Magnetism in atomically thin functional materials can be an important phenomenon for exploring two-dimensional magneto-optics. Magneto-optical experimental data have revealed significant Kerr signals in insulator thin films. Here, the magneto-optical Kerr effect of oxygen functionalized and doped hexagonal boron nitride (hBN) has been investigated by performing first-principles calculations. We calculated Kerr angle and Kerr ellipticity for functionalized hBN as an attention-drawn material. Moreover, increasing of oxygen doping percentage leads to the introduction of surface plasmon to hBN. Our findings show that the functionalized hBN can tolerate high-temperature conditions, keeping oxygen atoms bridge-bonded. These giant opto/magnetic responses of insulating 2D materials provide a platform for the potential designing of magneto-optical devices. Magneto-optical Kerr effect (MOKE), rotation of polarization plane of reflected light from magnetic substrates, has been used as a means of observing magnetic and electronic properties1. A recent discovery of two-dimensional (2D) magnets by using MOKE revealed their magneto-optical properties3 and aroused interest in applications in sensors, filters, and polarizers to nonlinear optical devices4.The magneto-optical (MO) effect as the output of interaction of magnetic materials with light has been characterized experimentally by measuring polarization state, phase, and intensity of light1. Among 2D materials, hBN is the most stable boron nitride structure6, the best graphene counterpart, large band-gap material, and a promising structure for opto-electronic and nanophotonic applications9, without dangling bonds and charge traps11. Furthermore, hBN successively has been used as dielectric gate material13. Also, it has been shown that graphene devices on hBN dielectric possess enhanced stability, atomically smooth surface, intrinsic potential, and also lower scattering charge traps in comparison with graphene devices on SiO2 dielectric so it is an evidence for the most comprehensive dielectric layer used so far for graphene electronics15. The density of nanoparticles on the surface of boron nitride nanosheet (BNNS) can be controlled accurately through the synthesis adjustment and changing the reaction parameters16. Li et al.17 in a comprehensive DFT calculation, have considered the atomic structure and magnetic properties of configurations of a wide range of transition metals adsorbed on single-layer boron nitride. They divided these elements into two groups: one with adsorption energies lower than 0.5 eV and the other with higher ones which are following physical and chemical adsorption processes, respectively. Therefore, they concluded that this behavior is strongly related to the occupation of electrons in the electronic structure of each atom.The atomically thin 2D materials with diverse opto-electronic properties demonstrate the interplay of large shape anisotropy based on featuring the thickness of a few nanometers as well as anisotropy in opto-magnetic properties, which provide unlimited possibilities for the MO applications19. Nevertheless, there is limited number of reports of plasma treatment on 2D materials but very few on hBN especially in the form of monolayer as a more sensitive structure to the energetic Ions. Singh et al.20 reported  100 fold improvement of electrical resistance based on optical and electrical measurements for Searching for a reliable method for chemical functionalization without using poisoning chemicals and avoiding structural deformation leads to the plasma treatment due to its powerful ability for surface modification and adding active functional groups with the help of plasmaH 1S orbitals, which is beyond what occurs in the pristine hBN22. BNNS during chemical reactions with Au nanoparticles shows reduced band-gap and the linear relationship between conductance and Au concentration, which is the evidence of the Lewis base interactions of boron atoms and amine functionalized Au nanoparticles16. As Xiong et al.23 have found that an adsorption behavior directly depends on the electronic properties of hBN.Also, it has been shown that hydrogenation can tune the electronic structure of hBN sheets by inducing extra interactions between N 24 but also the high potential of Kerr effect in materials research possessing high sensitivity and high accuracy without loss of the magnetism in low dimensional materials1.Investigating Magneto-optical related properties of materials has been extensively welcomed in recent years due to not only the necessity of high-density magnetic data storage25. Huang et al. reported on magneto-optical Kerr effect (MOKE) microscopy of monolayer chromium triiodide 3. DFT calculations are extensively used on MOKE for 2D materials and Heusler alloys, revealing the effect of strongly bounded excitons of charge-transfer on magneto-optical properties, interband transitions, spin-orbit coupling, and half-metallic geomagnetism in such magnetic materials28.2D magnetic materials are attracting attention in the field of magnetism and spintronics due to the potent ability of electrical control reinforcement on electromagnetic devicesHere, we propose a computational framework enabling one to unveil magnetic properties of non-magnetic nature materials such as hBN in terms of doping and surface engineering, comparing its magnitude with the intrinsic magnetic materials. We have extensively investigated the electronic and optical properties of these materials. Furthermore, For the first time we report on the calculation of MOKE for the surface engineered hBN nanostructures as nonmagnetic and extrinsic ferromagnetic 2D materials using DFT calculations to assert that magneto-optical Kerr rotation is a reliable technique to evaluate the magnetic properties of materials as it has been used so far for the determination of the level of ferromagnetism in new-found materials theoretically and experimentally Table .Table 1We consider a  and the partial density of states (PDOS) graphs projected on oxygen atoms in Fig. Here we have considered low level doping concentrations , volume (V), and temperature (T)) ab initio MD simulation at 700 K was done to survey the thermal stability of hypothesized structures. According to Fig. 34. On the other hand, by increasing the oxygen percentage on the surface the absorption peaks are decreasing in intensity which is an indication of optical transition and redistribution of hBN’s electron-hole density near the excited states35.In Fig. Figure 36. In the case of 37.The diagonal and off-diagonal elements of dielectric function for the functionalized structures are presented in Fig. 30 concluded, oxygen functionalization is introducing a FM phase to 2D hBN which is indeed a manifest of spin-interfering property of such manipulated materials. Mainly, theoretical accounting for MO effects manifests in investigating the diagonal and off-diagonal energy/frequency-dependent macroscopic dielectric functions28. In the process of reflecting a linearly polarized light from a magnetized material, MOKE appears to be observed in terms of the Kerr angle, 24. Among three different orientations of magnetization vector 242427As Ataka et al.mentclass2pt{minim29. As Weng et al. stated this attributes to the substitution of oxygen atoms with Nitrogen resulting in unpaired electrons.On the other hand, as predicted before different levels of doping increases the Kerr rotation up to We have performed electronic, optical, and magneto-optical calculations for the proposed hBN based surface engineered nanomaterials using DFT method. It has been shown that by different values of surface functionalization, the band-gap decreases from 4.67 eV to a desired value of 2.43 eV depending on the arrangement of adsorbed atoms and the different types of orbital couplings. Subsequently, we investigated the thermo/mechanical stability of such materials leading to the confirmation of dynamical stability of 6 proposed functionalized/doped structures. Besides, keeping high oxygen coverage structure up to 600 fs in the temperature of 38. As Catarina et al. stated39 the Kerr rotation is the sum of different curves of spin and valley components which have resonant peaks around the absorption spectra so it is highly related to the effective band-gap of the materials. Also, we showed that MO signals in hBN and its functionalized/doped nanostructures are strong which can be extensively used as an optical switch. Interestingly, we have found that for the 11% doped structure a small value of surface plasmon is created near 0.61 eV which is a valuable improvement in a 2D material that can lead to wider applications.As compared to Pristine hBN, the absorption peak position for 41 on the induced magnetic properties for surface modification by fluorine and carbon, our future aim is to consider magneto-optical investigation considering such elements.Although, oxygen functionalization caused the hBN to lose the maximum transparency by about 1%, it still poses an accepted level of transmission (up to 98.93 for the high oxygen coverage) which makes it a proper material for microelectronic and opto-electronic applications. Furthermore, as there are several reports43. We have used a double-44 was conducted for the exchange-correlation functional. We considered different concentrations of adatoms where the electronic, optical, and magnetic properties of hBN structures developed accordingly.We performed first-principles, spin-polarized calculations on the hBN-derived materials. The geometry optimizations and electronic structure calculations were performed under certain conditions where the total energy difference lowered down to 45k-point grid of In our calculations, The Brillouin zone integrations are performed on the Monkhorst-Pack47. This code uses norm-conserving pseudopotentials to evaluate eigenfunctions and eigenvalues of Kohn-sham equations, and also (PBE-GGA) is applied to consider the exchange-correlation functional. The converged energy cutoff and Monkhorst-Pack kpoint sampling was chosen to be 560 Ry and Optical properties Calculations were performed using the plain-wave pseudopotentials as implemented in the OpenMx 3.9 package48. We considered a sufficiently large vacuum pad of 20 Å for these periodic structures to avoid any interaction between adjacent layers and the atomic positions were optimized using a quasi-Newton algorithm, where the force acting on each atom was less than As the conductivity and dielectric function can be calculated based on the Kubo-Greenwood formula in this work we did not take into account the electron-hole interaction which is causing excitonic effects


