Most COVID-19 survivors report experiencing at least one persistent symptom after recovery, including sympathovagal imbalance. Relaxation techniques based on slow-paced breathing have proven to be beneficial for cardiovascular and respiratory dynamics in healthy subjects and patients with various diseases. Therefore, the present study aimed to explore the cardiorespiratory dynamics by linear and nonlinear analysis of photoplethysmographic and respiratory time series on COVID-19 survivors under a psychophysiological assessment that includes slow-paced breathing. We analyzed photoplethysmographic and respiratory signals of 49 COVID-19 survivors to assess breathing rate variability (BRV), pulse rate variability (PRV), and pulse–respiration quotient (PRQ) during a psychophysiological assessment. Additionally, a comorbidity-based analysis was conducted to evaluate group changes. Our results indicate that all BRV indices significantly differed when performing slow-paced breathing. Nonlinear parameters of PRV were more appropriate for identifying changes in breathing patterns than linear indices. Furthermore, the mean and standard deviation of PRQ exhibited a significant increase while sample and fuzzy entropies decreased during diaphragmatic breathing. Thus, our findings suggest that slow-paced breathing may improve the cardiorespiratory dynamics of COVID-19 survivors in the short term by enhancing cardiorespiratory coupling via increased vagal activity. The COVID-19 disease, caused by the novel coronavirus SARS-CoV-2, emerged at the end of 2019 and has rapidly spread worldwide since it first appeared in China, resulting in more than 673 million cases and 6.8 million deaths at the time of writing this article ,5,6. A sA high prevalence of autonomic alterations in respiratory and cardiovascular systems, which modify cardiopulmonary interactions as a sign of dysautonomia or orthostatic syndromes, occurs in subjects who suffered an acute phase of the disease ,13,14. SSlow-paced breathing has been introduced as a relaxation technique that consists of reducing the breathing rate (BR) to about 6 cycles per minute (0.1 Hz), usually with 5-s deep inhalation and exhalation phases . This brThus, this work aimed to study the cardiorespiratory dynamics by linear and nonlinear analysis of photoplethysmographic and respiratory time series on COVID-19 survivors under a psychophysiological assessment (study I). In addition, as a secondary exploratory study, the effect of different comorbidities on the cardiorespiratory dynamics of COVID-19 survivors was examined (study II). We hypothesized that relaxation induces increased cardiorespiratory parasympathetic activity in COVID-19 survivors.This exploratory study involved 49 survivors of COVID-19 illness (32 men and 17 women) aged 27 to 84 years old (49 ± 12 years) who were hospitalized between 2020 and 2022 at the Instituto Nacional de Enfermedades Respiratorias  due to COVID-19 complications in the acute infection phase. All the participants were laboratory-confirmed with SARS-CoV-2 and surveyed at three months post-hospital discharge. The research protocol was approved by the Ethics Committee of the National Institute of Respiratory Diseases, Mexico . All volunteers in this study signed an Informed Consent form when they agreed to participate, and all methods were performed following the relevant guidelines and regulations. The exclusion criteria involved limited mobility and receiving treatment at home instead of being hospitalized. The sample size for this exploratory research was determined by convenience sampling.A validated protocol of 10 min for relaxation ,33 was cThe COVID-19 survivors were instructed to follow all the phases in this protocol. Before the test, the medical staff guided the patient on how to perform a paced-breathing technique at a fixed rate of six breaths/minute with a 1:1 ratio of inhalation to exhalation time (5 s each). Additionally, for the natural relaxation phase, individuals were asked to relax without an explicit indication of modifying their breathing pattern or frequency as requested for diaphragmatic breathing. In this study, the protocol for relaxation belongs to a preliminary psychophysiological phase of examination of participants who subsequently were enrolled in biofeedback therapy based on their heart rate and breathing rate values.Simultaneously to the protocol for relaxation, the COVID-19 survivors were instrumented with a finger-clip pulse oximeter sensor on the thumb of the left hand, followed by two adjustable sensor belts, one on the chest and another on the abdomen . The senThe physiological data recordings were exported as text files to Matlab R2022a . The extracted raw RESP signals were filtered with a second-order IIR Butterworth bandpass filter with a bandpass frequency range of 0.05 Hz to 1 Hz. Subsequently, a fourth-order IIR Butterworth low-pass filter with a cutoff frequency of 5 Hz was used to filter the raw PPG signals to remove noise interference.After the pre-processing stage, the PPG and RESP time series with more than 10% loss of information at any phase were discarded. In addition, RESP signals with an abnormal breathing pattern were not considered for further analyses. In consequence, forty-nine signals were included for breathing rate variability (BRV), pulse rate