In this experimental study, the physico-mechanical and microstructural properties of sulphate-bearing clays have been investigated. Sulphate bearing soils constituted by mixing kaolin and gypsum at 0%, 15%, 25%, and 35% gypsum contents were treated with 12% ordinary Portland cement (OPC) and 4%Lime (L) and 8% ground granulated blast furnace slag (GGBS) and subjected to compaction, swell, unconfined compressive strength (UCS), California bearing ratio (CBR), and scanning electron microscopy (SEM) and energy dispersive spectrometry (EDX) analyses. The results of the study showed that the use of L-GGBS improved the soaked CBRs of the treated samples by over 43% when compared to OPC-treated samples after 7-days curing. A reduction in water absorption by 82% was also observed with L-GGBS treatment after 28-days curing. The UCS results also showed better performance with L-GGBS treatment exceeding 856% at 28 days. The effect of increased cementitious product with increasing gypsum content was negated by simultaneous and rapid growth of ettringite minerals which reduced the strength and increased swelling of OPC treated samples up to 18.92%, exceeding allowable limits of 2.5% as specified in Highway Agency Advice Note HA 74/07. The L-GGBS treated gypseous soil samples meet the strength requirement for stabilised sub-base (CS) and stabilised road-bases (CB1 and CB2) as described in TRL ORN31. Hence, the use of L-GGBS combination was found to be effective in ameliorating sulphate-induced expansion and therefore encouraged in the stabilisation of subgrade and road-base materials with high sulphate contents. There is an ever-increasing need for proper characterisation of the engineering behaviour of stabilised soils underlying road pavements and other civil engineering structures. The safety and durability of facilities sited on engineered earth materials are a direct function of correct modeling of such materials’ behaviour. The application of cement-bound earth materials as road pavement layers have been widely undertaken, following its first successful use in the USA in 1935 ,11,12,13Sulphates are common in soils containing salts due to the oxidation of sulphides. These soils are common in the UK following weathering of ancient strata of clay, shale, and mudstone deposits from the carboniferous time-periods . Figure 6Al2(SO4)3(OH)12⋅26H2O] in the presence of sulphate (SO42-), as expressed below [The hydration process leading to the formation of strength-giving compounds, such as calcium silicate hydrates (CSH) and calcium aluminate hydrate (CAH), simultaneously produces expansive minerals like ettringite [Caed below .6Ca2+ +These expansive minerals are susceptible to large volume changes up to 2.5 times the soil volume with sufficient moisture ,24,25 anThis deleterious impact has informed the evaluation of alternative binder combinations in combating sulphate-induced expansion in sulphate-rich soils where the total potential sulphate (TPS) exceeds allowable values ,32. AccoAdditionally, the inclusion of GGBS with other binders such as lime has been shown by several laboratory and field trials to ameliorate sulphate induced heave by immobilizing dissolved sulphates in the alkalinized pore fluids of treated soils ,37,38. AWhile the combination of lime and GGBS has been utilised for stabilisation of gypseous soils ,45,46,474⋅2H2O), a product of the reaction of calcium carbonates and sulphuric acid (H2SO4), can be used to constitute sulphate-bearing soils in the laboratory [The materials used in this experimental work include kaolin(K), gypsum (GYP), lime(L), and ground granulated blast furnace slag (GGBS). Gypsum  of the artificially synthesised gypseous soils were determined using the Standard Proctor compaction method according to . The conThe OPC treated samples were prepared by mixing dry kaolin with gypsum and allowed for 24 h before applying 12%OPC treatment and compacting, as stated earlier. For the L-GGBS treated soils, samples were prepared by mixing pre-constituted gypseous soils first with 4%lime and left for 24 h to allow for mellowing, after which 8%GGBS by weight of dry gypseous soil was added and mixed thoroughly to ensure homogeneity. The addition of lime before GGBS has been suggested by Higgins  to be suFurthermore, to evaluate the effect of 12%OPC and 4%L-8%GGBS treatment on the compaction characteristics of the treated gypseous soils, the seven days cured OPC and L-GGBS-treated gypseous soils were air-dried at room temperature of 22 °C for 14 days and then pulverised, remixed, and tested for compaction as before. The details of the mix compositions used in sample preparation is given in For the CBR samples, a total of 96 cylindrical samples of 152 mm diameter and 127 mm height were prepared for both soaked and unsoaked CBR test. The CBR samples were also cured while preventing loss of moisture according to  before sThe vertical swell of the CBR samples during soaking was measured with dial gauges and recorded. The weight of the treated soils was also measured before and after the soaking period and used to determine the water absorption of the samples.UCS was conducted on cured cylindrical samples using in a VJ Tech 50 kN triaxial load frame in accordance with . Three sThe CBR penetration test was conducted on 150 mm diameter × 127 mm depth samples in accordance with  using thThe effects of the Treatments were measure by conducting swell test on treated gypseous soils. Samples were soaked in water under a surcharge of mass 930 kg while measuring the vertical deformation. The swelling of the samples was recorded for 56 days and expressed as a percentage of the original height of the samples.−7 Torr and an accelerating voltage of 5–20 kV [To investigate the microstructural characteristics and mineralogical composition of the soil samples, SEM and EDX studies were carried out on chunks of stabilised samples. The soil samples for SEM and EDX analyses were taken from the middle sections of large CBR samples in order to obtain better representative samples for microstructural study following treatment. The samples were gold-coated in an Emscope SC 500 unit within 1 min using a current of 7.5 mA at a vacuum pressure reading of 0.1 Torr during coating. Samples were glued with a Leit-C conductive carbon cement and allowed for 48 h to dry prior to analysis. The samples were put in a FEI QUANTA FEG 650 SEM Unit at a chamber pressure of about 9.5 × 10 5–20 kV . The micThe results of the standard Proctor compaction test on the treated and untreated artificially synthesised gypseous soils are presented in The effect of 12%OPC and 4%Lime-8%GGBS on the compaction characteristic of the gypseous soils is shown in Swelling of OPC treated sulphate bearing soils is an unwanted behaviour, especially underneath light-weight structures such as road pavements. OPC treatment of sulphate-bearing soils has been shown to result in significant swelling and expansion when subjected to water ingress ,62,63. T2+-Al3+-SO42− crystals leading to a slower swell rate and percentage [The 15% OPC-treated gypseous soil showed the greatest swelling of 18.92% and was greater than that of the 0% gypseous soil and maybe is attributed to combined gypsum crystal expansion and ettringite-induced heave . Howeverrcentage ,67.However, the L-GGBS treated gypseous soils showed much slower expansion rate and overall reduction in total volume change at the end of the 56 days soaking. A maximum swell of 0.2% and 0.04% respectively was observed in 0% and 15% gypseous soils treated with L-GGBS. The L-GGBS-treated sample containing 25% gypsum showed only 0.2% swell while that of 35% gypsum content had 0% swell at the end of 56 days soaking period. The combination of Lime and GGBS treatment enhanced the performance of treated soil under soaked condition. This indicates that, although the formation of the strength-yielding compounds was accompanied by the development of ettringite minerals, the associated expansive tendency of the crystals in the presence of water was significantly reduced when compared to that of the OPC-treated samples. Similar results from L-GGBS treated sulphate soils have been reported in both laboratory studies and field trials ,69. The Water absorption characteristic is useful in evaluating the performance of treated gypseous soils in the event of harsh environmental conditions such as flooding which could lead to rapid break-down of the soil-binder fabric and eventual strength depreciation. The effect of the binders in reducing the pore spaces and cutting down on the amount of water absorbed was studied following 96h soaking of treated and untreated CBR samples. The water absorption characteristics of the gypseous soils show that both OPC and L-GGBS are effective in reducing the water absorption propensity of the stabilised soils when compared to the untreated gypseous soils as expected .For the untreated gypseous soils, the highest water absorption was observed in the 15% gypseous sample and could be linked to a rapid dissolution of gypsum particles within soil pores during soaking. The lower gypsum content of the 15% untreated gypseous soil resulted in poor cementitious effects which was worsened by soaking, leading to increased water absorption, as shown in The water absorption of the gypseous soils with higher gypsum content was observed to be lower for both Untreated, OPC, and LG treatment. This is a direct effect of increased cementation with the known effect of sealing pore spaces with cementitious gel, increasing density, and reducing soil permeability . The redThe water absorption of seven days-cured OPC-treated samples, as shown in The results of UCS tests on both treated and untreated gypseous soils show that the strength of the gypseous soils were significantly improved following OPC and L-GGBS treatment, as shown in Consequently, the OPC-treated gypseous soils exhibited further