Interventions for increasing the uptake of COVID-19 vaccination among Black young adults are central to ending the pandemic. Black young adults experience harms from structural forces, such as racism and stigma, that reduce receptivity to traditional public health messaging due to skepticism and distrust. As such, Black young adults continue to represent a priority population on which to focus efforts for promoting COVID-19 vaccine uptake.In aims 1 and 2, the Tough Talks digital health intervention for HIV disclosure will be adapted to address COVID-19 vaccine hesitancy and tailored to the experiences of Black young adults in the southern United States . In aim 3, the newly adapted Tough Talks for COVID-19 digital health intervention will be tested across the following three southern states: Alabama, Georgia, and North Carolina.Our innovative digital health intervention study will include qualitative and quantitative assessments. A unique combination of methodological techniques, including web-based surveys, choose-your-own-adventures, digital storytelling, user acceptability testing, and community-based participatory approaches, will culminate in a 2-arm hybrid type 1 effectiveness implementation randomized controlled trial, wherein participants will be randomized to the Tough Talks for COVID-19 intervention arm or a standard-of-care control condition (N=360). Logistic regression will be used to determine the effect of the treatment arm on the probability of vaccination uptake (primary COVID-19 vaccine series or recommended boosters). Concurrently, the inner and outer contexts of implementation will be ascertained and catalogued to inform future scale-up. Florida State University’s institutional review board approved the study (STUDY00003617).Our study was funded at the end of April 2021. Aim 1 data collection concluded in early 2022. The entire study is expected to conclude in January 2025.If effective, our digital health intervention will be poised for broad, rapid dissemination to reduce COVID-19 mortality among unvaccinated Black young adults in the southern United States. Our findings will have the potential to inform efforts that seek to address medical mistrust through participatory approaches. The lessons learned from the conduct of our study could be instrumental in improving health care engagement among Black young adults for several critical areas that disproportionately harm this community, such as tobacco control and diabetes prevention.ClinicalTrials.gov NCT05490329; https://clinicaltrials.gov/ct2/show/NCT05490329DERR1-10.2196/41240 Black) young adults aged 18 to 29 years. In 2020, a population-based study indicated that only 42% of Black Americans reported being likely to accept vaccination against COVID-19, whereas 63% of White and Hispanic or Latinx adults were likely to accept COVID-19 vaccination . Yo. Yo35]. The TT-C intervention will be finalized to be self-directed and fully asynchronous, so that there will be no need for the participants to engage with an interventionist. The initial assessments suggest that to complete all activities and review all content, the study participants will need to dedicate about 2 to 4 hours of time (spread across 1 month). Our standard-of-care control will be the provision of COVID-19 vaccine materials, which will be adapted from the Centers for Disease Control and Prevention and shared via email. Standard-of-care materials will be hosted via the internet and will be accessible to the general public. In the final phase of aim 2, the YAB and community partners will participate in an assessment of the TT-C intervention to assess intervention feasibility and acceptability and finalize RCT study procedures.In aim 3, we will conduct a hybrid type 1 effectiveness implementation RCT. We will enroll 360 Black young adults from Alabama, Georgia, and North Carolina who are unvaccinated, have only received 1 dose of a 2-dose series, or have not received boosters against COVID-19 in accordance with current Centers for Disease Control and Prevention booster eligibility criteria . After cPower calculations were conducted based on the assumptions that dropout would be equivalent across arms and approximately 15% of participants would be lost to follow-up; therefore, we assume that 306 participants will complete the primary end point assessment. If the rate of COVID-19 vaccination in the control arm is between 10% and 20%, we will have 80% power to detect an odds ratio of 1.92 to 3.21 when comparing vaccination uptake between arms, assuming a sample size of 306 and a 2-sided α of .05. We anticipate that the vaccination rate in the control arm will be low, given that COVID-19 vaccines have been available for some time. Therefore, we expect that a total sample size of 360 will provide sufficient power to detect a clinically meaningful difference in vaccine uptake.The aim 3 primary effectiveness outcome is COVID-19 vaccine uptake, which will be defined as the receipt of any COVID-19 vaccine (primary series or boosters). The secondary effectiveness outcomes are vaccine hesitancy and confidence , as wellg-formula command in Stata (StataCorp LLC), which uses the mediational g-formula, to estimate the controlled direct effects, natural direct effects, and natural mediated (indirect) effects [We will use logistic regression to determine the effect of the treatment arm on the probability of vaccination uptake (“yes” or “no”) at month 3. We will focus on the odds ratios for comparing the probability of vaccination in the treatment group with the probability of vaccination in the control group. As an exploratory analysis, we will examine primary and secondary outcomes by enrollment vaccination status (not vaccinated vs vaccinated with 1 or 2 doses and no booster shot). The secondary outcomes—vaccine hesitancy ; vaccine effects .In sensitivity analyses, we will also use inverse probability of treatment weights to account for missing data and potential differential retention between study arms over the study period. We will weight outcome models by using stabilized inverse probability of censoring weights that include the treatment arm as a predictor to account for differential loss to follow-up.We will conduct qualitative interviews with a group of purposively selected participants (we estimate 18-24 participants) to assess how the intervention was internalized and experienced. We will conduct in-depth exit interviews on a rolling basis after participants have concluded the 3-month study cycle. All interviews will be audio-recorded and transcribed verbatim. Qualitative analyses will be conducted in the NVivo  coding program. Study participants will be asked questions on how sociocultural nonintervention contexts affected the likelihood of vaccine acceptance, vaccine series completion, and vaccine hesitancy. Interviews will last about 1 hour. We will perform a rapid content analysis, which is routinely used in implementation science to assess and disseminate results quickly and accurately . The finOur study was funded at the end of April 2021. Approval from the University of North Carolina, Chapel Hill Institutional Review Board was obtained shortly thereafter. Aim 1 data collection concluded in early 2022. The entire study is expected to be complete at the end of January 2025.The TT-C intervention will address COVID-19–related vaccine hesitancy among Black young adults in Alabama, Georgia, and North Carolina by including tailored content to engage Black young adults and promote agency and autonomy in decision-making related to vaccination, while also addressing the persistent effects of historic contexts and structural stigma and racism against Black populations in the United States. The TT-C DHI will address issues that not only impact COVID-19 vaccine uptake but also influence the acceptance of other vaccines and health services, such as addressing medical distrust, highlighting the role of Black scientists in vaccine development and medicine, and providing tailored content on how to assess misinformation. The TT-C app will be developed to retain relevance as the pandemic shifts, and it can be adapted to address other conditions that disproportionately affect Black young adults.fully vaccinated, etc), ideally, the app should be flexible and responsive. Although the content delivered through the TT-C app is adaptable, not all components can be adjusted once they are developed.In assessing trial designs, we considered stepped wedge and waitlist formats. However, since our aim is to reach Black young adults who are often not engaged in care, particularly those in the southern United States, we determined that multipronged recruitment and individual-level randomization would be the best approaches. Because the landscape of COVID-19 prevention and related science are quickly changing (eg, masking, the definition of If the TT-C DHI is effective in increasing COVID-19 vaccination uptake among Black young adults in the southern United States, we will be poised for rapid dissemination and broad implementation to reduce COVID-19 morbidity and mortality among unvaccinated or partially vaccinated Black young adults in the southern United States.


