washability of their product.0 < 5%) and their surface morphology was completely preserved. Alternatively, the same substrate showed greater resistance variations (ΔR/R0 ~ 13%) with substantial damage to the morphology in machine washing ..271].The waterless or water-free non-aqueous washing technique holds great promise in reducing the water footprint. Ryan et al. investigated the effect of dry cleaning and machine washing on PEDOT: PSS dyed silk yarn. The yarn showed no change in electrical resistance after four cycles of domestic machine washing following the “hand wash” program, while dry cleaning with a common solvent (tetracholoroethylene) resulted in a decrease of conductivity by a factor of two m 254]. . 254]. KFrom the above discussion, it can be concluded that, depending on the type of substrate to be washed either in a dry or wet medium, the intensity of the washing damage varies. It is obvious that not all textile substrates are suitable for all wash strategies in different media. Therefore, the proper selection of the substrate, washing techniques, drying procedure, assessment criteria, and all other influential parameters must be in sync to understand and describe washability in the best way. The limited number of standardized washing and assessment protocols not only forces researchers to rely on different ideas to describe durability but also hinders the reliability of e-textiles.Durability can be termed as the ability of electronic textile components to maintain their functionality completely intact or to be affected less without compromising the comfort of the wearer when exposed to any harsh environment involving a variety of physical, chemical, and mechanical stresses. Therefore, the washability of the e-textiles is measured in the form of a relative change in their electrical output, i.e., resistance, capacitance, conductivity, voltage, current, and other performance indicators, which are attributed to changes in contact properties of nanomaterials inside or at the interface of the substrate. So far, researchers have followed different alternative standards from other fields, laboratory-scale techniques, and sometimes personally customized operations to evaluate the washability of electroactive textile components due to the limited number of standard protocols specially designed for the e-textile systems. It is undeniable that substantial progress has been achieved in recent years towards highly durable electronic textiles, but mostly from a laboratory perspective, not on a large scale. Therefore, large-scale production along with optimum endurance performance will expedite market readiness and adaptability. This is where more standards will play a great role through proper improvisation of the current achievements toward customer-reliable e-textile products. Different international institutions such as AATCC, ISO, ASTM, IEC, IPC, and others are relentlessly working to develop standards for the durability assessment protocol of electronic textiles, and some of them have even come up with a draft of their proposed standards, but they have yet to be finalized and approved. The following table summarizes different existing and upcoming standards related to e-textiles that could be beneficial to the research community working in a similar area.So far, several methods have been proposed regarding the terminology and resistance measurement of e-textiles. However, only a few already published methods are found to be dedicated to the evaluation of e-textiles’ durability under different conditions, but surprisingly, they have never been adopted by researchers to date. Besides, different standards specialized for the assessment of washability of electronic textiles are currently under development and are expected to be published shortly.The wearable electronic textile utilizes different action-driven signals in measurable quantities with exciting possibilities in versatile areas along with personalized algorithms. Flexible electronic textiles are of great interest due to their ease of use, comfort, and compatibility at the user level. As discussed in the preceding sections, it is obvious that remarkable advances have been achieved in all possible aspects, from material selection to end-user-reliant, durable e-textile product design. Researchers have explored different architectural textile assemblies with numerous innovative fabrication techniques, along with various performance enhancement strategies toward highly durable and washable wearable e-textiles. However, challenges related to stability, repeatability, durability, washability, scalability, and other process-induced flaws limit the manufacture and commercialization of customer reliable high-end wearable electronic textiles products see . TherefoReliable durability enhancement strategies are to be adopted according to the substrate, nanomaterials, and processing involved in designing the e-textiles device. Different surface modification approaches in the pre-treatment stages involving bio proteins, adhesives, cross-linkers, plasma, and other chemicals should not affect the structural integrity of the textile substrate. Bioproteins as surface modifiers are assumed to be eco-friendly, but other organic cross-linkers and bonding agents may have a higher environmental impact which cannot be unattended. Besides, post-treatments such as encapsulation of the conductive textiles with traditional encapsulants  have been proven to be effective in protecting functional properties securely, but in some cases, the lamination layer was found to be vulnerable and washed away. The encapsulation of the e-textiles should not affect the breathability, comfort, flexibility, and other inherent properties of the substrate and should be compatible with human skin.The internal wiring of the wearable components is very much crucial for the optimum performance of the entire unit but is mostly overlooked and needs more attention. Therefore, a reliable interconnection pattern among different functional units within the wearable system is essential for consistent performance, that is, data acquisition and processing without interruption. Commercial metallic wires  are mostly explored for e-textile interconnections, but they are stiff, incompatible, and may malfunction under mechanical stresses involved in the wash and wear. The failure or malfunctioning of interconnections can cause short-circuits within the system, which may pose a serious safety threat to the wearer. The flexible electroconductive fibers/yarns can be the best alternative but need to be extensively studied to improve their robustness for interconnections of various patterns. In addition, the seamless integration possibilities of the electronic components into the clothing needs broader investigation toward a robust wearable system.The scalability of electronic textiles cannot be ignored as it is also directly related to the productivity and cost of the wearable garment. Future research should be more focused on designing e-textiles beyond the laboratory environment at a large scale. Fast and facile manufacturing in combination with traditional textile processing techniques will promote mass production compared to sophisticated laboratory techniques. In addition to the higher endurance properties, the cost-effectiveness of the e-textile