strength improvement over the untreated gypseous soils based on further precipitation of strength yielding compound namely calcium-silicate hydrates (C-S-H) and calcium-aluminate-hydrates (C-A-H). At seven days curing, the OPC-treated samples had UCS of 1.62 MPa to 1.46 MPa for 15% to 35% gypsum contents respectively. The 7-days UCS of the OPC-treated samples meets strength requirements for stabilised sub-base (CS) applications as stated in . As showThe 28-days cured L-GGBS treated samples performed better than the OPC-treated. The treated samples increased in strength as more bonding was achieved with increased precipitation of the strength compounds over time. However, a reduction in UCS was also observed with increasing gypsum content which was like the trend of the 7-days cured samples. Slow strength gain has been highlighted to be synonymous with the use of GGBS and reported in previous studies as shown in ,75. HoweThe stiffness modulus of the stabilised soil is presented in The performance of treated soils as subgrade and subbase materials in road construction is usually evaluated based on the soaked and unsoaked CBR tests. In the current study, gypseous soil samples stabilised with both 12%OPC, and 4%L and 8%GGBS combination were subjected to 96h soaking and tested for CBR. The untreated gypseous soil was also tested to compare the improvements. Whereas the untreated gypseous soils showed very low penetration resistance following 96h soaking, the stabilised soils showed higher resistance as shown in The increased CBR of the 28-days cured samples is linked to more strength gain because of increased precipitation of the strength-giving compounds over a longer hydration period. Like the 7-days cured samples, the results of the 28-days cured samples showed better performance with L-GGBS treatment than OPC-treatment. Samples with higher gypsum contents showed a slight reduction in soaked CBR and may be linked to excessive unreacted gypsum and OPC or L-GGBS particles within the matrix of the treated soils. Upon soaking these particles will dissolve in the pore fluid and contribute to lower CBRs. This behaviour indicates that an optimum gypsum-binder mix ratio for maximum penetration resistance under soaked conditions may exist and requires further investigation. Overall, the gypseous soil samples stabilised with 4%L and 8%GGBS showed better performance by offering the most resistance against penetration. This corroborates earlier conclusions from previous studies that the L-GGBS combination is effective in maintaining the strength of the inter-particle bonds of the treated soils under soaking conditions ,79,80.The unsoaked CBR result shows similar behaviour of the treated gypseous soils. Increasing the gypsum content increased the sulphate content and reduced the penetration resistance of the stabilised soils. As with the soaked condition, the 28-days cured samples performed better with higher CBR values as shown in However, the unsoaked CBR values were lower compared to the soaked values for the treated soils. The results show that soaking the treated samples improved the cementation process in the treated soil since more moisture enhanced the hydration process which increased the strength of the treated soils. On the contrary, the untreated gypseous soil were somewhat better under unsoaked condition than in soaked condition as more water molecules adsorbed within the clay mineral structure caused expansion and reduction in the bond within the kaolin-gypsum matrix which reduced the strength of the untreated soil even further. In terms of the performance of the binders, L-GGBS treatment proved better in both soaked and unsoaked condition compared to OPC treatment.The performance of the binders has also been compared with standard requirements for subgrade strength prescribed as S1, S2, S3, S4, S5, and S6 as stipulated in . The untThe morphological characteristics and oxide compositions of the treated and untreated gypseous soils have been studied by SEM and EDX analyses. The micrograph of the compacted untreated kaolin (0% gypsum) is presented in 3A) in OPC which seeks to slow down the setting rate [Upon treatment with OPC, an increase in formation of C-S-H compounds is observed in the matrix, as shown in ing rate .For the 7-days cured samples, the samples with 35% gypsum content showed a higher compactness, as shown in The micrographs also show a simultaneous increase in ettringite crystals with curing duration for both treatments with increasing sulphate content.However, the 15% gypseous samples were observed to have more ettringite crystals than the 35% for both treatments resulting in the adverse expansive effects as seen in the swell curves. The LGGBS treated samples showed higher percentage of ettringite crystals compared to the OPC samples due to the high alkaline soil-water environment created by the lime. However, the ettringite crystal appeared to be flat and shorter when compared with the more common longer cylindrical prism-shaped crystals in the OPC treated samples. Variations in ettringite crystal shapes have been observed in different sulphate-bearing clays with different additives ,83. The The use of L-GGBS and OPC treatment are both effective in improving the compressive strength of gypseous soils. However, L-GGBS treated soils showed higher strength than OPC-treated samples for both 7 and 28 days across all dosages of gypsum contents.OPC-treated sulphate-bearing soils are prone to excessive swelling which could pose high risk to light-weight structures such as road pavements, utilities, and some simple shallow foundations due to significant heave upon water ingress. On the other hand, L-GGBS treatment is effective in suppressing sulphate-induced heave for pavement application. The presence of expansive minerals such as ettringite in sulphate-bearing soil poses more concern with OPC than with lime and GGBS. The addition of GGBS appears to modify the cylindrical ettringite needle-like crystals into a squashed cylinder and might have contributed to reducing the expansive tendency of the crystals in the presence of water.The UCS and stiffness modulus of gypseous soils could be improved by treating with L-GGBS combination. An early gain in UCS and stiffness of L-GGBS treated gypseous soils exceeding OPC treated samples suggests that using L-GGBS is a preferable option for rapid strength gain on sites characterised by highly sulphated soils.The CBRs of OPC and L-GGBS-treated soils are enhanced following 96h soaking and could be related to enhanced hydration reaction in the presence of water. Adequate curing is required for stabilised soils to achieve optimal performance as sub-base and sub-grade materials. However, at 7-days curing, the CBR of L-GGBS treated gypseous soil meets the strength requirement for stabilised road-base and sub-base application even at high gypsum content. This indicates that L-GGBS is effective in enhancing the mechanical properties of highly sulphated soils.The physico-mechanical and microstructural properties of L-GGBS and OPC treated sulphate-bearing soils have been studied with a view to evaluating key parameters of the treated soil relating to pavement design. From the study, the following conclusions have been reached.


Post-coronavirus disease (COVID) syndrome involves the presentation of various new, returning, or ongoing symptoms, more than four weeks after COVID-19 infection. Post-infectious myocarditis is a potential sequela, associated with greater arrhythmogenic potential. Thus, it is an outcome that should be considered in athletes. An undiagnosed heart condition associated with adrenergic stimulus caused by high-intensity exercises can lead to sudden cardiac death. Electrocardiography (ECG) plays a role in cardiac screening for potential cardiac changes associated with myocarditis. Therefore, this study aimed to evaluate the occurrence of electrocardiographic alterations in athletes during the post-COVID period.A systematic review of longitudinal observational studies in the PubMed, LILACS, and CENTRAL databases that evaluated athletes in the post-COVID period with ECG was performed. A total of four articles involving 5371 patients were included in the analysis. The athletes mostly presented with mild asymptomatic or symptomatic COVID-19. A low prevalence of electrocardiographic alterations suggestive of cardiac involvement by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in this population.Electrocardiographic abnormalities indicative of myocarditis are uncommon in young athletes throughout the post-COVID era. However, anomalies that may signify and need further cardiovascular testing were found. The coronavirus disease 2019 (COVID-19) pandemic has resulted in the development of post-COVID syndrome (PCS). PCS occurs in individuals with confirmed or probable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, at least three months after disease onset, with a symptom duration of at least two months, and where the symptomatology cannot be explained by another diagnosis. Symptoms include fatigue, dyspnea, and cognitive changes, which may be intermittent or persistent [In athletes, myocarditis secondary to viral infection is alarming due to the degree of adrenergic and hemodynamic stimulation caused by high-intensity exercise. This increases the arrhythmogenic potential of heart disease . HoweverRegardless of PCS, electrocardiographic evaluation is one of the key aspects of the pre-participation evaluation of athletes since several disorders associated with sudden cardiac death (SCD) of athletes can be identified by electrocardiogram (ECG). Previous SARS-CoV-2 infection can be identified by observing T-wave inversion and ST-segment abnormalities since, in 33% of cases, such changes are associated with myocardial inflammation .In this sense, the cardiovascular evaluation of athletes is important in the