Exploring new topological phases and phenomena has become a vital topic in condensed matter physics and materials sciences. Recent studies reveal that a braided colliding nodal pair can be stabilized in a multi-gap system with  The authors constructed ideal acoustic metamaterials to realize non-abelian braiding of band nodes and provided the first compelling experimental evidence, at the wavefunction level, for the creation, collision, braiding, and repulsion of band nodes. Symmetry plays an essential role in distinguishing topologically inequivalent band structures9; this has recently culminated in systematic classification schemes that address the global band topology in terms of irreducible representation combinatorics and symmetry-based indicators15. The paradigm leading to this success of topological band theory is to divide energy band structure into two subspaces, i.e., an occupied subspace spanned by bands below an energy gap and an unoccupied subspace above the gap. This yields additive group structures for topological invariants when adding extra occupied bands. Physical systems captured by this framework of single-gap topology are characterized by abelian groups with commutativity and additivity, with a prominent example being the tenfold way classification rooted in the K-theory18.Over the last decade, the study of topological phases of matter has made fruitful achievements with far-reaching impacts. A particular example is the discovery and characterization of hundreds and thousands of topological materials protected by time-reversal and/or crystal symmetries22. With multiple bandgaps entangled together, the underlying new paradigm is characterized by non-abelian groups. The multi-gap topology exhibits appealing noncommutative braiding structures and reflects an entirely new category of band topology. The braiding in energy-momentum space can be described by non-abelian charges22. For example, a 23, and the eigenstate trajectories along a closed path define a non-abelian frame charge for the system. According to the homotopy group theory, the charge is associated to the flag variety 20. Particularly, the multi-gap nodes can braid reciprocally in two-dimensional (2D) momentum space as they evolve with external parameters. The non-abelian quaternion charge of a node can change sign through braiding with another node in an adjacent gap, which can result in a pair of nodes of an identical charge in the same gap. The identically charged nodes will not annihilate after collision, as the key signature of a nontrivial nodal braiding process22. Besides the quaternion charges, the nodal braiding can also be characterized by Euler classes24 and Dirac strings25. Non-abelian topological systems have been ingeniously realized by photonic28, transmission line network29 and acoustic32 means. And relevant phase transitions have also been clearly observed30. However, unambiguous experimental evidence for the long-desired nodal braiding remains elusive, because of the extreme challenges in resolving the evolution of nodal points in energy-momentum space, demanding the extraction of wavefunction information in Hilbert space, and hence concluding the non-abelian phase transition at the ultimate level of wavefunctions.Very recently, symmetry-protected multi-gap band topology have been predicted theoreticallyIn this work, we report an elegant acoustic realization of non-abelian nodal braiding using a simple square-lattice model, in which the braiding protocol is implemented by using a sequence of acoustic samples. Unambiguously, we observe a nontrivial nodal braiding process in energy-momentum space, benefiting from the extremely clean bulk dispersions with minimal nodes residing only at high symmetry lines (HSLs) of the Brillouin zone (BZ). Particularly, we present the first experimental evidence, at the level of wavefunctions, for the band inversion and the resultant stability transition of a colliding nodal pair at a high symmetry point (HSP), as a hallmark manifesting the nontrivial multi-gap braiding effect. Moreover, we explore the intricate bulk-edge physics of our 2D system from the perspective of braiding 1D subsystems, and unveil the nodal braiding through a global evolution of multi-gap edge states.22  and gap-II nodes ' and '  With these, we can explore the bulk-edge physics of each 2D sample from the perspective of braiding 1D subsystems, and track the bulk nodal braiding through the global evolution of the multi-gap edge states in different 2D samples. Similar edge manifestation of the bulk nodal braiding was reported in ref. 30.Our t=2 Fig. , the loo' . The photosensitive resin used for sample fabrication can be considered acoustically rigid, owing to the huge impedance mismatch with air  as the phase reference, and used a needle-like microphone (B&K Type 4182) to detect the pressure signals of all cavities one by one. Similar measurements were performed to obtain the edge spectra, where the sound source was relocated to the middle unitcell of the bottom edge of the sample. Through spatial Fourier transform, we obtained the spectra in momentum space.Supplementary InformationPeer Review File


There are two types of testicular torsion: complete and incomplete. The degree and duration of symptoms of this condition are critical for treatment decision-making, as the consequences for untimely diagnosis and management can be serious. The preoperative assessment of the degree of acute testicular torsion using ultrasonography is particularly important for determining the appropriate intervention. The purpose of this study was to compare the effectiveness of high-frequency versus contrast-enhanced ultrasonography in determining the degree of acute testicular torsion.Fifteen patients with clinically diagnosed acute testicular torsion underwent both high-frequency and contrast-enhanced ultrasonography. We compared the characteristics of the ultrasonographic images of the testicular parenchyma in both the afflicted and contralateral  testes to determine the reliability of contrast-enhanced ultrasonography in assessing the degree of acute testicular torsion.2 = 2.50, P ≤ 0.05).The high-frequency ultrasound and contrast-enhanced ultrasound diagnosis of 4 complete testicular torsion and 11 incomplete testicular torsion were correct before operation. However, 5 patients with incomplete testicular torsion were misdiagnosed as complete testicular torsion because no blood flow was detected by high frequency ultrasound. Finally, low speed blood flow was detected by contrast-enhanced ultrasound and the diagnosis was corrected. The accuracy of diagnosing incomplete testicular torsion was 100% using contrast-enhanced ultrasonography and 66.7% using high-frequency ultrasonography; the difference between the two methods was statistically significant (χContrast-enhanced ultrasonography can diagnose testicular torsion with high accuracy and can detect low-velocity blood flow and show microcirculatory blood perfusion in the testicular parenchyma. This can avoid misdiagnosing incomplete testicular torsion as complete, thus averting unnecessary orchiectomy. Testicular torsion is a common cause of acute scrotal distension, which occurs especially in children and adolescents but can occur in adults; it has an incidence rate of 1/4000 . HoweverThe inclusion criteria of this study were patients with incomplete testicular torsion confirmed by surgery. The exclusion criteria consisted of the following : (1) patients with complete testicular torsion; (2) patients without surgical confirmation and conservative treatment; and (3) patients who cannot cooperate with ultrasonic examination before and after treatment. All patients were admitted to the emergency department of Zhongshan Hospital of Traditional Chinese Medicine between January 2021 and September 2022 and suspected of testicular torsion after preliminary diagnosis by clinicians. A total of 15 patients with acute incomplete testicular torsion  were enrolled. They were aged 9–74 years; 9 were children or adolescents and 6 were adults. The patients presented with a sudden onset of scrotal swelling and pain, and all underwent high-frequency as well as contrast-enhanced ultrasonography. The study was approved by the Ethics Committee of Zhongshan Hospital of Traditional Chinese Medicine. All methods were performed in accordance with relevant guidelines and regulations. Each of the subjects and/or their representatives was instructed on the purpose of the study and signed an informed consent form.The Hitachi Spiral 850 Ultrasound Diagnostic Instrument, Toshiba Aplio 500 Ultrasound Diagnostic Instrument, and GE-logicE9  were used for the examinations. Each patient was instructed to lie in a supine position and fully expose the scrotum. The positions of both testes as well as their morphologies, sizes, envelope integrity, and internal echogenicity were observed with high-frequency ultrasonography using the 2-dimensional mode. Subsequently, the sampling frame was adjusted to the low-speed scale, and multiple sections of both testes were scanned using high-frequency color ultrasonography without changing the machine’s settings to observe the blood flow. The images were stored for graphical analysis, and testicular torsion was diagnosed based on the obtained 2-dimensional and color images. Next, we used contrast-enhanced ultrasonography that was tuned to low mechanical index imaging; 2.4 ml SonoVue contrast agent was injected through the left or right median vein by the same ultrasound doctor who observed testicular parenchymal blood perfusion from multiple angles and sections in real time without interruption for 3 min, focusing on the testicular blood perfusion characteristics, distribution, and contrast filling of any defects on both sides.2 test in a paired design, with differences considered statistically significant at a P-value ≤ 0.05.The data were analyzed using SPSS statistical software version 25.0 . The diagnostic accuracy of high-frequency and contrast-enhanced ultrasonography was compared using the χNine of the 15 patients were found to have complete testicular torsion using high-frequency ultrasonography; conversely, contrast-enhanced ultrasonography indicated that only 4 of them had complete torsion, while the remaining 9 had incomplete torsion. Furthermore, the remaining 6 patients were found to have incomplete torsion using both modalities. The interval between symptom onset and diagnosis of testicular torsion ranged from 1 to 6 h, with a mean of 3.4 h. Subsequently, the patients’ diagnoses were confirmed by surgery, which revealed that 4 and 11 had complete and incomplete testicular torsion, respectively; this was consistent with the contrast-enhanced ultrasonography findings.Four patients with complete testicular torsion as confirmed surgically showed morphological derangement, enlargement, and hypoechogenicity of the affected testis with no detectable blood flow on high-frequency ultrasonography. No contrast accumulation was observed inside the testicular parenchyma on contrast-enhanced ultrasonography.Among 11 patients ultimately diagnosed with incomplete testicular torsion, high-frequency ultrasonography showed no significant changes in the echogenicity of the affected testis in 5 of them. Moreover, the morphology of the affected testis in these patients was altered, and there was no detectable blood flow in any of them. Therefore, these patients were misdiagnosed by high-frequency ultrasound. In contrast, a trace blood flow signal was detected in all 5 when using contrast-enhanced ultrasonography. Finally, these patients were correctly diagnosed by contrast-enhanced ultrasound before surgery. In the remaining 6 patients with incomplete torsion, high-frequency ultrasonography showed reduced testicular echogenicity compared to the contralateral side Fig. . TherefoScrotal fluid accumulation was observed in 9 of the patients with incomplete torsion, whereas 2 experienced an increase in epididymal volume. In all 11 of these patients, spiral torsion of the spermatic cord was observed above the testis. The torsioned spermatic cord exhibited echogenic enhancement and was rich in blood flow Fig. ; the masP ≤ 0.05). The patients’ data are summarized in Table The accuracy of high-frequency ultrasonography in diagnosing the degree of testicular torsion was 66.7% 10/15), which was lower than that of contrast-enhanced ultrasonography . The difference in diagnostic accuracy between the two methods was statistically significant  , 13. UltIn this study, 11 patients with incomplete testicular torsion saw uneven distribution of contrast agent filling inside the testes, and 5 patients were misdiagnosed as complete testicular torsion by high-frequency color ultrasound. However, a small amount of contrast agent filling was still seen inside the testes, but the echo intensity was significantly lower than that of the healthy side, showing extremely low enhancement. Furthermore, the local defect area of contrast agent was visible, which was consistent with the results of surgical verification. This shows that high-frequency ultrasound can only show the shape, size, signal and blood supply of the testicular parenchyma, while contrast-enhanced ultrasound can monitor the low-speed blood flow in microvessels through the injection of contrast agents and can more accurately find subtle and low-speed blood flow signals. In addition, the main component of the ultrasound contrast agent is sulfur hexafluoride microbubbles, which are discharged from the body through respiratory metabolism.However, toxicity from the injection of contrast-enhanced ultrasound may cause mild adverse reactions, such as headache, nausea, and sweating. In orderfor patients to recover in a short time and with no residual effects, they need to be properly informed and sign the consent form before examination. Our data show that contrast-enhanced ultrasound has a unique advantage in evaluating microcirculation perfusion of testicular parenchyma, so as to detect very low velocity blood flow in microcirculation small vessels. This makes it an ideal choice to evaluate the degree of acute testicular torsion and observe the ischemia-reperfusion after testicular surgery. However, because the sample size of this study is not large enough, the quantitative standard still needs to be further verified by collecting more cases in future studies, which is the next research direction of the author.We found that contrast-enhanced ultrasonography can accurately visualize the microcirculatory perfusion characteristics of the testicular parenchyma, and that it can diagnose incomplete testicular torsion more accurately than high-frequency ultrasonography. As such, contrast-enhanced ultrasonography can provide clinicians with accurate quantitative information when evaluating patients with suspected testicular torsion, compensates for high-frequency ultrasonography’s deficiency regarding microvessels and low-speed blood flow, and promotes the application of ultrasound technology in the preoperative evaluation of testicular torsion, and thus aids in devising treatment options.