variability (PRV), and pulse–respiration quotient (PRQ) data analyses, as indicated in In this study, two main stages were assessed. In study I, forty-nine signals were included for breathing rate variability (BRV), pulse rate variability (PRV), and pulse–respiration quotient (PRQ) data analyses, as indicated in Peak detection was performed to RESP signals from the local inspiration maxima of each phase to extract the breath-to-breath (BB) time series (expressed in seconds) . The meaA peak detection analysis was performed on PPG signals to obtain the pulse-to-pulse time series (IBI) expressed in milliseconds (ms); it is reported as pulse rate variability (PRV) since the data were obtained from pulse recordings instead of ECG signals ,40. The The pulse–respiration quotient (PRQ) is a parameter reintroduced by Scholkmann and Wolf, obtained from the ratio of the heart rate to the breathing rate that effectively reflects the changes in the cardiorespiratory dynamics mediated by age, sex, physical and cognitive activity, body posture, and chronobiological state, and it is sensitive to the activity executed at the time of the recording . It can As proposed by Scholkmann and Wolf, all data regarding the PRQ index are reported as daytime functional PRQ (D-f-PRQ)  since ouInstantaneous heart rate and breathing rate time series were obtained from IBI and BB time series, respectively. To ensure equidistant signals, the instantaneous breathing rate time series b was upsThe PRQ analysis included the mean PRQ and standard deviation of instantaneous PRQ (SD-PRQ) as the linear indexes, followed by sample entropy (SampEn) and fuzzy entropy (FuzzyEn) as the nonlinear parameters; the computing of the nonlinear indexes is described below.Sample entropy is a widely known parameter used to evaluate how regular the fluctuations of a time series are, reducing the measured bias usually found when using approximate entropy (ApEn) associated with the signal length and self-matches . This mem successive points:m being the embedding dimension of the vector length. From that, the distance From a vector rmalized ,44,45,46Then, we calculate the number of times the distance of The average similarity Therefore, SampEn is obtained by:Fuzzy entropy, introduced by Cheng et al. and based on the fuzzy set theory proposed by De Luca and Termini, evaluates the complexity and ambiguity of a given data set ,48. ThisFrom a time series of Afterward, Then, the average similarity expressed by m = 2, r = 0.2) and fuzzy entropy  [These entropies were evaluated using PyBios 1.0.0 software , setting the following parameters for sample entropy  .t-tests were conducted if data met the normality assumption; otherwise, we conducted a non-parametric Wilcoxon signed-rank test instead. A non-parametric Kruskal Wallis test was carried out for all indices extracted from BRV, PRV, and PRQ analysis at the induced relaxation phase for comorbidity-based statistical analysis. All these statistical tests were performed using Matlab R2022a software .The mean values of linear and nonlinear indices obtained from BB, IBI, and PRQ time series were evaluated by a Lilliefors (Kolmogorov–Smirnov) test to assess normal distribution. Subsequently, multiple comparisons between phases with respect to Phase 4 were performed; paired p < 0.001) following a slow breathing pattern (p < 0.001) in Phase 4 compared to the other three Phases  compared to the other three Phases  is exhibited for SDNN and LF/HF ratio in Phase 4 compared with the other three phases. A significant increase  at Phase 4 of the protocol  between the no comorbidities (NOC) and diabetic (DIAB) groups  was observed among diabetic individuals compared to those with no pre-existing comorbidities  significantly increases cardiac parasympathetic activity and global variability, depicted by SDNN and RMSSD-PP values . This fiIn the nonlinear analysis, we observed a decrease in SampEn during slow-paced breathing. This parameter measures the regularity and complexity of a time series, with lower values indicating more regular patterns . In our 2 value was lower than theirs for all phases. This difference can be partially explained by our small sample size, compared to other studies, and the comorbidities present in our group. Additionally, a study concluded that diabetic individuals exhibited an increased α2 compared to the short-term exponent α1, which indicates decreased parasympathetic activity. Conversely, healthy subjects showed the opposite [Previous studies have reported a distinct behavior of the DFA scaling exponents in COVID-19 survivors compared to a healthy group. Our results partially agree with those reported by Kurtoğlu et al. . Our groopposite .1 and a decrease in the long-term exponent α2  still showed a higher heart rate a, possibVanzella et al.  assessedLachowska et al. reported that HR and blood pressure responses decreased considerably with slow breathing exercises in heart failure patients with reduced ejection fraction and enhanced a variety of health-related scores of quality of life (QoL) , while aApart from the diabetic group, no significant difference was found among comorbidities and healthy individuals during slow breathing a,b. We sIn this study, we encountered some limitations; first, the reduced sample size to address autonomic changes among patients