context of PCS. Moreover, ECG findings should be correctly interpreted to differentiate physiological cardiac changes associated with regular and intense exercise and features suggestive of heart disease, as recommended by the International Criteria for interpretation of the athlete's ECG . FurtherAn uncertain risk of myocarditis exists in young athletes; therefore, pre-participation screening to identify athletes who may require additional testing and medical care before returning to sports is essential. As the rate of myocarditis related to abnormal ST or T waves may be high, additional cardiac testing is essential. All athletes with such findings should be placed under permanent observation, as even asymptomatic myocarditis can result in permanent cardiac damage and sudden cardiac death .The following aspects of ECG should be considered to prevent sudden cardiac death in young athletes: first, additional cardiac examinations should be performed in cases where abnormalities in the P wave, QRS complex, ST segment, T waves, QT interval, cardiac rhythm, and conduction are present -9. SeconMaterials and methodsThis study was a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Articles were obtained by searching the PubMed (36 articles), LILACS (1 article), and CENTRAL (4 articles) online databases for articles from the last two years. Articles were selected based on previous knowledge of the authors in the literature on the subject under investigation. Articles with the descriptors "COVID-19" "Athletes" AND "Electrocardiogram" were included. Our search description: (("COVID-19" or "Long Covid-19" or "Late Covid-19") AND (" Athletes") AND ("Electrocardiogram")).Two researchers evaluated the articles separately and independently, first reading the article titles and abstracts to verify their eligibility for the theme addressed in this study. Articles that could be included were read in full by the researchers and included or excluded based on their characteristics. There were no limitations regarding the language of the studies, sex, or age of the participants. Longitudinal observational studies that evaluated athletes after the resolution of COVID-19 were included to determine the incidence of electrocardiographic changes in athletes previously infected with SARS-CoV-2. In the first database search, 41 articles were obtained, of which 12 were selected for full reading and 4 met the inclusion criteria of our study.ResultsIn total, four studies were included in the integrative review, as seen in Figure Four studies used the international criteria for the interpretation of the athlete ECGs to categorize the findings as normal or abnormal. Erickson et al. identified six athletes 3.5%) out of 170 with abnormal or borderline electrocardiographic alterations, and they were subsequently referred for cardiovascular evaluation [.5% out oet al. studied 789 elite athletes who tested positive for COVID-19 before resuming team sports [Martinez Two individuals (2.0%) out of 99 tested by Guevarra et al. had abnormal results that were consistent with post-infectious cardiovascular dysfunction [In an electrocardiographic study by Casasco et al. arrhythmic events were found . In totaDiscussionThe correct interpretation of ECG of athletes becomes important in the context of the post-COVID syndrome since physiological findings associated with regular practice of high-intensity exercises and alterations that increase the risk of sudden cardiac death (SCD) in this population should be differentiated. Therefore, international criteria define normal, borderline, and abnormal findings for the interpretation of athlete ECGs. The presence of at least two borderline or one abnormal finding warrants further cardiovascular evaluation. The association of alterations, such as T-wave inversion and ventricular arrhythmias, with myocarditis, is well-documented as a possible sequela of SARS-CoV-2 infection .Before the COVID-19 pandemic, the isolated use of 12-lead ECG for the diagnosis of myocarditis had a sensitivity of 47% and an unknown specificity. Moreover, ECG abnormalities were mostly found in sinus tachycardia with nonspecific alterations of the T-wave . HoweverThe results of this review support those of the existing literature, suggesting that ECG readings of high-performance athletes have low specificity, especially where ECG abnormalities occur in the absence of other cardiovascular examination findings. One study demonstrated that even in the absence of cardiovascular alterations, 9% of athletes in the study cohort had late enhancement with gadolinium on CMR, and half of these athletes met the criteria for myocarditis associated with previous SARS-CoV-2 infection .Observing the possible symptoms associated with the post-COVID syndrome is also necessary to indicate cardiovascular evaluation after ECG. In a study that evaluated 137 athletes, it was demonstrated that only one athlete presented with ECG abnormalities. However, five athletes were diagnosed with cardiac sequelae associated with SARS-CoV-2 infection. Moreover, 21% of athletes with chest pain induced by exercise after returning to sports had cardiac involvement in CMR, possibly related to COVID-19 .The adoption of ECG as an isolated strategy for the evaluation of sports pre-participation after the resolution of COVID-19 should not be recommended, despite being a low-cost alternative. This is due to ECG being ineffective in detecting possible cardiac diseases in athletes with mild asymptomatic or symptomatic previous SARS-CoV-2 infection. However, ECG may represent a valuable strategy for initial screening and indications for further cardiac evaluation. In a study of 19,378 athletes, cardiac involvement was detected more frequently with CMR, in patients who underwent CMR following preliminary ECG, troponin, and transthoracic echocardiogram, than in athletes who only underwent primary CMR .The low lethality of COVID-19 among individuals aged 15 to 24 years associated with preliminary findings, indicates that cardiac involvement of COVID-19 is rare and that the low incidence of ECG alterations in the post-COVID study suggests the risk for young athletes is low. However, ignorance regarding the long-term effects of SARS-CoV-2 infection supports pre-participation sports evaluation, especially for athletes with persistent symptoms after the resolution of the acute viral condition. Moreover, athletes should take precautions to prevent initial SARS-CoV-2 infection and, if infected, resume activities with caution and monitor the persistence of symptoms .The Brazilian Guidelines for Sports Cardiology, recommend a resting 12-lead ECG for pre-participation screening (PPS) of both amateur and professional athletes. This enables the identification of any possible changes correlating with previously mentioned diseases as the most common causes of SCD . AlteratFindings of an Italian study showed 26% of patients hospitalized with COVID-19 linked with pneumonia developed new ECG abnormalities within 51 days mean, 20-30 days) of symptom onset when compared to their admission ECGs. The most frequent ECG abnormalities were bradycardia (2%), atrial fibrillation (6%), and persistent ST alterations (14%). Higher levels of troponin were observed in 38% of patients. However, these alterations did not correspond with the severity of pulmonary symptoms, occasionally manifested on the eve of hospital discharge, and after a recent reverse transcription-polymerase chain reaction (RT-PCR) test returned negative results [-30 days As physiological changes occur in the heart as a direct result of physical activity, it is essential to emphasize that physically fit people and athletes often exhibit a distinctive ECG pattern compared to that of the general population. Considering this, ECG interpretation should preferably be performed by a cardiologist with previous experience in sports, and by the most recent international recommendations for the interpretation of electrocardiographic studies in athletes . FurtherŠarčevićet al. reported an increased number of ECG findings requiring further additional cardiac examinations in young athletes during the coronavirus . The stuA case-control study investigated the effects of asymptomatic and mild COVID-19 on transmyocardial repolarization parameters in children without treatment . The finFurthermore, another study  describeLimitationsRegarding the methodological limitations of the articles included in this systematic review, it is necessary to highlight that they corresponded to longitudinal observational studies, which do not present the highest quality level of evidence, with reduced sampling and the absence of a control group for comparison purposes. Moreover, because COVID-19 is a recent disease, the number of articles found in the databases that associated the condition with electrocardiographic alterations was reduced.Athletes in the post-COVID group had a low prevalence of ECG alterations suggestive of myocarditis, indicating that cardiac complications associated with a previous SARS-CoV-2 infection in this population are rare. However, ECG evaluation may provide clinical indications for abnormalities that warrant further subsequent cardiac evaluations with more sensitive and specific tests. This is especially important for athletes with persistent symptoms following the resolution of acute viral infections.Further experimental studies are needed for the real evaluation of electrocardiographic alterations in athletes with symptoms characteristic of post-COVID syndrome. Due to the different methods of data collection and analysis used in the studies, it is necessary to establish a protocol that guides pre-participation sports evaluation for athletes with suspected cardiovascular findings with a history of previous SARS-CoV-2 infection, allowing further research on the subject and evaluating the population linearly.