products should also be taken into account for potential market expansion. Moreover, inclusive simulation and modeling of current techniques  are required to achieve greater efficiency and in fact to develop new strategies.Electronic textile fabrication involves various organic or inorganic chemical treatments  in a wet medium, which can release substantial amounts of toxic elements to the environment and even pose a significant threat to the consumer such as skin irritation or carcinogenic disease when in contact with the human body. Superior washability of e-textiles will promote the lower toxic release to the body when encountered with a wet environment  during wearing. However, the risk of toxic release both to the environment and the human body is so evident that it cannot be ignored, and greater attention is required for a more sustainable and cleaner approach. As the e-textile market continues to grow, a huge burden of countless used wearable electronic textile materials is expected to be added to the current solid waste chain in the coming years. Such waste is significantly more toxic and dangerous than the solid waste generated from regular textile wear; therefore, a sustainable and eco-friendly solid E-waste management is required.Traditional domestic laundry involves a huge amount of water which may contain toxic chemicals released from e-textiles during washing, and the release of such contaminated water into the environment without further purification may have a catastrophic effect on the aquatic ecosystem. Waterless washing techniques will prevent such a level of pollution by lowering the water footprint, but may also increase the operating cost associated with alternative approaches. The environmental compatibility of dry-cleaning chemicals should be investigated. Each washing technique (wet/dry) may have a distinctive impact on the properties of the substrate; therefore, it is important to understand the washing damages for a particular type of material to be washed following a specific technique. More research should be devoted to the synchronization of different washing techniques with the type, structure, and composition of the e-textile product to be laundered to minimize washing damages.Imparting high-end functionality such as self-cleaning properties toward e-textiles will significantly reduce their washing needs, as they are expected to repel and decompose dirt through photocatalytic action. The superhydrophobic surface achieved via the coating of different chemicals is also capable of repelling or removing dirt, dust, and other impurities by rolling water droplets inspired by the lotus effect. Although various chemical compounds have been explored to exert such functionalities on e-textile components, they should be biocompatible and not affect the comfort and aesthetic properties. The environmentally friendly fluorine-free chemical reagents or polymers can replace traditional toxic hydrophobic coatings but require more research for a better understanding of the cleaning mechanism and efficiency. The self-healing property, i.e., automatic repairing of different stimuli-induced damages, will substantially improve the robustness of the e-textiles and make them more viable for practical application. Therefore, extensive research is required on the development of self-healable polymers and their performance under different hostile events throughout the life span of the e-textile components.Despite the efforts of different international organizations to standardize e-textiles’ washing protocols, researchers should focus on mitigating the underlying mismatch in materials, structure, fabrication, and product design to validate and adopt forthcoming standards widely. The stability and repeatability of the device performance cannot be ignored, which needs to be given the same priority as washability and requires standardized documentation. It is very possible that an e-textile component is claimed to be washable but may exhibit an unstable, irregular, and unreproducible performance profile for a prolonged duration. Flexible, lightweight e-textile batteries in fibrous shape are promising and are expected to replace traditional rigid and heavy power sources embedded in wearables, but the efficient power generation and management, mobility, and endurance of such flexible devices require more research attention. Moreover, future work should also address the accuracy and reliability of the data measurement of the durable wearable electronic textile system in the context of practical applications.


We quantified social mobility from childhood to later-life using data on childhood family characteristics, educational attainment, and wealth accumulation. We quantified biological aging using 3 DNAm “clocks” and 3 blood-chemistry algorithms. We observed substantial social mobility among study participants. Those who achieved upward mobility exhibited less-advanced and slower biological aging. Associations of upward mobility with less-advanced and slower aging were consistent for blood-chemistry and DNAm measures of biological aging, and were similar for men and women and for Black and White Americans . Analysis restricted to educational mobility suggested differential effects by racial identity; mediating links between educational mobility and healthy aging may be disrupted by structural racism. In contrast, mobility producing accumulation of wealth appeared to benefit White and Black Americans equally, suggesting economic intervention to reduce wealth inequality may have potential to heal disparities in healthy aging.Lower socioeconomic status is associated with faster biological aging, the gradual and progressive decline in system integrity that accumulates with advancing age. Efforts to promote upward social mobility may, therefore, extend healthy lifespan. However, recent studies suggest that upward mobility may also have biological costs related to the stresses of crossing social boundaries. We tested associations of life-course social mobility with biological aging using data from participants in the 2016 Health and Retirement Study (HRS) Venous Blood Study who provided blood-chemistry ( Significance StatementUpward social mobility may disrupt effects of early-life disadvantage on aging-related health decline. However, the stresses of crossing social boundaries can have biological costs. To investigate the balance of these forces, we analyzed social mobility from reports of childhood circumstances, education, and later-life wealth in 9,286 older adults in the US HRS. We quantified life-course health impacts of social mobility from blood-chemistry and DNAm analysis of biological aging. We found that educational mobility alone benefited Black Americans less than White Americans, whereas mobility that produced accumulation of wealth into later-life was associated with delayed biological aging across social categories. Black–White disparities in healthy-aging outcomes of educational mobility may reflect inequalities in social gains realized from education.Children who grow up poor get sick and die younger than their peers who grow up in more socioeconomically advantaged families , 2. ThisConversely, upward mobility may also have biological costs. The stresses of climbing the social ladder, such as prolonged, high-effort coping, can