Text-to-speech (TTS) synthesizers have been widely used as a vital assistive tool in various fields. Traditional sequence-to-sequence (seq2seq) TTS such as Tacotron2 uses a single soft attention mechanism for encoder and decoder alignment tasks, which is the biggest shortcoming that incorrectly or repeatedly generates words when dealing with long sentences. It may also generate sentences with run-on and wrong breaks regardless of punctuation marks, which causes the synthesized waveform to lack emotion and sound unnatural. In this paper, we propose an end-to-end neural generative TTS model that is based on the deep-inherited attention (DIA) mechanism along with an adjustable local-sensitive factor (LSF). The inheritance mechanism allows multiple iterations of the DIA by sharing the same training parameter, which tightens the token–frame correlation, as well as fastens the alignment process. In addition, LSF is adopted to enhance the context connection by expanding the DIA concentration region. In addition, a multi-RNN block is used in the decoder for better acoustic feature extraction and generation. Hidden-state information driven from the multi-RNN layers is utilized for attention alignment. The collaborative work of the DIA and multi-RNN layers contributes to outperformance in the high-quality prediction of the phrase breaks of the synthesized speech. We used WaveGlow as a vocoder for real-time, human-like audio synthesis. Human subjective experiments show that the DIA-TTS achieved a mean opinion score (MOS) of 4.48 in terms of naturalness. Ablation studies further prove the superiority of the DIA mechanism for the enhancement of phrase breaks and attention robustness. The text-to-speech (TTS) technique has played a vital role in interaction platforms to help generate natural and human-like speech based on input texts, especially for people with vision impairment ,2,3. It WaveNet  is an auTacotron is a typical end-to-end model based on a DNN. It consists of three main blocks: an encoder for robust sequential representations of text; an attention-based decoder for text–audio alignment; and a vocoder to reconstruct the waveform audio based on the generated Mel-spectrogram. Text and audio are aligned through purely content-based attention  that lacIn this study, we introduce a deep-inherited attention-based TTS (DIA-TTS) that is superior to the traditional TTS models in (1) high speech quality, including word pronunciation and accuracy; (2) appropriate phrase break position, especially in circumstances when no punctuation marks are used in long sentences; and (3) greater detail in acoustic features . The proposed DIA-TTS is a typical encoder–decoder structure that is connected by an improved local-sensitive attention with an adjustable local-sensitive factor (LSF). Instead of directly using acoustic, we use Mel-spectrogram as the input during the model training stage due to convenience. Furthermore, Mel-spectrogram contains more informative acoustic features by transferring signals in the time domain into the frequency domain using Fast Furious Transform (FFT) followed by 80-channel Mel-scale filters. The deep inheritance mechanism enables multi-processing of token–frame pairs by the iterative DIA, which fastens the alignment process, as well as enhances the alignment robustness. LSF controls the attention concentration region, ensuring a steady alignment process and a tight context connection. A multi-RNN layer is adopted in the decoder for deeper acoustic feature extraction; dropout layers were added to avoid increments in feature entropy by using Bernoulli distribution. The predicted Mel-spectrograms from the decoder are reconstructed into waveform audio by WaveGlow . The intThe proposed DIA-TTS is composed of three main components: (1) an encoder for input text feature extraction and analysis; (2) a DIA-based decoder to generate corresponding acoustic Mel-spectrogram; and (3) a WaveGlow-based vocoder to reconstruct the audio signals with the predicted Mel-spectrogram. The general model architecture is shown in The encoder of the DIA-TTS takes English characters as the input and returns a fixed-dimensional word embedding as the output. The input characters are first coded as a 512-dimensional vector by one-hot embedding and then passed through a stack of three one-dimensional convolutional layers with 512 filters and a kernel size of 5, followed by a bidirectional Long Short-Term Memory (LSTM) layer with 256 hidden units per direction. Dropout layers were added to each convolutional layer with a 0.5 probability using Bernoulli distribution, which avoids the increment in feature entropy caused by deepening the convolutional layers. The LSTM layer helps to find out contextual dependencies along time series.The DIA mechanism acts like a bridge that connects the input textural information from the encoder and the corresponding Mel-spectrogram generated by the decoder. Herein, an improved local-sensitive attention with an adjustable LSF controls the range of weights involved for convolutional computation among time series. It takes three components as inputs: the hidden-state information from the attention RNN layers, the contextual memory from the encoder, and the convolutional features computed from a concatenation of weights among adjacent time steps based on LSF. During training, an inheritance mechanism is introduced, by which the DIA is utilized repetitively for tribal times; each repetition inherits the training parameters from the last DIA while updating the hidden-state information from the corresponding attention RNN layers. This inheritance mechanism deepens the alignment scheme, as well as avoids attention loss by maintaining stabilization during training. Moreover, additional attention RNN layers are added to the DIA-based decoder to enhance the locality feature correlations between the linguistic context and acoustic expression during alignments by sending extra hidden-state information, computed after a residual connection , to the Local-sensitive attention is a hybrid attention that combines the content and location information for effectively utilizing the monotonicity and locality of alignment . It actsThe proposed DIA-TTS improves the connection between the input text and the output Mel-spectrogram by using an optimized DIA mechanism that reloads the local-sensitive attention tribal times for every decoder step. Each reloading process takes the updated hidden-state components from the corresponding attention RNN layers and generates a new attention context. The newly produced attention context carries information from the previous alignment and again is used as the input of the attention RNN for the next iteration. The repetition of the attention inherits the overall training parameters from itself, affording a smooth and stable alignment. Moreover, instead of using commutative weights only from previous time steps, we introduced LSF, which controls the total number of weights among time series that are used for the computation of local-sensitive features. The modified local-sensitive component The decoder is a DIA-based autoregressive RNN mechanism. It consists of four unidirectional LSTM layers: three attention RNN layers and one decoder RNN layer, each with 1024 hidden units in our model that act like a Mel-channel feature extractor and provide the details of the time series dependency between each Mel-spectrogram frame, as well as the time steps for attention alignment. During training, the predicted Mel-frames from the last iteration were passed through a pre-net consisting of two linear normalization layers with 256 hidden ReLU units, followed by a dropout layer with a frequency rate of 0.5. Then, the processed frames were fed into the four-layer RNN block that produces three attention hidden states and one decoder hidden state. The three attention hidden states were used as attention queries for repetitive attention alignment at each decoder time step. A residual connection was adopted to integrate attention with the hidden states at each iteration, as shown in WaveNet  was implThe acoustic signal in the frequency domain provides more information. Compared to the linear scale signal, a signal converted to a Mel-scale spectrogram is easier to analyze and contains more compact representations . For theIn this paper, we utilized the LJ Speech dataset to train the model. The LJ Speech dataset is a public-domain speech dataset consisting of 13,100 short audio clips from a single female speaker. All the speech is spoken in US English, with a total duration of 23.55 h and 225,715 words. All the speech clips come with the corresponding translations in normalized text.−8, and a fixed learning rate of 10−3. Instead of using the cross-entropy loss function, our loss adopted the mean square error (MSE) during training for autoregression issues. The whole training process involved 500 epochs and 200 k steps in total. The training and validation process is illustrated in The proposed model was trained with a batch size of 32 distributed across two NVIDIA GEForce RTX 3090 GPUs, where each has 24 GB of memory for high-quality model training. The CUDA version for all the experiments is 11.7, and the model programming utilizes python 3.7 with pytorch version 1.9.1 + cu111. We applied teacher forcing during the training process by feeding the model with the ground truth. We used the Adam optimizer [Compared to Tacotron2, the proposed DIA model shows a faster and more stabilized convergence during the training and validation process, indicating that increasing the DIA iteration depth speeds up the alignment.The overwhelming majority of people in this country know how to sift the wheat from the chaff in what they hear and what they read”. As for generative models, there is often no ground truth for a subjective comparison [For the purpose of comparison, we generated Mel-spectrograms using Tacotron2 and the proposed model based on the same representative input text: “mparison ; the refFor the subjective speech evaluation, both Mean Opinion Score (MOS) and Comparative Mean Opinion Score (CMOS) experiments were conducted. During the MOS experiments, for each model, 100 synthesized speech clips were rated by eight different raters based on the Absolute Category Rating scale. Raters were asked to score each speech carefully, ranging from 1 to 5 with a 0.5-point increment, in terms of speech naturalness and accent performance. All the MOS experiments were independent, which means each group of raters only evaluated speech from one model or the ground truth. All the raters are native US English speakers with good hearing ability.For the CMOS experiments, 50 groups of synthesized speech generated by Tacotron2 and the DIA-TTS model, respectively, were rated by eight raters for comparison, each group with the same text reference as the input. The score ranges from −3 to 3, where a negative score means Tacotron2 is better, while the positive score means the DIA-TTS is better, and 0 means both models perform the same. All the raters were blind testing when listening to the speech. The results are shown in From To optimize the model structure with an appropriate attention inheritance depth and LSF, we carried out the ablation studies on six models with a different attention inheritance depth and LSF. The inheritance depth is defined as the number of attention RNN layers in the decoder. During each training step, attention updates its input variances, including the hidden-stage information from the attention RNN layers. While each RNN layer renews the hidden states for the attention mechanism, the attention increases its inheritance depth as it again inherits the training parameters. Since Tacotron2 has one attention RNN layer and uses a single local-sensitive attention with a weight concatenation of the previous weight and the cumulative weight, it is regarded as the model with one attention inheritance depth and LSF equal to two. The model details can be found in Visited Mr. Fauntleroy, my application for books for him not have been attended, I had no prayer book to give him”. During the ablation studies, the same representative input text