Dissipative Kerr soliton (DKS) microcomb has emerged as an enabling technology that revolutionizes a wide range of applications in both basic science and technological innovation. Reliable turnkey operation with sub-optical-cycle and sub-femtosecond timing jitter is key to the success of many intriguing microcomb applications at the intersection of ultrafast optics and microwave electronics. Here we propose a novel approach to demonstrate the first turnkey Brillouin-DKS frequency comb. Our approach with a Chimera cavity offers essential benefits that are not attainable previously, including phase insensitivity, self-healing capability, deterministic selection of DKS state, and access to the ultralow noise comb state. The demonstrated turnkey Brillouin-DKS frequency comb achieves a fundamental comb linewidth of 100 mHz and DKS timing jitter of 1 femtosecond for averaging times up to 56 μs. The approach is universal and generalizable to various device platforms for user-friendly and field-deployable comb devices. Dissipative Kerr soliton (DKS) frequency comb, generated by pumping an ultrahigh-quality-factor resonator, has been a ground-breaking technology with a remarkable breadth of demonstrated applications , 2. DKS In time domain, DKS timing jitter is the key property that determines its applicability as an optical flywheel –9, whereSub-optical-cycle and sub-femtosecond timing jitter has long been theoretically predicted to be the DKS timing jitter’s quantum limit . HoweverThe remaining major obstacle to the widespread application of the Brillouin-DKS frequency comb is the lack of turnkey operation that mitigates the complex comb initiation dynamics and eliminates sophisticated feedback electronics  to achieve compact footprint, low power consumption, and environmental ruggedness for the long-sought-after goal of user-friendly and field-deployable comb devices.Here, we devise and demonstrate the first turnkey Brillouin-DKS frequency comb by combining the two-step pumping scheme and active laser gain that realizes decoupling between the pump generation and the comb generation. We build a Chimera cavity that consists of a comb-generating passive FP microresonator nested in a pump-generating active ring cavity . The Chi8, and 10.087 GHz respectively . If the offset frequency between pump and Brillouin mode resonances is set to be slightly larger than the SBS frequency shift, blue-detuned pump and red-detuned SBL can simultaneously exist in the microresonator. Their opposite thermal nonlinearities can compensate each out and render such Brillouin-DKS thermally stable and manually accessible with expanded existence range. In the Chimera cavity, the pump-generating active ring cavity keeps the pump detuning around the resonance peak as the lasing will self-organize itself to the minimum loss and the maximum gain . When thWhile the DKS attractor state is mainly defined by the microresonator, the turnkey dynamics closely follows the optical pathlength change of the active ring cavity that is caused by refractive index increase and thermal expansion resulting from the EDFA pump absorption –34. FiguTo demonstrate repeatable turnkey operation, the 980-nm laser of the EDFA is modulated by a chopper with a square-wave profile to mimic the turn-on process. As shown in The generated Brillouin-DKS in our Chimera cavity is strongly immune to the environmental perturbation, including the fiber cavity length change, the vibration and temperature change. f2 trend with the offset frequencies, but also reaches lower noise of −166 dBc/Hz at 1 MHz offset frequency. The ultralow soliton phase noise can benefit critical applications including photonic ADCs, ultrafast optical ranging, coherent waveform synthesizers and timing distribution links.Owing to the narrow linewidth for both the lasing pump and the SBL, the achieved SBS frequency shift at10.347 GHz is a good frequency synthesizer with low SSB phase noise of −107 dBc/Hz at 100 kHz , whose pThe long-term stability of the SBL soliton microcombs is also examined to be excellent in the laboratory environment . During Our Chimera cavity, where pump generation in the active cavity and DKS generation in the microresonator are decoupled, is a universal topology for turnkey DKS generation and has the potential for fully on-chip integration. Silicon nitride Vernier microring filter has been proven effective as a narrow on-chip BPF . HeterogIn conclusion, we demonstrate a novel and universal approach to mitigate previous challenges and achieve reliable turnkey DKS frequency comb generation. Phase insensitivity, self-healing capability, deterministic selection of DKS state, and access to the ultralow noise comb state are all successfully accomplished. The turnkey Brillouin-DKS frequency comb achieves a fundamental comb linewidth of 100 mHz and DKS timing jitter of 1 femtosecond for averaging times up to 56 μs, rendering it suitable for applications at the intersection of ultrafast optics and microwave electronics such as photonic ADCs, ultrafast optical ranging, coherent waveform synthesizers, and timing distribution links. The approach can be generalized to photonic integrated circuit platforms for mass production of user-friendly and field-deployable comb devices.Our high-Q MMF FP microresonator is fabricated through three steps: (i) commercial MMF  is carefully cleaved and encapsuled in a ceramic fiber ferrule; (ii) both fiber ends are mechanically polished to sub-wavelength smoothness; (iii) both fiber ends are coated with optical dielectric Bragg mirror with reflectivity over 99.9% from 1530 to 1570 nm. The large mode area of the MMF leads to low diffraction losses in the thick dielectric Bragg mirror coatings at both ends and results in ultra-high Qs for both the internal pump mode and Brillouin mode [2/mm [The 10-mm long FP microresonator, corresponding to a OPL of ~29 mm, results in a cold-cavity free spectral range of 10.087 GHz, which is ready for microwave photonics applications. The group velocity dispersions of all the supported modes are simulated to be anomalous of ~−28 fsThe ultrahigh-Q microresonator acts as two roles here: (i) a high-finesse etalon filter in the fiber laser cavity responsible for single-frequency pump mode with low frequency noise; (ii) the device generating SBL and corresponding DKS.The fiber cavity includes 2-m gain giber, 5-m passive fiber and 1-m free space length, resulting in OPL of 11.2 m and a FSR of 26.8 MHz. The EDFA is home-made, consisting of a 2-m highly Erbium-doped fiber . The narrow BPF is consisted of a circulator and a temperature-controlled FBG centered at 1552.436 nm with 3-dB bandwidth of 0.068 nm (8.5 GHz). In order to achieve low coupling loss, free-space components are introduced to couple the light into and out from the MMF FP microresonator with one-end coupling efficiency of ~70%. We believe all-fiber integration is feasible due to the compatibility between the MMF FP microresonator and other fiber components. The EDFA part and narrowband filter part with 3-m total bare fiber is shielded but not temperature controlled while the other components are exposed to the lab environment including the 4-m passive fiber protected with 0.9-mm jacket. The optical circulator ensures the unidirectional lasing of the fiber cavity and couples out the high-power single-frequency pump laser. The polarization controller is used to maximize the coupling efficiency into the microresonator.8 according to our previous experiment data with the same kind of large-mode-area FP microresonators [The Q of the Brillouin mode is not measured due to the difficulty of finding the high-order MMF mode and the low coupling efficiency between the single-mode fiber and MMF. However, we can still estimate its Q to be large than 1´10sonators . In addiA phase modulator is inserted in the fiber cavity for all the experiments to monitor the detuning of the lasing pump mode via the powerful PDH technique. The phase modulator is inserted before the BPF . The modThe pump laser frequency shift is monitored by the beat note between the pump laser and a tunable ECDL. The beat note is measured by an electrical spectrum analyzer  at 4 Hz to show its evolution.The comb power is monitored by a filter centered at 1554.5 nm with 3-dB bandwidth of 0.5 nm.The fine tuning of the fiber cavity length at micrometer level is realized by a piezoelectric stack, whose voltage-displacement curve is calibrated by an MZI.We choose the 2-FSR perfect soliton crystal to characterize the turnkey soliton performance in A self-heterodyne frequency discriminator using a fiber based unbalanced MZI and a balanced photodetector (BPD) is employed to measure the laser phase noise and fundamental linewidth. One arm of the unbalanced MZI is made of 250-m-long single mode fiber, while the other arm consists of an acousto-optic frequency shifter with frequency shift of 200 MHz and a polarization controller for high-voltage output. The FSR of the unbalanced MZI is 0.85 MHz. The two 50:50 outputs of the unbalanced MZI are connected to a BPD  with a bandwidth of 400 MHz to reduce the impact of detector intensity fluctuations. The balanced output is then analyzed by a phase noise analyzer . The minimum fundamental linewidth that can be measured by this frequency discriminator is below 10 mHz. Other details of the laser frequency noise measurement can be found in Ref. .The RF beat note of the soliton repetition rate is directly detected by a fast photodetector  and measured by an electrical spectrum analyzer  at 5 Hz to show its evolution. Since the soliton phase noise measurement based on fast photodetectors is limited not only by the shot noise but also the available electronics operating at high frequency, we introduce the ARMI setup ,9,40,41 We electrically divide the RF beat note of the SBS frequency shift of 10.347 GHz by 8 times to 1.29 GHz and then measure its phase noise with a downconverter  and a phase noise analyzer .