damage health . This efWe tested if life-course socioeconomic mobility was associated with slower or faster biological aging in a national sample of US adults, the US Health and Retirement Study (HRS). We quantified social mobility from childhood to later-life based on retrospective reports by participants about their childhood socioeconomic conditions and structured interviews about household wealth. We quantified biological aging using DNA methylation (DNAm)- and physiology-based methods. Our analysis proceeded in 3 steps. We first tested how life-course socioeconomic disadvantage was associated with accelerated biological aging. We next tested whether upward social mobility was associated with blunting or amplification of associations between early-life socioeconomic disadvantage and accelerated biological aging. Finally, we tested if associations of mobility with biological aging were consistent for men and women and for Black and White adults to evaluate the hypothesis that the cost of social mobility could be more pronounced for groups who face structural barriers to upward mobility. We conducted parallel analysis of participants’ educational mobility.https://hrs.isr.umich.edu/documentation). The HRS has been fielded every 2 years since 1992. A new cohort of 51–56-y-olds and their spouses is enrolled every 6 years to maintain representativeness of the US population over 50 years of age. Participants are asked about 4 broad areas: income and wealth; health, cognition, and use of healthcare services; work and retirement; and family connections. As of the 2016 data release, the HRS included data collected from 42,515 individuals in 26,600 households. The 2016 VBS collected biomarker data from a subset of HRS participants who consented to a venous blood draw, as part of a larger effort to understand biological mechanisms linking social factors and health . DNAm assays were done on a nonrandom subsample of VBS participants representative of the larger HRS sample . We linked HRS data curated by the RAND Corporation with new data collected as part of the HRS's 2016 VBS . The HRS is a nationally representative longitudinal survey of US residents ≥ 50 years of age and their spouses   . Blood-cBioAge/) .DNAm measures of biological aging were obtained from the HRS . We condWe refer to individual differences in the measures of biological aging as reflecting more/less advanced biological aging in the case of the blood-chemistry measures and DNAm clocks, and as reflecting faster/slower aging in the case of the DunedinPoAm DNAm measure. The blood-chemistry measures and the DNAm clocks have similar interpretation: They quantify how much biological aging a person has experienced up to the time of measurement. For those whose clock-ages are older/younger than their chronological ages, biological aging is more/less “advanced” relative to expectation. In contrast, DunedinPoAm measures how rapidly a person has been aging over the recent past. Values above the benchmark range of 1 year of change per 12-months interval indicate “faster” biological aging, whereas values below 1 indicate “slower” biological aging. Measures are described in more detail in Table We measured social mobility from participant reports about their socioeconomic circumstances before age 16, and from structured interviews about later-life wealth conducted by HRS between 1993 and 2016.n = 30,062). Second, we imputed missing values for father's occupation and parents’ education at the means for groups of participants matched on race, HRS birth cohort, and family financial circumstances score. Third, to compute the final factor scores, we multiplied the values of variables by their factor loadings from the complete-case principal component analysis and then averaged the products. Factor scores were computed for participants with nonmissing or imputed data on at least 3 of the 4 social origins variables . Additional details are reported in A2. For analysis, we converted factor scores to Z scores (M = 0 and SD = 1) and percentile ranks within 5-year birth cohorts. For the final childhood social origins index, higher values indicate more advantaged families of origin and lower values indicate less advantaged families of origin.We constructed a childhood social origins index based on participants’ retrospective reports about their family's general financial circumstances relative to other families, their father's occupation, the family's experiences of economic hardship , and their parents’ educational attainment. We composed the childhood social origins index as follows: first, we conducted principal components analysis of financial circumstances, father's occupation, family economic hardship, and parents’ education scores for HRS participants with complete data on all items  and liabilities over the course of multiple waves of participation in the HRS. Wealth data were chosen on the basis of evidence that wealth is more informative about social status in older adults as compared with income and educational level , 33, andr = 0.76). We conducted parallel analysis of both measures. We also conducted analysis of social mobility measured in terms of percentile-rank change from childhood to later-life using both residualized-change and difference score approaches. Details of social mobility variables are reported in We measured social mobility from childhood to later-life using 2 complementary approaches. (1) Residualized-change: we regressed participants’ later-life-socioeconomic-attainment z-score on their childhood-social-origins z-score and calculated residual values as a measure of mobility. This approach quantifies mobility as the difference between the attainment a person achieved and the attainment expected based on their social origins. (2) Difference-score: we calculated mobility as the difference between the later-life socioeconomic attainment z-score and the childhood social origins z-score. This approach quantifies mobility as the absolute difference in rank between attainment and origins. These 2 measures of mobility were highly correlated , those who had graduated from high school but had not completed a college degree (53%), and those who had completed at least a college degree (25%).We calculated educational mobility as the difference in education categories between participants and their parents. We assigned index scores of 1, 2, and 3 to respondents’ educational attainment  and their parents’ educational attainment . We calculated educational mobility by subtracting parental education index scores from participant education index scores, such that negative values represent downward social mobility and positive values represent upward social mobility . Details of educational mobility variables are reported in We used linear regression to test associations of social mobility with biological aging using the following specification:We tested if associations of social mobility with biological aging varied by childhood socioeconomic status, sex, or race by adding cross-product interaction terms to our models: BA = alpha + (beta*SES_T)+. The coefficient Z.where We used the same models to test associations of educational mobility with biological aging. In these models, the SES terms were replaced with terms for parents’ educational attainment, participants’ educational attainment, and