with comorbidities and healthy individuals, where both groups coursed COVID-19 sequelae, and the lack of previous research on the use of the PRQ to evaluate cardiac and respiratory interactions in a similar population to the one presented in this work, that must be considered in the interpretation of the provided data. Despite participants reducing their BR, we also noted that several did not meet the 6 breaths/min breathing rate  that canCOVID-19 sequelae negatively impact survivors’ physical and mental health in the short and long term ,74,75. IAdditional studies may be conducted to assess the long-term effect of slow breathing and other psychophysiological interventions on COVID-19 survivors who present post-infection sequelae and may or may not have other comorbidities. Moreover, further analysis of the differences between men and women is suggested with an increased sample size. However, the study of the PRQ index seems like a feasible technique to evaluate cardiac and respiratory interactions and the changes mediated by breathing rate modifications.Our results demonstrate that implementing a psychophysiological assessment based on slow paced-breathing induces significant changes in the breathing rate variability and pulse rate variability of COVID-19 survivors. These changes may improve the cardiorespiratory dynamics of this population by enhancing cardiorespiratory coupling in the short-term via increased vagal activity. Additionally, our findings suggest that patients with comorbidities, such as type 2 diabetes mellitus, may still benefit from diaphragmatic breathing despite changes in sympathovagal balance. However, further research is needed to confirm the efficacy of this practice in the long term.


Functional Magnetic Resonance Imaging (fMRI) block-design experiments typically include active ON-blocks with presentation of cognitive tasks which are contrasted with OFF- blocks with no tasks presented. OFF-blocks in between ON-blocks can however, also be seen as a proxy for intermittent periods of resting, inducing temporary resting-states. We still do not know if brain activity during such intermittent periods reflects the same kind of resting-state activity as that obtained during a continuous period, as is typically the case in studies of the classic Default Mode Network (DMN). The purpose of the current study was therefore to investigate both similarities and differences in brain activity between intermittent and continuous resting conditions.There were 47 healthy participants in the 3T fMRI experiment. Data for the intermittent resting-state condition were acquired from resting-periods in between active task-processing periods in a standard ON-OFF block design, with three different cognitive tasks presented during ON-blocks. Data for the continuous resting-state condition were acquired during a 5 min resting period after the task-design had been presented.The results showed that activity was overall similar in the two conditions, but with some differences. These differences were within the DMN network, and for the interaction of DMN with other brain networks. DMN maps showed weak overlap between conditions in the medial prefrontal cortex (MPFC), and in particular for the intermittent compared to the continuous resting-state condition. Moreover, DMN showed strong connectivity with the salience network (SN) in the intermittent resting-state condition, particularly in the anterior insula and the supramarginal gyrus. The observed differences may reflect a “carry-over” effect from task-processing to the next resting-state period, not present in the continuous resting-state condition, causing interference from the ON-blocks. Further research is needed to fully understand the extent of differences between intermittent and continuous resting-state conditions. Measures of resting-state functional connectivity have been of great interest in the field of neuroimaging for predominantly two reasons: Firstly, studies have provided new insight in understanding the human brain including possible overlaps between functional and structural connectivity . SecondlFunctional connectivity studies of the resting brain have revealed consistent large-scale spatial distributions of coherent signals which we refer to as Resting State Networks (RSNs). It is now confirmed that these networks reflect functional brain systems supporting core perceptual and cognitive processes . Interest-tests.These observations provide a back-drop for the present study, where the focus was to examine and compare RSN-data acquired during a single prolonged resting period with data acquired during repeated brief resting-periods in between task-processing periods . PreviouThe participants were 47 healthy adults, 27 males and 20 females . The participants were recruited in the local Bergen municipality area through general, open announcements. Self-reported absence of any psychiatric and neurological disorder was an inclusion criterion. Before MRI data acquisition, the participants were interviewed for body implants such as pacemakers and any signs of claustrophobia. Furthermore, the participants were presented with an informed consent form to sign. Female participants were additionally asked about pregnancy, which was an exclusion criterion. The study was conducted according to the Declaration