COVID-19 case was first identified in Canada on January 25, 2020, on a Toronto resident who had travelled to Wuhan China, and not long after, the WHO declared the viral infection a pandemic. Ontario health West created an online self-assessment portal that allowed individuals in the health region and adjourning areas to report any COVID related symptoms. The purpose of this study was to evaluate the utility and usefulness of the Ontario Heath West online COVID-19 self-assessment portal. Record level data obtained from the Ontario Health West self-assessment portal was analyzed. Descriptive statistics using charts and graphs were used to characterize the distribution of responses to the portal. In-depth analysis using correlation, lead-lag analysis, and trend comparison with actual Government of Ontario COVID-19 cases for the region were also conducted. A total of 34,144 distinct responses were recorded on the portal between April 10 and July 29, 2020, with 1,250 (3.7%) responding positively to one of the emergency symptoms questions. Trend analysis showed a peak portal response in May 2020 with a smaller rise subsequently in July 2020, coinciding with the actual COVID-19 peak in the region. The five most reported symptoms on the portal were sore throat (17.2%), headache (12.9%), fatigue (12.3%), digestive problems (12.2%) and cough (9.1%). For four sub-regions, the trend of self-report on the portal positively lagged actual Public Health Ontario reported COVID-19 cases, while for one sub-region, the trend positively led the actual Public Health Ontario reported COVID-19 cases for the area. We found correlation between online COVID-19 self- assessment data and the confirmed COVID-19 cases in the Southwestern region of Ontario. Trends in the COVID-19 associated emergency symptoms reported on the portal also tracked confirmed COVID-19 cases in the community. Peak response to the portal coincided with the peak volume of confirmed cases in Ontario during the first wave of COVID-19 pandemic in Canada, suggesting some consistency between the experiences of portal users and patterns of COVID-19 illness in the community. The portal was a useful tool at the person-level because it provided guidance to individuals about how to access appropriate health services according to the symptoms that they reported and connected them with primary care, reducing unnecessary visit to health facilities for COVID-19 related care. The World Health Organization declared a global pandemic of Coronavirus disease (COVID-19) on March 11, 20202. By March 24, 2020, Health Canada reported that local transmission was the primary cause for new cases in Canada with 2,792 cases confirmed by that point. There was a clear need for a systematic approach to managing the response to COVID-19 that would: (a) identify new cases in the community; (b) educate and guide the general population to help them to detect and respond appropriately to potential COVID-19 symptoms, and (c) provide a linkage mechanism that would provide a targeted referral for testing and clinical follow-up with their primary care based on those potential symptoms.The first case of COVID-19 in Canada was identified on January 25, 2020, and involved a Toronto resident who had travelled to Wuhan, China5. The Ontario Health West Region created such a tool in partnership with Input Health, and the system became fully operational in early April 2020. The portal which is now deactivated [URL link: http://lmcovid19.inputhealth.com] provided individuals in the region and other neighbouring regions with the opportunity to self-assess for COVID-19 related symptoms.One aspect of the response undertaken by multiple jurisdictions in the world was to create online tools that would allow members of the public to self-assess their own health status to receive advice on what response may be appropriate given their resultshttps://data.ontario.ca/dataset/confirmed-positive-cases-of-covid-19-in-ontario/resource/455fd63b-603d-4608-8216-7d8647f43350]. The symptoms variables were treated as binary categorical, and a K-Mode clustering algorithm was applied to find hidden clusters in the dataset.We analyzed record level data obtained from the Ontario Health West Region self-assessment portal. All data were anonymous and do not include demographic measures . Individuals who responded positively to any of the initial emergency symptoms screening questions did not receive further self-assessment screening on the portal and were therefore excluded from the comprehensive analysis. The initial emergency symptoms include a) severe difficulty breathing , b) severe chest pain (Constant tightness or crushing sensation), c) feeling confused  and d) losing consciousness with a No/Yes response. However, we performed a specific trend comparison between reported emergency symptoms and actual Public Health Ontario general population COVID-19 cases for the region. Information regarding the government of Ontario confirmed COVID-19 cases can be obtained by clicking on the link: [Descriptive statistics including frequencies and bar charts were used to describe the comprehensive data. Spearman’s correlation was used to determine associations between the reported portal symptoms, while a plus-minus 3 weeks lead-lag correlation matrix was created to determine correlations between the number of people who reported symptoms on the portal and the number of actual reported COVID-19 cases per region. All analyses were restricted to responses from persons residing in the forward sortation area (FSA) beginning with ‘N’ representing southwest Ontario.This study conforms to applicable and relevant guidelines. Being a completely anonymized, non-intervention online survey, no ethics approval was required. No identifying information was collected for this study and all analyses were conducted at the population level. This study was carried out using only data from the Ontario Health West self-assessment portal and there was no direct involvement of participants.rd week of June.A total of 34,144 distinct responses were collected between April 10 and July 29, 2020. Out of these, 1250 (3.7%) responses were positive for having any emergency symptoms and were subsequently referred to the next step in care management. A further 14,340 responses (42.0%) indicated the presence of other, non-emergency symptoms potentially related to COVID-19. Another 3112 (9.1%) responses indicated the presence of high-risk health conditions  without potential COVID-19 symptoms being present. Figure Responses to the portal questionnaire differentiated between the presence of any of a set of emergency symptoms  that would require immediate medical attention and other symptoms that may be indicative of COVID-19 but were not considered to require emergency care. Figure A total of 31,016 (99.6%) responses came from individuals who stated that they live in the FSA ‘N’ area, the primary catchment area for which the portal was set up. Figure 6 to estimate the number of responses per 1000 residents in each postal code sub-region. FSA beginning with N6 had the highest per capita response, whereas those beginning with N7 had both the lowest per capita response , 74.2%  had a primary health care provider that they were referred to for follow-up. These respondents were able to avoid emergency room visits and directed to contact the COVID-19 assessment center, because they could be appropriately served by primary care based on their response profile. About 17% of responses with symptoms had no primary health care provider; however, they were supported through access to an on-call provider.Following the initial analysis suggesting similar trends between number of respondents with symptoms on the portal self-assessment and actual number of COVID-19 cases in the region, we conducted further in-depth statistical analysis of this association. We standardized the number of portal symptoms and COVID-19 case by computing each number per 1000 population of the respective postal code. To ensure we covered for possible temporal variations in association, we computed up to 3 weeks lag and lead correlations between the portal symptoms and actual COVID-19 outbreaks.negatively correlated with the number of COVID-19 cases. However, in a few sub-regions there were some significant positive correlations between number of symptoms reported through the portal and the actual number of COVID-19 cases reported to government of Ontario.For all the sub-regions, the number of people who reported each symptom were mostly after the increase in actual COVID-19 cases reported to government of Ontario for each of the sub-regions. This suggests that individuals came to the portal in response to outbreaks happening in their sub-region.In regions with first two digits of the postal code, ‘N4’–‘N6’, the symptoms inconsistently showed significant positive correlation with actual number of COVID-19 cases for the region, with a 2–3 weeks lag time. This seems to suggest that in these sub-regions, portal symptoms reports started to rise about 2 or 3 weeks before COVID-19 cases began to rise in the area. Table Conversely, for sub-regions with the first two digits of postal code of ‘N3’, there were some positive correlations between some symptoms and actual COVID-19 cases, but with a lead time suggesting that people increasingly began to report such symptoms on the portal one to two weeks 7. This does not suggest the portal data could be used for epidemiological purposes, but it does suggest some consistency between the experiences of portal users and patterns of COVID-19 illness in the community.In this analysis, we found some correlation between online COVID-19 self- assessment data and an actual confirmed COVID-19 cases in the Southwestern region of Ontario. Although trends in the two self-assessments (emergency symptoms and any symptoms) and actual COVID-19 indicators were not identical, there was a somewhat consistent pattern between the portal symptom responses and confirmed cases in the community. Peak response to the portal coincided with the peak volume of confirmed cases in Ontario during the first wave of COVID-19 pandemic in CanadaThe inconsistent picture obtained from the analysis of portal responses may have been due to several reasons. First, awareness and utilization of the portal among the general population in the region of may have been low. Reduced utilization rates compared to the population size could potentially bias the finding towards the characteristics of only those who are aware of the portal.Secondly, the different correlations showing lead in some regions and lag in others, might reflect the actual difference in epidemiology and management response to COVID-19 by region during the period under this review. Different regions  began to experience COVID-19 cases at different times and the rate and speed of detection also differed by the sub-regions. The picture obtained through the Ontario Health West Region portal may suggest that postal code areas in the region experienced their COVID-19 outbreaks differently. Also, testing and detection may have proceeded at different pace and coverage during the 1st wave of the pandemic. Therefore, these results suggest that caution should be used with respect to the utility of such a portal in foretelling subsequent infection patterns in the population.While the Ontario Health West COVID-19 self-assessment portal had some limitations that constrained its utility for public health or epidemiological reporting, it served a valuable health system function in providing the public with an accessible source of information about COVID-19 and linked them to appropriate services they may use like a primary care assessment. The patterns evident in our early analyses suggested that there was some tendency for response patterns in the portal to mirror trends related to COVID-19 reported by government of Ontario. However, there was an inconsistent relationship between symptom reporting on the portal and subsequent COVID-19 outbreaks. Nonetheless, at the person level, this portal served a useful health system function in helping individuals to better understand their health needs and the services they may require.With respect to any future waves of the COVID-19 pandemic, we would note the following recommendations for improvement of this or similar portals. First, these portals should capture information on demographic characteristics including age, sex, and ethnicity, since it is known that COVID-19 affects different subgroups with differing severity and different event rates for adverse outcomes. Second, skip patterns should generally be avoided. The small-time savings gained by not gathering additional information is not worth the loss of information that could have informed symptom profiling or severity measures. Third, it is essential to track clinical and service use outcomes. The portal did not allow adequate linkages to determine what levels of service use or clinical outcomes were associated with the symptom characteristics reported in the portal. This limited the ability to use statistical analyses or machine learning to identify important subgroups of respondents that may have warranted additional attention based on symptom clusters. Fourth, while the portal had limited population level applications for epidemiological tracking or analyses, it was a useful tool at the person-level because it provided guidance to individuals about how to access appropriate health services according to the symptoms that they reported and connected them with primary care. In that sense, continued public access to portals of this type for subsequent waves of COVID-19 could be beneficial.Supplementary Information.