from the following LJ Speech recording were transferred into speech by six different models: “In this paper, we introduced a neural end-to-end TTS model based on the DIA mechanism involving a wide range of communitive weight concatenation controlled by LSF. Instead of using one attention RNN layer in the traditional TTS decoder, we implemented three attention RNN layers, each correlated with the DIA mechanism. The outputs of the attention RNN layers went into the same attention, respectively, for the alignment process for each decoder time step. In this case, the DIA reused the training parameters and inherited the hidden-state information from each RNN layer’s tribal times, resulting in a repeat and deep process for each token. The deep inheritance of the hidden state’s information also improves the linguistic feature extraction, as well as enhances the correlation between the context input and audio output, which contributes to an accurate prediction of the Mel-spectrogram. In addition, to tighten the feature connection between adjacent tokens, we added additional convolutional features controlled by LSF from extra weight concatenation among multiple time steps, capturing more locational information during alignment.The results of the model comparison experiments show that the proposed model is superior in accurately predicting phrase breaks at the appropriate position simply based on the textual input without assistance from the ground truth, demonstrating that the proposed model is capable of mimicking the way people talk. Since there is no objective evaluation for generative models, visual comparisons are of vital importance. The Mel-spectrogram comparison indicates that our model is advanced in producing acoustic details, especially in the high-frequency domain. This advantage is perceptually expressed when reconstructing the Mel-spectrogram into waveform audio. Compared with Tacotron2 (MOS = 4.38 ± 0.052), the proposed model achieved a MOS of 4.48 ± 0.045, indicating that the proposed model has a better performance in synthesizing high-fidelity speech. The CMOS experiment achieved a score of positive 0.257, representing that the speech synthesized by our model is more pleasant than that generated from Taocton2 in aspects of the fluency, articulation, and naturalness of the audio. To acquire a high-quality speech signal in a real-time process, we utilized WaveGlow as the vocoder for audio reconstruction based on the predicted Mel-spectrograms. In this task, WaveGlow receives a MOS of 4.48 ± 0.045, while WaveNet receives 4.41 ± 0.047, representing that WaveGlow has a slightly better performance in the reconstruction of acoustic signals but with a faster inference time.The results of the ablation study on investigating the optimal number of attention inheritance depths and LSF prove that a model with three inheritance depths and an LSF of four achieves the best performance by a comparison of the Mel-spectrogram, attention alignment, MOS, and the inference time. Among the six TTS models, Taocotron2, the proposed DIA model, and Model 4 produce a relatively clear and bright attention alignment line, representing good attention robustness and a tight connection between the encoder and decoder. Both the proposed DIA model and Model 4 receive a satisfactory MOS of 4.48 ± 0.045 and 4.49 ± 0.043, which are higher than the others. However, when taking training time duration as a factor into consideration, the proposed DIA-TTS is considered the optimal model for speech synthesis. Since the increment in RNN layers slows down the synthesis process, Li et al.  replacedIn conclusion, we introduced a novel DIA-TTS synthesizer that can correctly predict phrase breaks and generate audio with high intelligibility and naturalness in real-time speech synthesis applications. The core invention of this work is based on a novel deep-inherited local-sensitive attention mechanism, which fastens the attention alignment process, enhances robustness, and ensures stabilization.


Immunogenic cell death (ICD)-mediated immune response provides a strong rationale to overcome immune evasion in acute lymphoblastic leukemia (ALL). ICD will produce damage-associated molecular patterns (DAMPs) in tumor microenvironment. However, there are few studies on the application of DAMPs-related molecular subtypes in clinically predicting stage III of ALL prognosis. The current study is to identify the DAMPs-associated genes and their molecular subtypes in the stage III of ALL and construct a reliable risk model for prognosis as well as exploring the potential immune-related mechanism.We used Target and EBI database for differentially expressed genes (DEGs) analysis of the stage III pediatric ALL samples. Three clusters were identified based on a consistent clustering analysis. By using Cox regression and LASSO analysis, we determined DEGs that attribute to survival benefit. In addition, the Gene Set Enrichment Analysis (GSEA) was performed to identify potential molecular pathways regulated by the DAMPs-related gene signatures. ESTIMATE was employed for evaluating the composition of immune cell populations.A sum of 146 DAMPs-associated DEGs in ALL were determined and seven transcripts among them were selected to establish a risk model. The DAMPs-associated gene signature significantly contributed to worse prognosis in the high-risk group. We also found that the high-risk group exhibited low immune cell infiltration and high expression of immune checkpoints.In summary, our study showed that the DAMPs-related DEGs in the stage III of children ALL could be used to predict their prognosis. The risk model of DAMPs we established may be more sensitive to immunotherapy prediction. Acute lymphoblastic leukemia (ALL) is the most common type of cancer that affecting children and teenagers , 2. The Cancer immunotherapy is an emerging therapy that activates host immune systems to eliminate tumor cells , 9. ReceTo understand the potency and mechanism of ICD, we collected ALL patient (0–18 years old) samples at stage III through Target and EBI database to decipher the singling molecules that govern the crosstalk between DCs and tumor cells through DAMPs. To analyze the function of DAMPs and their immune activation induced by ICD, the DAMPs-associated genes and molecular subtypes were analyzed through cell signaling pathways and immune-related responses.The RNA-seq data of ALL patients at stage III (Target-ALL-P3), within 0–18 years, was downloaded from the Target dataset , and samThe DAMPs-related genes and expression pattern of protein were obtained from previous study  and 32 rFor the Target’s RNA-seq data, we first removed the samples without clinical follow-up information such as survival time or status. Then, ensemble was converted to gene symbol and the average of the expressions with multiple gene symbols were performed. After that, we took the base 2 logarithm of the expression file (FPKM). For E-MTAB-1205 data analysis, we re-annotated the dataset through hgu133a.db in the R language to remove probes that matched one probe to multiple genes. When a gene symbol was matched with multiple probes, the mean was taken as the gene expression value.via consistent clustering  > 1.5, which were considered statistically significant. The Akaike Information Criterion (AIC) was applied for the regression analysis, which considered the statistical fit of the model and the number of parameters used for fitting by stepAIC in the MASS package  smaller than 0.05 was determined as statistically significant. The correlation coefficients were also calculated by R.Gene set enrichment analysis (GSEA) was performed to identify signaling pathways regulated by the different molecular subtypes . The MolWe used the ssGSEA algorithm  to quant1 to verify the effect of immune checkpoint inhibitor score (IMS) in the prediction of clinical responsiveness to immune checkpoint blockade (ICB). The TIDE algorithm is a computational method for predicting ICB responsiveness using gene expression profiling (We used the tumor immune dysfunction and exclusion (TIDE) algorithmrofiling .p < 0.05.Limma package was used to identified differentially expressed genes (DEGs) with threshold value logFC > 1.5 and The data analysis in this study was supported by Sangerbox platform . Data wek = 3, the clustering output was relatively consistent  values. GSEA was further performed based on differentially expressed genes (DEGs) for each cluster to analyze KEGG pathway. The results showed that cluster-2 has no significantly regulated pathways, and clust1 has three inhibited pathways and 21 activated pathways, while 21 inhibited pathways were shown in clust3 , including 85 genes in Risk group and 61 genes in Protective group .We then used the Target data as the training data set and the risk score of each sample was calculated based on the expression levels of the seven genes. As shown in P < 0.05).To better verify the robustness of the model, we used the E-MTAB-1205 dataset for validation and the risk model established by these seven genes was used to perform prognostic classification on RiskScore. As shown in Then, we showed the distribution of high- and low-risk groups in age, gender, and DAMPs type by Sankey diagram . The difWe first analyzed the immune checkpoint-related gene expressions between high- and low-risk groups in the Target dataset and found that some immune checkpoints showed significant differences between these two groups. The correlation analysis between 28 immune cell scores and risk scores were performed and we found that some immune cells including activated B cells, NK cells, effector memory CD4 and CD8 T cells were negatively correlated with risk scores , indicatp < 0.001) was performed to screen the pathways significantly related to the risk score. Finally, we used the GSVA package  to estimWe established a risk model for seven key DAMPs-related genes and found no significant difference in the distribution of risk models in terms of age and gender, which indicated that these two factors were not associated with ICD in ALL disease. To better analyze the DAMPs-related risk model, data showed that four of the seven genes belong to risk group and the other three genes were related to protective group . MoreoveThrough the existing analysis, we collected the clinical samples after immunotherapy (IMvigor210 and GSE135222) and constructed DAMPs risk model scores by using these seven screened genes. The online tool TIDE was utilized to evaluate the TIDE score of immunotherapy effect. As shown in Acute lymphoblastic leukemia is one of the leading causes of cancer-related mortality in children and teenagers. Extensive studies have demonstrated that various factors such as genetic condition and radiation/chemical exposures contribute to ALL development . While iHerein, we found that clust1 was associated with better prognosis and responsiveness to immunotherapy. A sum of 146 DAMPs-associated DEGs in pediatric ALL samples were identified. By screening of gene signatures, we obtained seven significant genes including HLA-DQB2, HIST1H1A, MEST, ALX3, KIF12, CCDC175, and HOXA11, showing robust correlation with ALL development. Among these genes, the partial control of human leucocyte antigen (HLA) genes like HLA-DQB2 on immune response to infection , 46 coulWe further established a prognostic model based on those genes and performed validation studies to test the prediction efficiency on high- and low-risk groups. The results showed that DAMPs-associated gene signature was significantly associated with worse prognosis in the high-risk group. We also found that the high-risk group exhibited lower immune cell infiltration and higher expression of immune checkpoints compared to low-risk group. The tumor-infiltrating immune cells and immune scores were estimated by ESTIMATE and ssGSEA for each ALL-patient sample. We found that the activated B cells, NK cells, effector memory CD4 and CD8 T cells was enriched in the low-risk group and correlated with good clinical outcome. Patients with higher effector T cells, NK cells, and B cells infiltration showed better prognosis, which was similar with previous observations , 50. As The findings here await further validation in experimental settings, which can be a potential future research direction. Additionally, the comprehensive tumor microenvironment within pediatric ALL including the interaction between tumor cells and immune cells is another promising direction worth further exploration.In this study, three molecular subtypes related to prognosis were constructed by DAMPs-related genes and their function and immune-related pathways in stage III ALL were analyzed through signaling pathway and immune analysis. The seven key DAMPs-related genes were analyzed and screened through univariate cox analysis, LASSO, and stepwise regression. Finally, a risk model was constructed through multivariate cox analysis. The clinical phenotype differences, immune and pathway characteristics were used to estimate the DAMPs risk model, which was further verified by two clinical datasets in immunotherapy. The risk model of DAMPs we established may be more sensitive to immunotherapy prediction.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/FZ designed the study and acquired the data. QL drafted the manuscript. WX and XX revised the manuscript. All authors contributed to this work and read and approved the manuscript.