of Helsinki regarding ethical standards and in agreement with good clinical practice framework in accordance with all ethical rules and guidelines at our institution for human research and was approved by the Regional Committee for Medical Research Ethics in Western Norway (#2014/1641/REK-Vest). Written informed consent was obtained from all participants.1) software platform. Presentation of the stimuli with acquisition of the MR data was synchronized using a NordicNeurolab SyncBox . The participants were instructed to keep their eyes open during presentation of the OFF-blocks. Each ON- and OFF-block lasted for 68 s, making up a total of 10 min and 2 s. For more detailed description of the stimuli  = 256 × 256 mm2, 200 Hz/px readout bandwidth, flip angle 8 degrees and total acquisition duration of 7.40 min. All fMRI-data were acquired using 2D gradient echo planar imaging (EPI) with the following parameters: TE/TR = 30 ms/2 s, 306 volumes for the task-based intermittent condition and 150 volumes for the continuous resting state condition, acquisition matrix = 64 × 64, slice thickness = 3.6 mm, 35 slices, FOV = 230 × 230 mm.Imaging data were collected using a Siemens 3T Magnetom Prisma MR scanner.Before preprocessing of the task fMRI data, the seven most central 3D volumes were extracted from each of the nine OFF-blocks from the 4D task-fMRI imaging for further processing. Each OFF-block consisted of 17 volumes where the first and last five volumes of each OFF- block were omitted. The first five volumes of the OFF-blocks were omitted to avoid the inclusion of a transient state of the BOLD (Blood Oxygen Level Dependent) signal from ON-blocks to OFF-blocks. We additionally decided to remove the last five OFF-blocks to avoid inclusion of the volumes when participants could anticipate the appearance of the next cognitive task. 4) functions spm vol and spm read vols. Furtherly, the volumes of interest were then saved as separate 3D nifti images using the SPM function spm write vol. The extracted “resting” 3D volumes were finally merged into 4D images consisting of 63 volumes  using SPM function collapse nii scan.5 The whole procedure was performed in Matlab R2017b .The data extraction procedure was as follows: The intermittent resting-state data were first disentangled into individual volumes using SPM12  coordinates, functional outlier detection (ART-based identification of outlier scans for scrubbing), functional direct segmentation and normalization, structural centering to  coordinates, structural segmentation and normalization and functional smoothing.All pre-processing was performed in Matlab R2017b using the CONN functional connectivity toolbox 17b.7 This was done to automatically select components which best reflected the DMN in the two data-sets, and to get an overview of the networks present in either condition.Spatial Independent Component Analysis (ICA) was performed separately on resting data from the two conditions. The ICA analysis was performed using Group ICA for fMRI toolbox (GIFT v3.0b). For each condition, 20 independent components were extracted using the algorithm type “Infomax”  with allp-value of 0.05 and cluster extent of 10 voxels were selected for all comparisons. Additionally, to test the spatial overlap of the components with the highest and second-highest correlation to the template DMN map, probability maps for all components and all participants were calculated using SPM 12. Firstly, all components were binarized using a threshold of z > 1.96 . Secondly, all binarized components were summed up voxel-wise, multiplied by 100 and divided by the total amount of images (images from two components of 47 participants from two conditions). Hence, the displayed voxel values represent the probability (%) of the highest and second-highest DMN-correlated components to be present in all participants in the two conditions.The resultant mean participants’ components with the highest correlation to the template DMN map were used to select individual participants’ components for a second-level conjunction analysis  across all relative component images for each individual. This allowed quantifying the level of similarity across identified DMN components in the two resting-state conditions. The conjunction analysis was performed in SPM 12. All relevant component maps (one for each participant and condition) were included in the second-order analysis (one-way ANOVA). After estimation of the model, multiple contrasts for comparison were defined. Statistical maps were corrected for multiple comparisons (FWE), and a significance threshold using a 8 The comparison was set up as a two-tailed paired t-test and utilized 10,000 permutations. The results were corrected for multiple comparisons using Family Wise Error correction (FWE) (p < 0.05).A region-of-interest (ROI) analysis was performed to explore functional connectivity differences for the DMN and eight selected networks between the two resting-state conditions. The ROI-to-ROI functional connectivity analysis was performed with the CONN toolbox (see text footnote 6). Functional connectivity z- scores were calculated between the four ROIs belonging to DMN: DefaultMode.MPFC , DefaultMode.LP (L) , DefaultMode.LP (R) , DefaultMode.PCC , and 32 ROIs belonging to eight selected functional networks  as defined in