Compared with combustible cigarettes, electronic cigarettes (e-cigarettes) can deliver a sufficient amount of nicotine with a significantly reduced emission of toxicants, which renders them as potential harm reduction candidates for tobacco and smoking replacement. However, the use of e-cigarettes is not harm free and the long-term health effect of using e-cigarettes is yet to be established. Given the high prevalence of e-cigarette use across the globe and its potential health concerns, it is imperative to conduct actual use behavior assessments to better understand how e-cigarettes are being consumed in real-world conditions. However, with the currently available technologies, there is still a lack of noninvasive, noninterventional, and convenient instruments for the real-time and real-world use behavior monitoring of e-cigarette product use. Novel technology-based systems that do not primarily rely on self-report or intrusive measurements to monitor e-cigarette use behaviors are therefore highly desired.The primary goal of this study is to investigate the e-cigarette actual use behaviors in the real world via a novel puff recording electronic nicotine delivery system (PR-ENDS). Specifically, we aim to analyze and summarize the survey and PR-ENDS use data and to study the relationships and effects of different factors on these variables.In real-world conditions, 61 enrolled UK e-cigarette users were instructed to use PR-ENDS as the primary source of nicotine with their selected e-liquids for at least 3 weeks (21 days). A baseline survey was conducted to collect information about participants’ demographics and nicotine use history (cigarette and ENDS). The puff data  were directly recorded by PR-ENDS and uploaded to the cloud for further analyses. The nicotine emission and nicotine consumption were estimated based on recorded puff data.Middle-aged adults with a nicotine history represented the major user profile during the PR-ENDS trial. A wide range of device power and e-liquid nicotine concentrations was applied and their combinations during actual use were found to be rather complex. Various puff parameters  were assessed with contributing factors from device, e-liquid, and user nicotine history in different effect sizes. The real-time observation revealed substantial intra- and interindividual variabilities in PR-ENDS use behaviors. The use pattern of a quick adaptation followed by consistent product use was recognized for at least 3 weeks during actual use.The actual use behavior assessment of PR-ENDS was conducted as a proof-of-concept application. The complex interactions of product attributes and significant intra- and interindividual variabilities in e-cigarette use behaviors provided new insights of compensatory behavior, which can inspire future studies in the field of nicotine addiction and abuse liability behavior assessment. Regardless of the increasing prevalence of electronic cigarettes (e-cigarettes) worldwide, little is known about how these products are being used in the real world . Indeed,Until now, many efforts have been made toward assessing the actual use behaviors of e-cigarettes -13. HoweTo conduct actual use behavior assessment of e-cigarettes in the real world, the ideal practice should incorporate several considerations. First, the assessment needs to be conducted in a noninvasive and noninterventional fashion, as e-cigarette users under managed observation tend toward behavior different from that in habitual use ,15. SecoVarious methods have been applied to monitor the puff topography and puffing behavior during the actual use of e-cigarettes. However, limitations still exist. These include recall and response bias -19, unnaThe aforesaid design features of PR-ENDS allow us to conduct real-time, actual use behavior assessment to investigate device-specific puff topography and puffing behaviors in a naturalistic manner at both individual and population levels. In this report, we investigate real-world and real-time e-cigarette use behaviors with the help of data collected from PR-ENDS devices. Specific objectives focus on (1) investigating the usage of PR-ENDS with combinations of different device powers and e-liquids; (2) assessing puff topography and puffing behaviors  of the observed cohort during actual use; (3) quantifying the correlation effects between puff topography and PR-ENDS–specific product attributes and user nicotine profile; (4) exploring real-time behavior patterns of PR-ENDS users during actual use and over a period of 3 weeks and beyond.The actual use behavior assessment of PR-ENDS includes observing a single group of e-cigarette users enrolled during a product trial study in the UK via vape shops. In total, 61 participants agreed to participate in the assessment, with a requirement of using the PR-ENDS device as their primary source of nicotine with their selected e-liquids for the trial duration. Additional inclusion criteria include (1) older than 18 years ; (2) does not have a history of chronic disease or psychiatric condition; (3) does not regularly use prescription medication; (4) not pregnant; and (5) not enrolled in a smoking cessation program. The recruited participants were instructed to use the PR-ENDS device together with a Bluetooth paired smartphone/computer-based app from the beginning of the product trial. A baseline survey was conducted to collect information about participants’ demographics and nicotine use history (cigarette and ENDS). Only the unique device ID was used to differentiate users, and no personally identifiable information was collected. Participants consented to release the survey and puff topography data for marketing research, regulatory submission, and publications.After completing the baseline survey, participants were instructed to use the PR-ENDS device in real-world conditions for 3 weeks (21 days). At the end of the third week, a follow-up survey was conducted to collect information about any adverse events experienced by participants. If no adverse events were identified or reported, and the participant expressed the willingness to continue using the PR-ENDS device, they had the option to be enrolled in an extension of the trial. The first data point of PR-ENDS use in the behavior assessment was observed on February 22, 2022, and as of April 21, 2022, more than 200,000 individual puff data had been collected. The duration of the actual use observation of the PR-ENDS device in this paper is therefore considered 2 months.During the actual use trial, participants were asked to use the PR-ENDS device as their primary source of nicotine with selected e-liquids. The number and duration for each puff were directly recorded by PR-ENDS and uploaded to the app, and synchronized with the cloud. The nicotine emission per PR-ENDS puff was estimated based on recorded puff duration, e-liquid nicotine concentration, device power, and nicotine emission laboratory testing result. The detailed computational formula and assumptions applied in the calculation are listed in Appendix S1 in R2 coefficient and Cohen d  were calculated to interpret the magnitude of effect size. Coefficient of variance was also calculated to estimate the variability of parameters such as daily puff number, puff duration, and daily nicotine consumption.Descriptive statistics, including mean (average), SD, and SE were calculated. The statistical significance is rather uninformative due to the large puff sample size  . InsteadThis observational study is on a commercially soft-launched product in the United Kingdom. Customers voluntarily participated and signed the product trial agreement with the distributor . The participants consented to have the puff behavior data recorded by PR-ENDS and used for market research, scientific research, and publications. No personally identifiable information was collected and available to the authors. Upon completing the product trial, participants received £30 (US $36) Totally Wicked store credit to redeem for their subsequent purchases.Information about participants’ demographics and nicotine history collected from the baseline survey is presented in As shown in The PR-ENDS device was designed with 3 discrete power settings for the purpose of supplying different ranges of wattage  to heat e-liquids. During the actual use session, the contribution to PR-ENDS total puffs was divided by combinations of different power settings and e-liquid nicotine concentrations . Instead, R2 coefficient and Cohen d  are better suited for interpreting the magnitude of effect size in statistical analysis.During the actual use, various factors, including device, e-liquid, and user profile, would influence the puff duration. To assess the effect of different factors on PR-ENDS puffs, the measured puff durations were compared by device power, e-liquid nicotine concentration, and nicotine use history (cigarette and ENDS). Given the large puff sample size , the statistical difference in puff duration identified by variable comparisons such as ANOVA is uninformative  on PR-ENDS puff duration. As shown in d=0.573). Based on the comparisons shown in R2=0.005-0.060). However, more years of ENDS use is moderately associated with higher puff durations, with the results shown in the differences of puff durations between >10 years and 6 months to 1 year, and between 1-5 years and 6 months to 1 year . Albeit, interestingly, as shown in d>0.5), but not between high and low power (Cohen d < 0.5). Such observations indicated that users preferred applying medium power instead of low or (even) high power for a higher nicotine emission within a single PR-ENDS puff. This can be ascribed to the complex interaction effect of combining different device power and e-liquid nicotine concentrations during the actual use of ENDS [To assess the effect of different factors on nicotine emissions during PR-ENDS actual use, the calculated values were compared by device power, e-liquid nicotine concentration, and nicotine use history (cigarette and ENDS) accordingly. Based on  of ENDS , and theR2=0.422), followed by years of ENDS use (R2=0.351) and cigarette smoking history (R2=0.246). Coherent with high R2 coefficients, d values , the daily puff numbers, puff durations, and daily nicotine consumptions for each user can be calculated and the statistics of actual use puffing behavior parameters are summarized in Table S5 in The real-time PR-ENDS use (in daily puff numbers per user) is presented in Besides the diverse PR-ENDS use patterns in different participants, substantial variabilities of puffing behaviors within the same user profile over time can be found. From the perspective of group behavior assessment, longitudinal observations of PR-ENDS puffing behaviors over time  should be treated as strong indicators to interpret the product-specific nicotine addiction potential and abuse liability ,37. SpecFor puffs per day, as shown in For puff duration per day, as shown in Lastly, for nicotine consumption per day of the cohort group, as shown in In this report, actual use behavior assessments of a novel PR-ENDS device during a 2-month long observation session were discussed. It was found that the PR-ENDS device was primarily consumed by existing nicotine product users who are well past young adulthood, which is likely due to the design feature of PR-ENDS as a complicated open e-cigarette system that entails smoking or vaping experience. It is expected that nicotine naïve users are not primarily interested in using this device. As an ENDS product that requires e-liquid refill and wattage adjustment , a diverse range of e-liquid nicotine concentrations and a complex interactive effect between e-liquid nicotine concentrations and device powers were recognized based on information collected from PR-ENDS. For example, high power was recognized as the most prevalently used power setting when the device was combined with low (≤6 mg/mL) and high (≥14 mg/mL) nicotine e-liquids; medium power of the device contributed much more puffs with medium (6-14 mg/mL) nicotine e-liquids, whereas low power is predominantly used for 0 nicotine e-liquid (0 mg/mL). Such observation highlighted the importance of being able to provide a wide range of device powers and e-liquid nicotine concentrations during e-cigarette actual use for reducing nicotine craving and smoking transition. In fact, previous clinical trials have clearly proven that open refillable e-cigarettes that enable free choices of e-liquids led to more significant smoking abstinence rates