The combined use of total-body photography and sequential digital dermoscopy has been validated as a standard of care for the early detection of cutaneous melanoma in high-risk individuals. However, the exact impact of this approach in low-risk subjects is not clear. We conducted a retrospective study to evaluate whether there were any differences of prognostic significance between melanomas diagnosed with handheld dermoscopy and sequential digital dermoscopy. In our study, no significant differences were detected in terms of tumor thickness and stage distribution in low-risk patients followed in the long term. Our data contribute to shape the role of sequential digital dermoscopy in patients without risk factors for melanoma.p = 0.030, with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD. Our results confirm that periodical dermoscopic examination enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination as this was associated in our patients with better prognostic features. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD.Sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total-body photography and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, we conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. We sought to compare the distribution of “early” cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodical handheld dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed in a four-year timespan; 471 melanomas were diagnosed by handheld dermoscopy and 150 by digital dermoscopy. Breslow tumor thickness was significantly higher for melanomas diagnosed by handheld compared to digital dermoscopy (0.56 ± 1.53 vs. 0.26 ± 0.84,  Melanoma is one of the most aggressive skin cancers, being responsible for the largest percentage of deaths among cutaneous neoplasms . Even wiTo establish the usefulness of SDD for low-risk individuals, we studied the distribution of “early” cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, in low-risk patients diagnosed by SDD as compared to periodical handheld dermoscopy. In addition, we assessed whether this distribution was different between those who were diagnosed with melanoma after only one dermatological examination or after repeated (≥2) periodical examinations.We conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored at our Dermatology Units for long-term follow-up of clinically suspicious melanocytic nevi which did not show any dermoscopic feature of melanoma on first examination. Patients who were diagnosed with melanoma during the same time frame but had a family and/or personal history of cutaneous melanoma, those who had a melanoma excised but had not been examined previously at our dermatology centers, and those with incomplete or missing data were excluded. Low-risk patients were defined as those without family or personal history of cutaneous melanoma and with nevus count < 50 . We alsoFor each patient, demographic data , the technique of dermoscopic examination , the number of dermoscopic examinations, follow-up interval, and duration of dermoscopic follow-up were recorded. The 7-point checklist score based on dermoscopic pattern analysis  was emplp value < 0.05 was considered statistically significant.Due to the exploratory nature of this study, its overarching goal was to assess the performance of SDD and handheld dermoscopy in time. Since no significant difference between the two techniques was anticipated, all the eligible patients were included in a 4-year time frame, without a sample size calculated a priori. Discrete parameters were reported as count and percentage. Continuous parameters were reported using frequency, mean, and standard deviation (SD) values. The differences between the different techniques were explored with chi-squared test or Mann–Whitney test, as appropriate. A p < 0.001; p = 0.004, A total of six hundred and twenty-one cutaneous melanomas were diagnosed between 1 January 2016 and 31 December 2019 in 606 consecutive low-risk patients . Demographic, clinical, and histopathological data of all 621 melanomas are summarized in p < 0.001). Mean age at diagnosis on first-time dermoscopy and periodical dermoscopy were comparable  were identified on first-time dermatological examination, although the proportion was statistically different between those diagnosed by handheld or digital dermoscopy . Remarkably, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness , ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD (p = 0.067) as were the mean number of examinations to diagnosis  and the mean follow-up period   were excised because they displayed changes since the last digital dermoscopy. The main reason for the surgical excision of these lesions was the evidence of concomitant increase in size and pattern change since the latest digital dermoscopy examination (in 19 melanomas). A total of 15 lesions exhibited an increase in size only and the other 15 exhibited change in dermoscopic pattern only. A total of 10 out of 59 lesions (16.9%) were excised after SDD because they were not evident on previous total-body photography. No significant difference in the 7-point checklist score based on patter analysis was observed between melanomas identified on first-time digital dermoscopy and those detected during SDD. Likewise, there was no significant difference in the 7-point checklist score between the 10 melanomas detected on SDD, which were not evident on previous digital dermoscopy, and the 91 melanomas detected on first-time digital dermoscopy.Overall, our results confirm that periodical dermoscopy carried out by a trained physician, regardless of the technique used, enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination . In our Together with younger age at diagnosis of patients undergoing digital dermoscopy, our data suggest that digital dermoscopy could select low-risk individuals with higher socio-economic status and better prognosis ,25,26. TAlthough the calculation of the number of digital dermoscopic examination needed to excise one melanoma is beyond the scope of this study, the relatively low number of melanomas diagnosed by digital dermoscopy compared to handheld dermoscopy in our 4-year study seem to be in line with the findings of Schiffner and colleagues, who after a median follow up of 24 months did not detect any melanoma by SDD in 145 low-risk individuals, concluding that long-term SDD seems to not be helpful for the detection of melanoma in these subjects .Our results confirm that regular dermoscopic examinations allow for earlier diagnosis of cutaneous melanoma compared with initial examination, as this was associated with better prognostic features in our patients regardless of the dermoscopy technique used. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD, suggesting that the precise selection of patient groups and of the lesions to be monitored is fundamental for an effective SDD that also achieves a good cost/efforts ratio . Althoug


Background. Limited evidence exists on the balance between the benefits and harms of the COVID-19 vaccines. The aim of this study is to compare the benefits and safety of mRNA-based (Pfizer-BioNTech and Moderna) and adenovirus-vectored (Oxford-AstraZeneca) vaccines in subpopulations defined by age and sex. Methods. All citizens who are newly vaccinated from 27 December 2020 to 3 May 2021 are matched to unvaccinated controls according to age, sex, and vaccination date. Study outcomes include the events that are expected to be avoided by vaccination  and those that might be increased after vaccine inoculation . The incidence rate ratios (IRR) of vaccinated and unvaccinated citizens are separately estimated within strata of sex, age category and vaccine type. When suitable, number needed to treat (NNT) and number needed to harm (NNH) are calculated to evaluate the balance between the benefits and harm of vaccines within each sex and age category. Results. In total, 2,351,883 citizens are included because they received at least one dose of vaccine . A reduced incidence of COVID-19-related outcomes is observed with a lowered incidence rate ranging from 55% to 89% and NNT values ranging from 296 to 3977. Evidence of an augmented incidence of harm-related outcomes is observed only for women aged <50 years within 28 days after Oxford-AstraZeneca . Conclusions. A favourable balance between benefits and harms is observed in the current study, even among younger women who received Oxford-AstraZeneca. Huge efforts directed at the development of efficacious and safe vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been made by the scientific community and the pharmaceutical industry, backed by government support . In the Concerns over the safety of vaccines have been spreading lately, particularly with respect to adenovirus-vectored vaccines. By mid-March 2021, vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S was paused in a number of European countries due to reports of thromboembolic events . On 11 MIn the current study, the platform specifically designed for monitoring and assessing the vaccination plan in the Italian Lombardy Region was used to compare the benefits and safety of the aforementioned mRNA-based COVID-19 vaccines (Pfizer-BioNTech and Moderna) and an adenovirus-vectored COVID-19 vaccine (Oxford-AstraZeneca) in subpopulations defined by age and sex.Residents in Lombardy born before 31 December 2005  formed the target population and consisted of just over 8.7 million candidates for vaccination. Three population-based data sources collecting individual health information were used for carrying out the current study. One, the healthcare utilization database aimed to facilitate Regional Health Service (RHS) management and collects a variety of information including hospital discharge records supplied by public or private hospitals , and outpatient dispensation of drugs reimbursed to pharmacies after filing doctors’ prescriptions  classification system). More details on the Italian healthcare utilization databases are reported elsewhere . Two, thAll the different data pertaining to a given individual may be interconnected because a single individual identification code is used by all databases. To preserve privacy, each identification code was automatically converted into an anonymous code. Further details of the healthcare databases used in the context of COVID-19 in Lombardy have been reported previously .According to the rules from the Italian Medicines Agency, retrospective studies using administrative databases do not require Ethics Committee protocol approval. Informed consent was not required since this study involves an administrative database and does not contain any identifiable information that could be linked to any specific participant. All the methods adhered to relevant ethical guidelines for handling human data.The Italian vaccination program started on 27 December 2020 and was structured into the following phases: (i) The