the difference in attainments between parents and participants.For all models, effect-sizes are scaled in standard deviation units of the outcome measure. Positive effect-sizes indicate more-advanced or faster biological aging; negative effect-sizes indicate less-advanced or slower biological aging. For social-mobility models, effect-sizes are reported for a 1 SD difference in the exposure. For educational mobility models, effect-sizes are reported for a single-category increases in educational attainment.To account for nonindependence of observations of couples who share a household, we clustered standard errors at the household level. We conducted all analyses in RStudio Version 1.3.1093.HRS participants included in analysis showed substantial social mobility (percentile-rank mobility SD=25). Compared to the full 2016 HRS sample, participants in the VBS subsample and the DNAm subsample for whom biological aging measures could be computed were somewhat more likely to be White and to experience more upward social mobility. Comparison of socio-demographic characteristics of the analysis sample to the full 2016 HRS panel is reported in We combined participants’ retrospective reports about their parents’ education, childhood experiences of economic hardship, and perceptions of their family's relative socioeconomic standing into a single index of childhood social origins. Participants who grew up in more socioeconomically advantaged households exhibited less-advanced and slower biological aging across all 6 aging measures included in our analysis . Participants with more upward mobility exhibited less-advanced and slower biological aging . This finding remained consistent when we restricted analysis to participants in the middle 50% of the childhood social origins distribution. Results are reported in The association between upward social mobility and biological aging was similar across the distribution of childhood social origins (interaction P > 0.113). Results are reported in For both women and men, upward social mobility was associated with less-advanced and slower biological aging . Results are reported in For both White and Black adults, upward social mobility was associated with less-advanced and slower biological aging  and 3 DNAm measures , although effect-sizes were smaller for the DNAm PhenoAge Clock. These 6 measures comprise biological clocks that estimate the extent of aging in a person , a measure of physiologic deviation from a healthy, youthful state (homeostatic dysregulation), and a Pace of Aging measure that estimates the ongoing rate of decline in system integrity (DunedinPoAm). Consistency of findings across biological levels of analysis and conceptually distinct measures of aging builds confidence in the robustness of the association of upward social mobility with healthy aging.Our results contrast with some previous reports suggesting that there may be physical health costs from upward social mobility , 41. A pThe difference in findings in analysis of social mobility as compared to educational mobility may reflect differences in the life stage timing of the measurements used to quantify these processes and in the ways that the different mobility processes themselves affect the lives of Black and White Americans. The data we used to quantify life-course attainment in social mobility analysis was derived from structured interviews the HRS conducted with participants about their assets and liabilities during follow-ups spanning 1992–2016. These data capture levels of resource participants accumulated across their lives and had access to during the years leading up to the blood draws from which we derived our measures of healthy aging. Conversely, participants mostly completed their education decades before aging measurements were taken. Educational attainment plausibly represents young adult potential to accumulate socioeconomic and material resources that may affect healthy aging. However, this potential is likely unequally realized for Black and White Americans . An explWe acknowledge limitations. There is no gold standard measure of biological aging . Our conThe observation that upward social mobility is associated with slower biological aging builds on evidence that people with more socioeconomic resources appear biologically younger than peers of the same chronological age with fewer socioeconomic resources . MobilitThis research was supported by the National Institute on Aging (grants R01AG061378 and R01AG066887), the Russell Sage Foundation (grant 1810–08987), and the Jacobs Foundation.GHG, YZ, and DWB designed the study, analyzed and interpreted the data, and wrote the first draft of the paper. GHG, YZ, BWD, KMH, MK, DK, PM, and DWB assisted with the analysis and interpretation of the data and the writing of the paper. GHG and DWB have had full access to all the data in the study and had complete freedom to direct its analysis and its reporting, without influence, editorial decision or censorship from the sponsors. The authors declare no competing interest and have all approved manuscript submission.pgac029_Supplemental_FilesClick here for additional data file.


BackgroundWidely used in anesthetic management, sugammadex is increasingly employed in the reversal of neuromuscular blocking agents (NMBAs) in the emergency department and critical care arena, where little evaluative data currently exists. This study explored the utility and safety of using sugammadex to facilitate neurologic assessments in critically ill, NMBA-exposed patients.MethodsWe pursued a retrospective case series and single-arm cohort analysis of all brain-injured patients receiving sugammadex to facilitate neurologic evaluation during one year at a high-volume Level 1 trauma center. The primary outcome was the qualitative impact of sugammadex administration on neurosurgeon decision-making. Secondary outcomes included the change to Glasgow Coma Scale (GCS) and hemodynamic parameters compared before and after sugammadex administration. Sugammadex dosing was also assessed across various weight scalars to explore dose-response trends and generate preliminary guidance for use in this setting.Resultsp=0.0215, median change of -8 mmHg [95%CI -25-3 mmHg]). No apparent dose-response trends were observed for changes to GCS or hemodynamic parameters.Our study criteria yielded 12 sugammadex administrations across 11 patients, the majority of whom had sustained a traumatic brain injury. All sugammadex administrations were adjudicated as beneficial to neurosurgeon decision-making and 50% were associated with a change to prognosis and plan. Sugammadex was associated with an increase in the GCS of 1-8 points among the 67% of patients who responded. Mean arterial pressure decreased significantly after sugammadex administration (median 94 vs. 104 mmHg, ConclusionsThe use of sugammadex to facilitate neurologic assessment after NMBA exposure in brain-injured patients was frequently associated with clinically meaningful changes to the neurologic exam and treatment plan. The risks of hemodynamic compromise and care complexity should be collaboratively weighed before pursuing this modality. An empiric sugammadex dose of 200 mg appears reasonable for this purpose, but further evaluation of NMBA reversal in the neurocritically ill outside of procedural settings is