compared with self-abstinence and nicotine-replacement groups ,39.R2 coefficient and Cohen d) unveiled that none of the aforesaid factors yielded a significant change in puff duration during actual use.The PR-ENDS device–collected information showed a reasonable distribution of puff duration  based on >200,000 individual puff data. The observed puff duration during actual use is very close to the value proposed in aerosol testing protocols ,32. The Considering that the puff topography and PR-ENDS–specific information in estimating nicotine consumption  was collected in situ, it is viable to evaluate the PR-ENDS device–based nicotine emission estimates, as well as to assess the implications on nicotine use by comparing nicotine emissions under different factors. For example, it was observed that medium power was associated with the highest average nicotine emission per puff compared with low or high power. This is probably due to the fact that medium power was much more frequently used with medium (6-14 mg/mL) and high (≥14 mg/mL) nicotine e-liquids and that higher nicotine concentrations are prone to yield higher nicotine emissions in product use . What isWith puff data recorded in real-time, we further considered the time course of PR-ENDS puffing behavior at both individual and population levels. When the puff data are viewed by each user profile over the period of actual use, different product use patterns in daily puff numbers can be recognized such that some participants had a consistent trend in puffs per day with PR-ENDS, while others chose to use the device sporadically without continuity of use over time. Further, the calculation of the coefficient of variance from puffs per day and nicotine consumption for the same PR-ENDS user showed a large variability over their own active period. These observations, taken together, highlighted the considerable unpredictability in both inter and intraindividual actual use of puffing behaviors and emphasized the importance of discovering puffing behavior patterns at the individual level with real-time feedback.By contrast, the time course of the entire PR-ENDS cohort consistently showed a quick adaptation to device use followed by a consistent use pattern. As presented in The observed trend of the PR-ENDS device–estimated daily nicotine consumption rendered a similar use pattern over time as the daily puff number in the user group. The users’ daily nicotine consumption was observed with an initial increase step in 1-2 days followed by consistent use for at least 3 weeks or 21 days. The eventually stabilized daily nicotine consumption was found to be around 12 mg/day. A direct comparison of daily nicotine consumption between PR-ENDS and other nicotine products is challenging. However, based on a previous study conducted on the daily intake of nicotine from cigarette smoking  with an We acknowledge that the actual use behavior assessment has a few limitations. First, because the assessment was conducted in a real-world condition, the participants were not closely monitored but only traced by the follow-up survey. As a result, 3/61 participants did not provide their PR-ENDS device ID, which did not allow the association with their actual use behavior. However, it is believed that the reported puff data of 58 participants with 200,411 puffs are sufficient to depict the actual use behavior of the observed PR-ENDS population throughout the period of 2 months. Second, the e-liquid information  collected from the PR-ENDS device was self-reported by users and was used to estimate the nicotine consumption per puff and per day. The calculation was theoretical and based on certain assumptions that have not been experimentally verified, although a similar example in nicotine consumption estimation has been clinically validated  and is rSome key strengths of the actual use behavior assessment are as follows: (1) This is the first observational behavior assessment conducted in real-world conditions that systematically examined the puff topography and puffing behavior at both individual and population levels. (2) For the first time, we identified the complex interactions between device power and e-liquid nicotine concentrations in e-cigarette actual use and their effects on puff topography and use behaviors. (3) The real-time observations on PR-ENDS actual use revealed that a significant variability of puffing behaviors exists between different users and within the same individual user over time. A quick adaptation pattern (an increase of puff number and puff duration followed by stabilized product use for at least 3 weeks) was observed for the first time when the cohort was assessed as a whole.In summary, a real-time, actual use behavior assessment was conducted to investigate PR-ENDS–specific puff topography and puffing behaviors at both individual and population levels. It was observed that middle-aged adults with nicotine use history represented the major user profile, and a wide range of device power and e-liquid nicotine concentrations was applied during PR-ENDS actual use. Various puff topography and puffing behavior parameters  were assessed with the identification of contributing factors from device, e-liquid, and user nicotine history. The real-time observations of PR-ENDS puffing behavior further revealed the intra- and interindividual behavior variabilities, as well as a quick adaptation pattern followed by stabilized product use for at least 3 weeks.


Anti-Spike monoclonal antibodies have been considered a promising approach to COVID-19 therapy. Unfortunately, the advent of resistant lineages jeopardized their effectiveness and prompted limitations in their clinical use. Change in the dominant variant can be fast to such an extent that, in the absence of timely medical education, prescribers can keep using these drugs for relatively long periods even in patients with resistant variants. Therefore, many patients could have been exposed to drugs with unlikely benefits and probable risks. We show here that about 20% of bamlanivimab+etesevimab, 30% of casirivimab+imdevimab, and 30% of sotrovimab courses were administered in Italy during periods in which a fully resistant variant was dominant. Additionally, for monoclonal antibody cocktails, the vast majority of usage occurred against variants for which one of the mAbs within the cocktail was ineffective. Given the high costs of these drugs and their potential side effects, it would be important to consider a frequent review of the appropriateness of these drugs and timely communication when the benefit/risk balance is no longer favorable. Anti-SARS-CoV-2 Spike monoclonal antibody (mAb), either as monotherapy or as a cocktail of mAbs, was a pillar of COVID-19 outpatient treatments in the second half of 2021, when sensitive variants of concern (VOCs) ravaged the globe. As for any other European Medicine Agency (EMA) member nations, the Italian Drug Agency  promptly granted mAb authorization. Despite growing evidence of treatment-emergent resistance ,4,5,6.While randomized controlled trials (RCT) that led to product authorization by regulatory authorities were led at the time of sensitive VOCs, in vitro data have consistently shown that the Omicron BA.1 VOC was notoriously resistant to both bamlanivimab and etesevimab ,15,16,17The tixagevimab plus cilgavimab mAb cocktail, approved to date only for pre-exposure prophylaxis, represents a special case: while the tixagevimab component has been ineffective against any Omicron sublineage so far , questioning whether continued medical education was timely in place to avoid hazardous and expensive prescriptions. While only a few patients had viral genome sequencing performed to confirm definitive resistance, statistical inferences can be made moving from prevalences detected by epidemiological surveillance. In this article, we investigated the use of anti-SARS-CoV-2 Spike mAbs in patients affected by resistant SARS-CoV-2 VOCs in Italy.https://www.iss.it/web/guest/cov19-cosa-fa-iss-varianti (accessed on 15 June 2022). Briefly, according to the indications from the Italian Ministry of Health, every 15 days about 2000 newly diagnosed COVID-19 patients with positive RT-PCR are further processed with whole-genome sequencing (WGS), and the sequences are attributed to PANGOLIN phylogeny using a dedicated web portal (ICOGEN).We collected prevalence data of different SARS-CoV-2 variants in Italy from the reports of the flash surveys led by the Italian Istituto Superiore di Sanità (ISS) from 25 May 2021 to 27 May 2022, available at https://www.aifa.gov.it (accessed on 15 June 2022). The monitoring registry was established according to a Ministry of Health decree issued on 6 February 2021. Briefly, every 7 days (every 15 days since May 2022) a report is issued showing the cumulative count of prescriptions for each anti-Spike mAb. In order to keep the graph at a weekly sampling, 15-day counts were manually estimated as 7-day counts, assuming a homogenous within-period daily distribution. In order to account for the high standard deviation related to the small sample size, we considered two different thresholds of SARS-CoV-2 VOC diffusion in the population (50% and 99%) to identify periods in which the prescriptions of the mAbs could have likely occurred in patients harboring a resistant VOC. We collected absolute prescription counts for each authorized anti-Spike mAb (or mAb cocktail) from the Italian Drug Agency  web portal, available at The bamlanivimab and etesevimab cocktail was authorized by the AIFA on 17 March 2021. The casirivimab and imdevimab cocktail was authorized by the AIFA on 26 November 2021, while sotrovimab was authorized on 23 December 2021. Finally, the tixagevimab plus cilgavimab cocktail was authorized by the AIFA on 25 March 2022. At the time of writing, neither the EMA nor the AIFA have withdrawn authorization for any of these mAbs.Our analysis showed that a relevant proportion of anti-SARS-CoV-2 Spike mAb prescriptions in Italy could have occurred in patients with resistant disease. Given that national regulatory authorities within Europe usually act in alignment with recommendations by the EMA, we cannot exclude that, in the absence of any communication by the EMA, the situation could be similar in many other European countries. To the best of our knowledge, no other study investigating this issue has been published so far using data from other European countries. In this regard, the policy of access to COVID-19 treatments deployed by the FDA appeared suitable to limit the use of these drugs in patients with probable resistant disease ,5.Despite the time shift of a couple of weeks between sample collection and flash survey reporting, this explanation is clearly not enough to account for the large share of mAbs used inappropriately. The alternate reasons for this delay in the adjustment of prescription habits should be analyzed in detail. We believe that the lack of RCTs to support in vitro evidence plays a prominent role in driving prescribers’ attitudes: e.g., most clinicians tend not to read or underestimate in vitro evidence, which was promptly released during the pandemic. Nowadays, resistance can be highly predicted on the basis of Spike mutational patterns observed in vitro . Our hypAn alternative hypothesis is that, when frail patients cannot tolerate small-chemical antivirals , available mAbs can apparently offer a tolerable option, particularly when other supposedly effective mAbs (bebtelovimab ) are notA third possibility is pressure from regional administrators to use large stocks that have been ordered and would otherwise remain unused. In this regard, fine-tuning of orders and pay-by-performance mechanisms could mitigate the risk.Although mAbs generally have a favorable safety profile, their prescription in patients with resistant COVID-19 disease comes with several drawbacks: under constrained resources (as it commonly occurs in pandemic settings), wastage of money invariably translates into less investment in alternative and possibly effective therapeutics. These considerations also apply to mAb cocktails where one of the ingredients is not effective.In summary, the timely medical update of the prescribers should be implemented in situations in which the epidemiological scenario of the disease is so dynamic. In these scenarios, regulatory agencies should consider closer monitoring of the epidemic patterns of the resistant variants of the disease and react with timely actions and communications.