following three categories were identified to be vaccinated in the initial phase: health workers, people resident in a nursing home, and people aged 80 years and older. The vaccination campaign for these categories mainly took place during the first two months of 2021, and the mRNA-based (Pfizer-BioNTech or Moderna) vaccines were adopted. (ii) Individuals involved in specific job categories  were prioritized to receive the vaccine because they were in essential categories and/or at high risk for infection. This stage started in March 2021, and the Oxford-AstraZeneca was used. (iii) From April 2021, the vaccination campaign for the general Italian population up to 79 years of age started and was based in a descending fashion on age alone  as well as on individually listed conditions or diseases that have shown a greater prevalence of severe or lethal COVID-19 in clinical studies. During the study follow-up (up to 3 May 2021), individuals aged 70 years or older and frail people received at least the first dose of the mRNA-based (Pfizer-BioNTech or Moderna) vaccines.Because the vaccination program plan of the Italian Ministry of Health was based on the best evidence available at that time (March 2021), the mRNA-based vaccines were adopted for individuals at higher risk of developing a severe manifestation of COVID-19.Among all candidates for vaccination, those who received their first dose of Pfizer-BioNTech, Moderna, or Oxford-AstraZeneca vaccines until 3 May 2021 were identified. Citizens who were not beneficiaries of the RHS, or who became beneficiaries after 1 January 2019 were excluded. The remaining citizens constituted the vaccinated cohort members, the date, and type of vaccine administered were recorded for each.Whenever a citizen who was vaccinated on a given day (the index date) was identified, from 1 to 10 controls were randomly selected from the remaining vaccination candidates who (i) had not yet been vaccinated, (ii) were the same age and sex as the vaccinated cohort member, and (iii) had been an RHS beneficiary since at least since 1 January 2019. That so-formed cohort constituted the  unvaccinated controls. The formal justification for choosing the number of controls matched to vaccines is provided in the Vaccines and controls were typed by recording their age and sex at the index date. Hospital admissions and drug prescriptions experienced within 2 years before the index date were used to investigate a list of 62 conditions possibly affecting the risks of severe/fatal clinical manifestations of SARS-CoV-2 infection, and/or venous thromboembolism ,17,18. TEach vaccinated citizen was matched 1:1 with an unvaccinated control . ObservaA composite outcome was built comprising hospital admission for COVID-19, admission to an intensive care unit for COVID-19, and death from COVID-19. A patient was considered to have experienced the outcome if at least one of these events occurred during the observation period, and the earliest event was considered the date of its occurrence.Vaccinated citizens were matched to unvaccinated controls at a 1:10 ratio . Each coPerson-months of exposure and non-exposure, respectively, started at the date of vaccination and the corresponding date for unvaccinated controls. The outcomes of interest included admission to hospital or an emergency room with a primary or secondary diagnosis of venous thromboembolism. The list of conditions used to track venous thromboembolism was the same as that used in a recently reported investigation , and theStandardized mean differences were calculated to compare baseline characteristics in vaccinated subjects and controls. In accordance with Austin , standarDifference metric, as opposed to IRR, was used to compare subperiod-specific incidence rates. This was performed using the number needed to treat (NNT) to measure vaccine benefits and the number needed to harm (NNH) to measure vaccine-associated harm. A low NNT value indicates more favourable effects of vaccination, because few citizens would need to be treated to expect one citizen to benefit. Similarly, NNH assesses undesirable treatment outcomes by estimating the number of citizens vaccinated per one harmful event. Therefore, a desirable vaccination profile would have a low NNT and a high NNH .NNT and NNH were calculated only in the presence of significant evidence of both protective  and harmful action (increasing venous thromboembolic events) . Where sA range of prespecified supplementary analyses were conducted.One, the first occurring among specific events used to measure vaccine benefits , and vaccine harms , were calculated separately.Two, due to the arbitrary nature of the choice of the time-window length after vaccination during which no exposure to vaccine benefits was assumed because immunity was gradually building, as well as the 14-day window used in the main analysis a shorter period (7 days) and a longer period (21 days) were considered.Three, the choice of the time-window length with respect to the risk of developing venous thromboembolism was also arbitrary, so as well as the 28-day window used in the main analysis a shorter period (21 days) and a longer period (35 days) were considered.Four, as well as multiple adjustments conducted by including covariates in the models, an approach based on propensity scores was utilized . Propensp values <0.05 were considered significant.For all hypotheses tested, two-tailed Of the 2,381,883 beneficiaries of the RHS who were vaccinated by 3 May 2021, almost a third (31.1%) received the Oxford-AstraZeneca vaccine. There was a lower prevalence of diabetes among subjects vaccinated with Oxford-AstraZeneca, and a higher prevalence of dyslipidaemia among subjects vaccinated with mRNA-based vaccines . More frDuring a median follow-up of 35 days (interquartile range: 12–37 days), 639 clinically severe infections were documented among vaccinated subjects and 6921 were documented among controls, equating to respective numbers of cases per 10,000 person-months of 4.8 and 16.9. In vaccinated subjects, the respective incidence rates of hospital admission, emergency room access, and mortality were 4.52, 0.03, and 0.28 per 10,000 person-months, and in unvaccinated subjects they were 16.03, 0.18, and 0.64.During a median follow-up of 28 days (interquartile range: 12–28 days), 307 venous thromboembolic events were documented among vaccinated subjects  and 4327 were documented among control subjects . The respective incidence rates of cerebral venous thrombosis and other venous thrombosis were 0.02 and 1.86 per 10,000 person-months spent during exposure periods, and 0.01 and 2.67 per 10,000 person-months spent during unexposed periods.There was evidence of reduced COVID-19-related outcomes until the age of 79 years, with adjusted IRRs decreasing from 69% (95% CI 44–83%) in women aged 60–69 years, to 89% (95% CI 77–95%) in women aged <50 years, and from 72% (95% CI 57–82%) in men aged 70–79 years, to 85% (95% CI 70–92%) in men aged 50–59 years . NNT valThere was evidence of a reduced incidence of COVID-19-related outcomes associated with Pfizer or Moderna vaccination, with adjusted lowering IRR ranging from 55% (95% CI 48–60%) in women aged ≥80 years, to 86% (69–94%) in women aged 50–59 years, and from 59% (52–65%) in men aged ≥80 years, to 82% (64–91%) in men aged 50–59 years . In womeIRR estimates were generally similar to those obtained in the main analyses, irrespective of the time-window length from non-exposure to benefit after vaccination . They weThe benefits of the COVID-19 vaccination campaign estimated in the current study must be interpreted with reference to previous observations. The effectiveness of vaccination for preventing severe forms of infection observed in the study is consistent with that expected based on previously reported randomized clinical trials and observational studies ,6,7,8,9.The effectiveness of the vaccination campaign with respect to avoiding outcomes that would have occurred in the absence of vaccination clearly depends on vaccine efficacy, but it also depends on both the speed of the vaccination campaign and the types of people vaccinated. The more citizens that are vaccinated, the greater the expected benefits will be, particularly if more people vulnerable to severe clinical manifestations of infection are vaccinated. During the first months from the start of the vaccination campaign in Lombardy, the incidence rates were strongly reduced in older people. From 13 to 33 cases every 10,000 person-months were avoided among citizens aged ≥80 years, but only 2 or 3 cases every 10,000 person-months were avoided among younger citizens. This leads to the obvious consideration that the clinical impact of the campaign is expected to be much higher in older citizens, and in general, in clinically more vulnerable citizens. The current study was limited to estimating clinical benefits, and among these, those applying to more severe symptomatic COVID-19 cases. The effects of the vaccination campaign on asymptomatic SARS-CoV-2 infections, paucisymptomatic COVID-19 disease, and the progressive reduction of viral spread were not investigated.In the current study, there was an increased rate of venous thromboembolic events 28 days after vaccination with Oxford-AstraZeneca in women aged <50 years. Consistently, there was an almost doubled rate 28 days after the Oxford-AstraZeneca vaccination in recipients aged 18–65 years in Denmark and Norway, and an even greater increase in younger citizens and in women . In the The present study provides evidence that the benefits of the Oxford-AstraZeneca vaccination clearly outweigh the corresponding risk of venous thromboembolic events, even in younger women. Vaccination of a little more than 3000 citizens yielded a unit of therapeutic benefit, whereas vaccination of >23,000 was required to yield a harmful event (a ratio of approximately 7.6-fold). Therefore, these findings support future vaccination programs in low- and middle-income countries (where the percentage of people vaccinated is very low) as well as in high-income countries (in which the third and fourth doses are ongoing/planned) through two main policy directions. First, the better benefit-harm profile of mRNA-based vaccines should be considered for managing vaccination campaigns in younger women. Second, the Oxford-AstraZeneca vaccine should be considered for younger women in the absence of the mRNA-based vaccines since the benefits outweigh the risks, at least with the virus spread observed during the study period (see below for a specific comment on this issue).Four further issues pertaining to interpreting the results of the current study should be discussed. First, few citizens had received the second dose of the Oxford-AstraZeneca vaccine by the endpoint of the study because it was scheduled for 12 weeks after the first one; therefore, we only assessed clinical benefits after the first dose. Because additional cases of severe/fatal infection are expected to be avoided after the second dose; however, the benefit-harm profile is expected to improve as more citizens complete the scheduled vaccination cycle . Second,The main strength of the present study is its population-based approach, implemented in a setting with regional health services providing free access to healthcare and well-defined and near-complete follow-up based on computerised registries with full population coverage and daily updates . The larThe present study also had potential weaknesses. First, the validity of the results ultimately depends on the accurate coding of outcomes . There aThe evidence of the effectiveness of mRNA-based and adenovirus vector-based vaccines for preventing severe/fatal forms of SARS-CoV-2 infection was obtained in the current large population-based investigation. An increased rate of venous thromboembolism within 28 days after the first dose of Oxford-AstraZeneca in women aged <50 years was observed. The most important observation in the present study was that the balance between benefits and harms was largely skewed towards vaccination, even in younger women. mRNA-based vaccines should be preferred for young women because of the better risk-benefit profile.