warranted. Sugammadex is a novel chelating medication for non-depolarizing aminosteroidal neuromuscular blocking agents (NMBAs) and is indicated for the reversal of paralysis caused by rocuronium or vecuronium -3. WhileTo date, very limited studies have described patient outcomes and clinical considerations associated with sugammadex use outside of anesthesia settings -12. WhilInstitutional review board approval was obtained for this study  and we used the STROBE checklist when writing our report . Our speWe pursued a retrospective, single-center, case series and single-arm cohort analysis of all patients who received sugammadex to facilitate neurologic assessment by the neurosurgical service at our high-volume tertiary care and Level 1 trauma center over the course of one year. All adult patients administered sugammadex outside of perioperative locations from July 1, 2019 to June 30, 2020 were screened for inclusion using electronic medical record data reporting. Both TBI and spontaneous intracranial hemorrhage (ICH) patients were eligible for inclusion. We excluded patients who were pregnant, those who did not receive an aminosteroidal NMBA prior to sugammadex administration, and those who were administered sugammadex for indications other than for the purpose of neurologic assessment .Sugammadex administration was demographically classified as facilitating initial neurologic assessment in the ED or facilitating postoperative neurologic assessment in the ICU. Patient case details, concomitant medications, neurologic assessments including the Glasgow Coma Scale (GCS), and hemodynamic variables surrounding the administration of sugammadex were collected via electronic extraction and manual chart review. The primary clinical outcome assessed was the impact of sugammadex administration on neurosurgeon decision-making. This designation was adjudicated retrospectively by a single resident neurosurgeon involved in the care of the patients and was described qualitatively as follows: change to the neurologic exam, change to the neurologic prognosis, change in the certainty of prior neurologic prognosis, change in decision to pursue further neuroimaging and/or other escalations of care, change to the neurosurgical treatment plan, or no discernible impact on neurosurgical decision-making.Secondary clinical outcomes included change in blood pressure (BP), mean arterial pressure (MAP), and heart rate (HR) associated with sugammadex administration, the incidence of new or worsened hypotension  or bradycardia (defined as a heart rate less than 60 beats per minute), and incidence of peri-administration cardiopulmonary arrest. Hemodynamic parameters used in these assessments were garnered from the medical record using the last documented vital signs prior to sugammadex administration and the first documented vital signs after sugammadex administration, as long as these occurred within two hours of administration. Hospital course details including neuromonitoring device placement, neurological procedures, intracranial pressure (ICP) trends, length of stay, in-hospital mortality, and discharge disposition were also collected demographically. Additionally, details of sugammadex administration were collected and dose response was assessed in terms of various patient weight scalars, i.e., total body weight (TBW) and ideal body weight (IBW) via the Devine method .A sample size determination was deemed beyond the scope of this project given the limited anticipated patients and single-arm design. To this end, we pursued a convenience sample of all patients meeting study criteria in the designated timeframe. Based on pharmacy medication order data regarding the rate of sugammadex administrations outside of perioperative locations, our case series sample was expected to not exceed 20 patients. Demographic variables, medication data, and primary clinical outcomes were summarized descriptively using frequencies and percentages for nominal variables and medians with interquartile or total ranges for ordinal and continuous variables. For the secondary clinical outcomes, two-sided, nonparametric confidence intervals were determined for the median changes in patient GCS, BP, and HR. These variables were also compared from post- to pre-sugammadex administration via the Wilcoxon Signed Rank Test (tests the hypothesis that the distribution of the difference has a median of zero) with alpha set at 0.05. Patients for whom complete GCS and vital sign data were not documented within the pre-specified timeframe relative to sugammadex administration were excluded from these secondary analyses. Pre-specified subgroup analyses included comparing secondary clinical outcomes among sugammadex “responders,” i.e., those who experienced a change in GCS after administration, suggesting residual neuromuscular blockade was masking a  neurologically intact patient, and among “non-responders,” i.e., those for whom GCS was unchanged after sugammadex administration. Lastly, sugammadex dose was also assessed in terms of weight-based and non-weight-based dosing scalars for correlation to changes in GCS, MAP, and HR using scatter plots and simple linear regression to generate coefficients of determination .Demographic outcomesOur initial screening criteria indicated 15 total sugammadex administrations across 14 unique patients during the pre-specified timeframe  sugammadex administrations were associated with a change to the neurosurgeon prognosis and plan, and three (33%) were associated with increased certainty in the neurosurgeon prognosis, affirming the previous plan. Of the postoperative neurologic assessments occurring in the ICU, three (100%) were associated with avoidance of unnecessary testing and escalations of care. Hence, all sugammadex administrations in the study population were deemed beneficial to neurosurgeon decision-making and 50% of all administrations were associated with a change to neurologic prognosis and neurosurgery plan. Eight of the 11 total patients (73%) in this analysis ultimately expired during hospitalization, and no deaths appeared related to sugammadex administration: death occurred one to 18 days after sugammadex use, and all deaths were documented as being related to catastrophic brain injury with or without subsequent multiorgan failure.All patients exhibited a GCS of 3T prior to sugammadex administration, and GCS increased after sugammadex in 67% of drug administrations, yielding eight sugammadex “responders.” Of these, one patient chart was missing vital signs documentation within two hours post-sugammadex administration and so was excluded from the secondary analyses, resulting in a final n=11 (seven responders and four non-responders) for the secondary quantitative analysis. A significant increase in median GCS was observed after sugammadex administration in the total included population , inherently owing to the sugammadex responders' subgroup  Figure .Overall, MAP was lower after sugammadex administration in nine of 11 administrations (82%) and HR was lower after sugammadex in six of 11 administrations (55%). New or worsening bradycardia or hypotension only occurred in three (27%) administrations, however, and no major cardiopulmonary events were noted within two hours of sugammadex administration in this cohort. Of the three patients who experienced new or