Coronavirus disease 2019 (COVID-19) has been responsible for an epidemic of devastating proportion, and it has represented a challenge for worldwide healthcare systems with the need of resources reallocation in order to face epidemic spread. Italy was one of the hardest hit countries by COVID-19, and the Italian government adopted strict rules to contain the spread of the COVID-19 pandemic, such as national lockdown and home quarantine; moreover, the Italian healthcare system had to rapidly re-organize the diagnostic and therapeutic pathways, with a reallocation of health resources and hospital beds, in order to manage COVID-19 patients. The aim of the present review is to provide an overview of the effects of the first pandemic wave on cardiovascular assistance in Italy with the purpose of evaluating the strengths and weaknesses of the Italian health system. Coronavirus disease 2019 (COVID-19) is the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly pathogenic human coronavirus responsible for an epidemic of devastating proportion (over 650 million cumulative cases and over 6 million cumulative deaths worldwide) . The ItaSeveral observational studies described the impact of the COVID-19 outbreak on cardiac pacing and electrophysiology activities during the first lockdown in Italy .p-value < 0.05), more likely because of the reduction in planned hospitalizations following Italian government measures to contain SARS-CoV-2 in-hospital diffusion. No significant differences in both pacemaker (PM) and implantable cardiac defibrillator (ICD) replacement procedures  have been shown, more likely because of the increase in urgent unplanned hospitalizations. The increased use of remote monitoring (RM) to optimize the hospital admission time during COVID-19 lockdown for CIEDs recipients may explain these data [A retrospective multicenter study , carriedNo difference in the admission rate at Emergency Departments for patients in need of cardiac pacing was shown, in particular for those who experienced syncope ,10. ThisAn Italian national survey involving 104 physicians from 84 Italian arrhythmia centers  reportedp-value 0.001). The remarkable changes in the third-level SUs activities were more likely due to the reduction of patients referred from other hospital wards, which were converted into COVID-19 care centers [A retrospective multicenter observational study including 10 Italian Syncope Units (SUs), certified by the Italian Multidisciplinary Working Group on Syncope (GIMSI), suggested that COVID-19 lockdown was associated with a significant reduction rate in all the clinical activities related to the differential diagnosis of transient loss of consciousness (from 141 to 51 (−63%),  centers .p-value < 0.05) of acute coronary syndrome (ACS) hospitalizations , reporting a reduction in ACS admissions ranging from 48.4%  to 52.5%Despite the reduction in ACS hospitalizations, the severity of clinical presentation was on average higher than in the pre-COVID 19 period. A study, carried out at the Trieste University Hospital , highligThe low physical stress and the resting state during quarantine may have reduced the ACS incidence during COVID-19 pandemic; however, the “missed” ACS diagnosis are principally due to a medical care avoidance in COVID-19 era.Several studies evaluated the rate of heart failure (HF) hospitalizations during the COVID-19 pandemic; a reduction ranging from 49%  to 58%  has beenDespite this reduction, a higher prevalence of high-risk features at admission  with a higher number of patients in need of intensive care units (ICUs) have been shown .A similar trend was shown by a multicenter study including eight Italian hospitals , which cp-value = 0.11).An observational, retrospective study in the Tuscany region  showed aAs suggested by the Heart Failure Society of America  and EuroAn observational study, based on the data sourced from the current administrative electronic archives available at Italian Local Health Units (LHUs) participating at Italian Health–DB project , reporteAn observational study reported an 8.5% temporary interruption of the Proprotein Convertase Subtilisin/Kexin type 9 (PCSK-9) therapy for a mean period of 65 ± 1.5 days in patients with dyslipidemias treated with PCSK9 inhibitors (PCSK9i) who missed the cardiologic follow-up visit during the first lockdown. The non-adherent patients showed a marked increase in low-density lipoprotein cholesterol (LDL-C), and 82% of patients moved out of the LDL-C therapeutic range . ProbablThe impact of the COVID-19 pandemic on Italian Healthcare was characterized by a decrease in both hospitalizations and interventional procedures for cardiovascular diseases, in line with the trend of other European Countries, despite the different capacities and local policies about restriction in hospital admission ,30,31,32There are several reasons explaining the reduction in CVD hospitalization in Italy. First of all, the strict rules adopted by the Italian government to contain the spread of the COVID-19 pandemic limited the hospital admission to urgent conditions; the outpatient medical evaluations were stopped, compromising both primary and secondary cardiovascular prevention. Moreover, some patients who required urgent treatment did not refer to hospital or delayed hospital admission, worsening their clinical conditions at presentation, for the fear of in-hospital viral contagion .During the COVID-19 pandemic, the response to non-COVID-19 related emergency was delayed, with longer time in the transfer between spoke-to-hub structures ,20 and lThe Italian Healthcare System experienced a reallocation of resources and personnel, as a response to this unexpected pandemic, with negative implications in the management of other diseases; these conditions caused indirect and collateral damages on cardiovascular assistance. On the other hand, pre-existing cardiovascular disease or cardiac involvement due to COVID-19 often influenced hospital course and prognosis of COVID-19 patients . So, newThe increased TMS use helped the healthcare personnel to select cases in need of hospital care, avoiding direct physical contacts in order to reduce the risk of COVID-19 transmission and ensuring continuity in medical assistance pathways ,39. MoreIn conclusion, the COVID-19 pandemic offered us the opportunity to understand the limits of the Italian Health service in managing a sudden and unexpected health emergency and the surplus value of telemedicine in the patient’s follow-up, even in the post-COVID 19 period .This narrative review presents some limitations. First of all, it provides a national overview without data subdivision on the basis of the different Italian regions. So, it is not possible to correlate between the reduction in hospitalization rate reduction and the epidemiological pressure across the different Italian regions. Moreover, the overview is focused on the first pandemic wave leaving out a comparison with data relating to successive pandemic waves, which would have provided an analysis of healthcare long-term response to pandemic. Therefore, further analyses will be needed to investigate these aspects.The first wave of the COVID-19 pandemic has been responsible for a drastic reduction in the hospitalizations and interventional procedures for cardiovascular diseases, both elective and urgent. The rate of PM implantations for syncope and of CIEDs replacements remained stable compared to the pre-pandemic period. The increased use of TMS and CIEDs remote monitoring helped us to assure continuous care and to reduce the SARS-CoV-2 exposure for staff and physicians. The reallocation of healthcare resources led to delays in the management of time-dependent cardiovascular disease with severe prognostic impact, including a higher CV mortality during the COVID-19 pandemic than previous years.