Low rates of vaccination, emergence of novel variants of SARS-CoV-2, and increasing transmission relating to seasonal changes and relaxation of mitigation measures leave many US communities at risk for surges of COVID-19 that might strain hospital capacity, as in previous waves. The trajectories of COVID-19 hospitalizations differ across communities depending on their age distributions, vaccination coverage, cumulative incidence, and adoption of risk mitigating behaviors. Yet, existing predictive models of COVID-19 hospitalizations are almost exclusively focused on national- and state-level predictions. This leaves local policymakers in urgent need of tools that can provide early warnings about the possibility that COVID-19 hospitalizations may rise to levels that exceed local capacity. In this work, we develop a framework to generate simple classification rules to predict whether COVID-19 hospitalization will exceed the local hospitalization capacity within a 4- or 8-week period if no additional mitigating strategies are implemented during this time. This framework uses a simulation model of SARS-CoV-2 transmission and COVID-19 hospitalizations in the US to train classification decision trees that are robust to changes in the data-generating process and future uncertainties. These generated classification rules use real-time data related to hospital occupancy and new hospitalizations associated with COVID-19, and when available, genomic surveillance of SARS-CoV-2. We show that these classification rules present reasonable accuracy, sensitivity, and specificity  in predicting local surges in hospitalizations under numerous simulated scenarios, which capture substantial uncertainties over the future trajectories of COVID-19. Our proposed classification rules are simple, visual, and straightforward to use in practice by local decision makers without the need to perform numerical computations.The online version contains supplementary material available at 10.1007/s10729-023-09629-4. Low rates of vaccination, emergence of novel variants of SARS-CoV-2 (such as the omicron variant), and increasing transmission relating to seasonal changes leave many U.S. communities at risk for surges of COVID-19Centers for Disease Control and Prevention (CDC) created the COVID-19 Community Levels framework to identify the potential for strain on the local health systems. The risk classification rules proposed by this framework, however, are not explicitly linked to the outcome of interest, which is whether the local healthcare capacity is expected to be surpassed due to COVID-19 hospitalizations.To address this need, our study describes a method to identify simple and easy-to-communicate classification rules that can provide early warnings when a pre-specified threshold of hospital capacity is likely to be exceeded within a 4- or 8-week period.These simple classification rules can be used by local decision makers to utilize data from existing surveillance systems to proactively respond to surges in COVID-19 hospitalizations.Many communities are at risk of surging COVID-19 hospitalizations due to low rates of vaccination, emergence of novel variants of SARS-CoV-2, and seasonal changes in transmission  or the ITo address this need, the Centers for Disease Control and Prevention (CDC) created the COVID-19 Community Levels framework to identify the potential for strain on the local health systems . The risLocal trajectories of COVID-19 hospitalizations are impacted by various factors, including the proportion of the population with infection- or vaccine-induced immunity, the duration of infection- and vaccine-induced immunity, uptake and effectiveness of vaccine boosters, the transmissibility, immune evasion, and virulence of novel variants (such as the omicron variant and subvariants) that may continue to emerge and spread, the effectiveness of vaccines against prevalent strains including novel variants, and population behavior and adherence to mitigating strategies , 6–9. TrData from hospital occupancy censuses, rate of new COVID-19 hospital admissions, and vaccination coverage are often available to monitor the local spread of SARS-CoV-2 and trends in COVID-19 hospitalizations . To enabMultiple indicators are collected through surveillance systems to monitor and predict local trends in COVID-19 hospitalizations  will most likely continue to change in the future. The types and the effectiveness of mitigating strategies during the near future could be markedly different than those employed in the past, novel variants such as omicron may gain hold over different time courses in different locations, and their characteristics in terms of transmissibility and virulence will be highly uncertain during their initial seeding, and vaccination coverage trends are also uncertain and contingent. Hence, to develop decision trees that are robust against changes in the data generating process and future uncertainties, we used epidemic trajectories simulated by a model of SARS-CoV-2 transmission in the U.S. between March 1, 2020 and June 1, 2022 to train and evaluate our decision trees.This simulation model is structured to incorporate factors, and the associated uncertainties, that impact the local size of COVID-19 hospitalizations during the winter 2021–2022 and spring of 2022  , 16, couWe assumed that vaccination began in December 2020 at an age-specific rate that gradually decreased over time Fig. . For theWith respect to the novel variant, vaccinated individuals were assumed to have partial immunity to infection (up to 100%), and if infected, experience a shorter duration of infectiousness by 25%-50%  and are To model the effect of control measures and population adherence to public health recommendations across different communities and since the beginning of the pandemic, we assumed that control measures went into effect whenever the rate of hospital occupancy due to COVID-19 exceeded the threshold ument}T2 . We furtThe estimates provided by certain surveillance systems are subject to error due to limited or unrepresentative samples. Among the surveillance systems of Table one week :\documenHere, we assume that  unclear ; therefoPrevalence of population with immunity from infection: The CDC’s seroprevalecnce survey estiamtes that on average 20.6% of the U.S. population had immunity from infection on Auguest 26, 2021 with the state-level mimimum of 1.6% and the maximum of 34.1%. To measure how well a simulated trajectory matches these estimates, we estimate the likelihood of observing the seroprevalence of e survey .Cumulative hospitalization rate: To measure how well a simulated trajectory matches the observed data on cumulative hospitalization rate , effect of mitigating strategies, and other factors that determine the trajectory of COVID-19 hospitalizations during the winter 2021–2022 and spring of 2022 , and specificity . For each model, we estimated the accuracy, sensitivity, and specificity using a separate set of simulated trajectories not used to train these models.In our main analysis, we assumed that some forms of non-pharmaceutical measures  with varying degrees of effectiveness would remain in effect during winter 2021–2022 and spring of 2022. Our first sensitivity analysis considered a scenario in which all non-pharmaceutical measures are removed  during this period [In our main analysis, we assumed that a novel variant with uncertain degree of transmissibility and virulence emerges and spreads during winter 2021–2022 and spring of 2022. Our second sensitivity analysis considers the scenario where no novel variant spreads during this period.Finally, we trained our predictive models assuming that the prevalence of novel variant among new infections are estimated using the sample size of While we developed and validated our decision trees using a wide range of simulated trajectories, we also evaluated whether the accuracy of our predictive models persists under three extreme scenarios:Figure With respect to the spread of novel variants, Fig. th percentile range  with mean 29.4 per 100,000 population  with mean 24.8  with mean 983.6 per 100,000 population  with mean 68.7 Below is the link to the electronic supplementary material.