worsening hypotension or bradycardia after sugammadex administration, two expired , as compared to six of eight patients  who did not experience one of these events. Similarly, mortality was 5/9 (56%) in patients whose MAP decreased after sugammadex administration vs. 2/2 (100%) in patients whose MAP did not decrease.In the quantitative analysis, the median MAP in the total population decreased significantly after sugammadex as compared to prior to drug administration   at a median time of 101 minutes after the last dose of antecedent non-depolarizing NMBA (range 42 to 231 minutes). Weight-based sugammadex doses ranged from 1.6 to 3.8 mg/kg TBW (median 3.25 mg/kg) and 1.9 to 7.3 mg/kg IBW (median 4.1 mg/kg). Changes in sugammadex dose, as assessed by any of the three studied dosing scalars, did not appear to predict the variation in change to GCS, MAP, or HR, as evidenced by very low R2 values ranging from 0-0.367 (Table Sugammadex mediates an impressively fast and consistent erasure of neuromuscular blockade and may be associated with improved perioperative clinical outcomes, prompting exploration of its utility beyond the operative theater ,21,22. WFrom the neurosurgeon's perspective, a neurological exam is the most basic and fundamental tool for patient evaluation. For example, when first encountering a patient with post-traumatic subdural hematoma with significant mass effect, it is essential to ascertain an accurate initial neurological exam. Patients with a poor initial neurological state, as indicated by a very low GCS, may not benefit from a neurosurgical intervention -26. PrioFrom the analysis of our data set, we conclude that prolonged residual paralysis after intubation interferes with neurologic exams with alarming frequency. This is evidenced by a positive GCS response being observed after sugammadex administration among patients who had their last antecedent NMBA dose administered 42-231 minutes prior, with the majority of these occurring after the oft-quoted one-hour duration of rocuronium/vecuronium. While this may seem unexpected, clinician-assessed duration of paralysis is likely to far exceed those reported in anesthesia texts since clinical trials defined NMDA duration as “median time to 25% recovery of first muscle twitch height” ,29. RealThese benefits were accompanied by evidence of adverse event risks. The significant reduction in MAP with sugammadex is an important finding that should not be overlooked by neurosurgical providers since maintenance of adequate blood pressure after brain trauma is vital for brain perfusion during periods of acute swelling. Current guidelines for the management of severe TBI advise maintaining systolic blood pressure ≥100-110 mmHg to decrease mortality and improve outcomes, with recommended target cerebral perfusion pressures of 60-69 mmHg to improve survival and favorable outcome . Of the We did not find a significant reduction in HR after sugammadex administration, which is an interesting finding given that sugammadex is known to cause transient bradycardia that may be more likely in vulnerable patients and at higher doses ,15,18,33In addition to the risk of negative hemodynamic effects, the use of sugammadex in this setting can complicate important components of neurocritical care. Subsequent indications for the neuromuscular blockade, such as surgical paralysis during emergent craniotomy, may become more challenging since larger doses of rocuronium or vecuronium will be required to overcome recent sugammadex exposure ,36. AlteThough the use of sugammadex in this setting is well within the labeled indication of reversing neuromuscular blockade from rocuronium or vecuronium, the tailoring of risk-benefit assessment, dosing, and monitoring to the neurocritically ill patient is warranted. Our present dataset is small, but we feel it is an accurate sample of severely brain-injured patients generalizable to those of other large trauma centers. In the absence of specific and evidenced-based recommendations for such patients, our institutional data and the aforementioned considerations were integrated with a thorough review of applicable literature by the multidisciplinary collaborators, whose expertise spans perioperative and emergency medicine clinical pharmacology, neurosurgery, and neuroanesthesia. Our guidance in Table We believe a flat dose of 200 mg sugammadex by intravenous push is reasonable in this setting for several reasons. It is important to reiterate that the goal of sugammadex administration in our study differs from that in perioperative assessments; here paralytic reversal is undertaken to facilitate a more accurate neurosurgical assessment, whereas in most surgical publications sugammadex is used to facilitate extubation and avoid residual paralysis to protect post-extubation respiratory function. A low level of residual paralysis primarily affects the very small muscle groups such as those responsible for the pharyngeal function and intraocular movement, and we consider this to be largely inconsequential in the setting of assessing GCS in an intubated patient. Additionally, the manufacturer-recommended dosing of 2 mg/kg and 4 mg/kg actual body weight pertain to the reversal of moderate and deep levels of neuromuscular blockade, respectively . At the This study does suffer from a number of limitations. Our retrospective, single-arm design and small sample size precluded meaningful analyses as statistical power could not be assessed, limiting our methodology to hypothesis-generating in rigor. We had no capacity to incorporate an assessment of the depth of neuromuscular blockade before and after reversal as such monitoring is not routinely available in our ED, though this appears to be a commonplace practice opportunity. Additionally, while we assessed changes to hemodynamic parameters to the extent of available documentation, there was no standard interval between assessments in relation to sugammadex administration, and we did not assess for other indicators of severe adverse hemodynamic events such as atropine administration or the initiation of vasopressors, which could have resulted in under-reporting of potential risks with sugammadex. Still, a comprehensive review of medical documentation for our population suggested against the occurrence of significant medication-related morbidity or mortality, such as the known rare risks of cardiovascular collapse or anaphylaxis with sugammadex ,45. FurtResidual neuromuscular blockade may frequently interfere with neurologic assessment after NMBA exposure in brain-injured patients in the ED and ICU, even more than an hour after NMBA administration. Trialing sugammadex in these situations may therefore benefit neurosurgical decision-making by removing residual neuromuscular blockade and facilitating timely, accurate neurologic exams. We recommend these benefits be weighed against the risks of lowering blood pressure and complicating subsequent care in collaborative decision-making when considering this modality. We feel an empiric sugammadex dose of 200 mg via intravenous push is reasonable for this purpose to balance benefits and risks. A more robust evaluation of sugammadex to facilitate neurologic assessment in neurocritically ill patients outside of procedural settings is warranted before this practice can be recommended routinely.


BRCA mutation) cells. This approach has proven successful clinically and there are now six PARPi approved for cancer therapy. Drugs targeting other aspects of the DDR are under pre-clinical and clinical evaluation as monotherapy agents and in combination studies. For this promising approach to cancer therapy to be fully realised reliable biomarkers are needed to identify tumours with the exploitable defect for monotherapy applications. The possibility that some combinations may result in toxicity to normal tissues also needs to be considered. A brief overview of the DDR, the development of inhibitors targeting the DDR and the current clinical status of such drugs is described here.The DNA damage response (DDR) is an elegant system, coordinating DNA repair with cell cycle checkpoints, that evolved to protect living organisms from the otherwise fatal levels of DNA damage inflicted by endogenous and environmental sources. Since many agents used to treat cancer; radiotherapy and cytotoxic chemotherapy, work by damaging DNA the DDR represents a mechanism of resistance. The original rational for the development of drugs to inhibit the DDR was to overcome this mechanism of resistance but clinical studies using this approach have not led to improvements in the therapeutic index. A more exciting approach is to exploit cancer-specific defects in the DDR, that represent vulnerabilities in the tumour and an opportunity to selectively target the tumour. PARP inhibitors (PARPi) selectively kill homologous recombination repair defective (HRD, e.g. through  Maintenance of DNA integrity is essential for the survival of all living organisms. The level of DNA damage inflicted from endogenous and environmental sources would be lethal without the DNA damage response (DDR). The DDR evolved as an elegantly orchestrated network of pathways that repair the DNA and arrest the cell cycle such that damage is neither copied during S-phase nor passed on to daughter cells during mitosis.DDR dysfunction causes genomic instability and mutations that can ultimately lead to cancer formation . SeveralDysfunction of one DDR pathway may lead to increased activity of compensatory pathways, resulting in resistance to DNA damaging chemotherapy and radiotherapy. The initial rationale for the development of drugs targeting the DDR was to overcome these resistance mechanisms. However, the strategy of inhibiting the DDR to chemo- or radiosensitise tumours also increases the toxicity to the normal tissues in line with increased antitumour activity such that there is only a minor impact, if any, on the therapeutic index. A much more exciting approach is to exploit the vulnerability created by the DDR defect to specifically target the tumour without harming normal tissues that have properly functioning DDR pathways (reviewed in ). This aThe most common types of DNA damage affect only one strand and are generally repaired rapidly so generally less critical to the survival of the cell than those lesions affecting both strands. Signalling to cell cycle checkpoints via p53 may occur . The simBase modifications and nicks in the DNA backbone, usually resulting from oxidative stress are estimated to occur between 10 000 and 100 000 times per genome per day. This rate is increased by inflammation, which is a promoter of carcinogenesis . These lExposure to UV light is another common source of damage with estimates of as many as 100 000–200 000 DNA photoproducts generated by an hour's exposure to bright sunlight . These aErrors in DNA, including a mis-matched base or, particularly in repetitive sequences (microsatellites), the skipping of bases or insertion of extra ones (Indels) may be introduced during replication. These are removed by the mis-match repair (MMR) pathway that includes MLH1 and MSH2 that are often mutated or silenced in cancers, particularly of the colon and endometrium. Defects in MMR leads to microsatellite instability and, because they act only on the daughter strand, cause tolerance to certain DNA lesions resulting in resistance to agents modifying the parental strand such as 6-thioguanine, DNA alkylating agents and platinums .DNA double strand breaks (DSBs), although rare, are much more catastrophic to the cell and more difficult to repair. DSBs can be caused by environmental ionising radiation, endogenous or environmental ROS, torsional strain during transcription or replication or if topoisomerase II is trapped on the DNA by some other lesion . HoweverATM mutation) have extreme radiosensitivity, immunological deficiencies, neurodegeneration and cancer predisposition [DSBs occurring during the G1 phase of the cell cycle chiefly signal cell cycle arrest via the ATM–CHK2 (Ataxia telangiectasia mutated–Check 2 kinases) pathway and are largely repaired by non-homologous end joining (NHEJ) pathway  3]. NHE. NHE3]. position .The most common endogenous source of DSBs is the collision of SSBs  with the replication fork. These lesions are generally repaired by the homologous recombination repair (HRR) also known as homology-directed repair (HDR) pathway. HRR is a complex pathway, using the sister chromatid as a template, resulting in high fidelity repair . It is tThe collision of unrepaired single-strand lesions with the replication fork along with replication stalling due to replication firing (often oncogene driven) with inadequate nucleotide supply causes RS . RS is aInterstrand cross-links (ICLs) also rarely occur naturally, with endogenous sources being products of lipid peroxidation, e.g. acrolein and crotonaldehyde, which can also be generated in fatty food during cooking . Repair Since the DDR causes resistance to DNA damaging anticancer agents DDR inhibitors were first developed to overcome this resistance mechanism. MGMT inhibitors were developed to sensitise tumours to alkylating agent chemotherapy . Pre-cliSimilarly PARP inhibitors (PARPi) were originally developed to prevent resistance to cytotoxic therapy-induced SSBs. Early inhibitors were developed using medicinal chemistry and an analogue by catalogue approach based around the by-product of the PARP reaction, nicotinamide ,26. TheyThe clinical experience with these early DDR inhibitors as chemo- and radiosensitisers has not lived up to the expectation from promising pre-clinical data. Neither MGMT nor PARP inhibitors have progressed beyond Phase II in combination with chemotherapy due to toxicity alongside only marginal improvements, if any, in efficacy.BRCA1 or BRCA2 mutation) cells [BRCA1 and BRCA2 mutation carriers have a high risk of developing cancer, predominantly breast and ovarian but also prostate and pancreatic cancer [BRCA 1 or BRCA2 mutations or epigenetically silenced BRCA1 compared with wt cells or those with heterozygous BRCA mutations [A more promising approach is to target vulnerabilities specific to the tumour. Many DDR components are tumour suppressors and lost during carcinogenesis. In addition to creating vulnerability to DNA damaging anti-cancer therapies this can be exploited by targeting a complementary or compensatory DDR pathway to create synthetic lethality to kill the DDR-defective tumour cells. Since normal tissues have fully functional DDR pathways they will remain viable. This approach was first demonstrated in 2 landmark papers describing the synthetic lethality of PARPi in HRR defective  cells ,35. Thisn) cells . BRCA1 ac cancer . Pre-cliutations . A key oBRCA mutations confirming anticancer activity with minimal toxicity was published [BRCA mutations were not the perfect predictors of response to PARPi (olaparib in this case) [BRCA mutations but an ex-vivo functional assay first demonstrated that ∼50–60% are HRD [In 2009, the first of many PARPi monotherapy trials in patients with ublished . Howeveris case) . Only ∼2 are HRD . Commerc are HRD ,42. The  are HRD ,43,44).  are HRD .in vivo activity [Anticancer radiotherapy and topoisomerase II poisons, such as doxorubicin, induce DSBs so NHEJ may cause resistance. DNA-PKcs, ATM, and ATR are members of the PI3-Kinase-like kinase (PIKK) family  and earlactivity . Multiplactivity ). Pre-clactivity . The firactivity . More reactivity .ATM inhibitors have also been developed pre-clinically and progressed to clinical trial (reviewed in ). The fiCHK2 knockout mice are radioresistant . Cliniciewed in .The loss of G1 control, a common feature in cancer ,57, and BRCA wt ovarian cancer and triple negative breast cancer [The first potent and selective CHK1 inhibitor was PF-477736, others include MK-8776 (SCH900776), SRA737 and LY2606368 (prexasertib). In pre-clinical studies CHK1 inhibitors sensitise cells to radiation, various cytotoxic drugs and PARPi (reviewed in ). PF-477t cancer ,75.AZD1775/MK-1775 is the only WEE1 inhibitor in clinical trial where there is published pre-clinical data. Pre-clinically it increases the activity of multiple DNA damaging agents (reviewed in ) There aThe success of the synthetic lethality with PARPi in HRD cancer stimulated the search for determinants of sensitivity to other DDR inhibitors that could be used as predictive biomarkers. Screens with knock-down/deletion of various genes offer great opportunities to identify predictive biomarkers, although often the complicated molecular pathology of cancer means they have not lived up to expectation ,78. In aBRCA gene that restores its function [53BP1  [Development of resistance to PARPi is common, usually through the restoration of HRR function, e.g. by secondary mutation in the function  or the lver HRR) ,82,83. Wver HRR) ,84–86 isver HRR) . The CHKInhibiting polθ to target MMEJ, the back-up pathway for HRR and NHEJ, may be another way to overcome PARPi resistance. Polθ has both ATPase and polymerase function and is an emerging target in cancer therapy  includinThe DDR is essential for life, with overlapping and complementary well-coordinated pathways of repair and cell cycle checkpoints. These pathways, evolved to enable survival from endogenous and environmental DNA damage, confer resistance to DNA damaging anticancer agents. DDR defects are also common in cancer. Drugs targeting the DDR have significant potential to overcome resistance and exploit DDR defects. The discovery of the synthetic lethality of PARPi in HRD cancers, first published in 2005, was validated clinically 4 years later and now 6 PARPi are approved using this approach.The approach of sensitising cancers to DNA damaging therapy with DNA repair inhibitors, although hugely promising in pre-clinical studies, has been disappointing clinically. The regulatory approval of PARPi monotherapy in patients with HRD tumours has massively stimulated research in DDR inhibitors, particularly those targeting ATR and CHK1, which also have the potential to reverse PARPi resistance.in vivo pre-clinical investigation of proposed combinations prior to experimenting on patients.Exploiting cancer-specific DDR defects by targeting other aspects of the DDR has immense potential for tumour-selective therapy with minimal toxicity. Reliable, robust biomarkers to identify tumour vulnerabilities are needed. Identification of determinants of sensitivity/predictive biomarkers using genetically modified cells may not translate to the complex phenotype of cancer cells. It is tempting to speculate that, since most tumours have dysregulated G1 cell cycle control, which may be exploited by targeting intra S and G2M checkpoints to selectively target a tumour vulnerability, ATR, CHK1 and WEE1 inhibitors may prove the most successful either as single agents or in combination. As Polθ is up-regulated in many tumours, and MMEJ is a back-up for both HRR and NHEJ, this is a potentially promising target.The genomic instability of tumour cells means that resistance is likely to develop. Combining different DDR inhibitors may reduce this but there are potential risks that the tumour-specificity will be lost and the combination will be toxic. Combinations should be guided by the evidence from careful and extensive