the CONN default network atlas. The resulting connectivity matrices for the two conditions were furtherly extracted and used to perform a between-condition comparison using the Permutation Analysis of Linear Models (PALM) in FSL.The spatial ICA decomposition of the resting-state data was designed to result in 20 independent component maps for each of the two conditions. After spatial sorting of the components, the two component-maps with the strongest correlation with the template DMN map were selected for each condition, I component from the intermittent condition primarily activated posterior DMN regions and ICA-2I primarily activated anterior brain regions. The corresponding ICA components in C component and primarily posterior regions for the ICA-2C component.As seen in I–intermittent resting condition and 1C–continuous resting-state condition) for each participant showed substantial spatial overlaps. This indicates that the DMN was activated in both the intermittent and continuous resting-state condition, see I and 2I components for the intermittent resting-state condition and 1C and 2C for the continuous resting-state condition). The probability map showed that the overlap between components was weaker in the frontal ROI of the DMN while the strongest overlap was in the posterior ROIs, see The conjunction analysis using the components with the highest correction with template DMN  > 1.301]. Each row shows pairs of ROIs creating a connection.Across the two conditions, six connections between DMN network ROIs and ROIs belonging to the other selected networks are shown in ated see . The prep(–log10) > 1.3010]. Thickness of the lines in the circular graph in p-value in logarithmic scale). The anatomical regions presented in the figure are: Posterior Cingulate Cortex (PCC), Medial Prefrontal Cortex (MPFC), Supramarginal Gyrus (SMG), Anterior Insula (AI), Lateral Parietal (LP). The right side of the hemisphere is marked by the letter R and the left side by the letter L.The connections shown in The current study examined similarities and differences in brain networks with data collected using two different experimental conditions, an intermittent resting-state condition and a continuous resting-state condition, with a focus on the Default Mode Network (DMN). Intermittent resting-state data were extracted from rest-periods (OFF-blocks) in between active task-processing periods (ON-blocks). Continuous resting-state condition data were from 5 min with task-absence, i.e., a classic resting-state period. We first used spatial ICA to identify the DMN network, and then examined differences in the overall spatial architecture and connectivity between the ROIs of the DMN and ROIs belonging to other main functional networks of the brain. Our results showed that the DMN network was present in both the intermittent and continuous resting-state condition. Although the overall DMN activity-pattern was similar between the two conditions, there were also some differences. Comparing functional connectivity between ROIs of the DMN and ROIs belonging to other functional networks revealed that the DMN in the intermittent resting-state condition was stronger connected with the SN compared with the corresponding analysis for the DMN observed in the continuous resting-state condition. This is to be expected considering that the DMN in the former condition is switched on and off when switching from active to passive processing .For two alternating conditions, for example, block lengths of more than 50 s would cause the majority of signal  to be removed when using a high- pass cut-off of 0.01 Hz. In fact, the optimal block length in an on-off design, regardless of any high-pass filtering, is approximately 16 s”  did not include the classic DMN frontal node (I) showed weak correlation with the template DMN, and weakly overlapped with frontal activation components that were obtained in the continuous resting-state condition. This is also seen in the percentage probability maps in C, 2C, 1I, and 2I), the activity in frontal region was less similar between the intermittent and continuous resting-state conditions. This could mean that the second component (2I) obtained from the intermittent resting-state condition is driven by different underlying mechanisms than the corresponding continuous resting-state component.The intermittent resting-state condition resulted in reduced activity in the medial prefrontal cortex (MPFC), and the first intermittent ICA-component , retrieving personal knowledge such as autobiographical memories and simulate personal future events or social interactions . This maThe comparison of DMN functional connectivity between the two resting-state conditions is a test of how network dynamics vary between conditions. There was a significant difference for the correlation between the DMN and the SN networks, with stronger connectivity between the DMN and SN in the intermittent resting-state condition compared to the connectivity in the continuous resting-state condition. This finding supports the hypothesis that the SN is modulating both the central executive network (CEN) and the DMN. The salience network (SN) includes activity in the anterior cingulate cortex (ACC) and the ventral anterior insular cortices, as well as the amygdala, hypothalamus, ventral striatum, thalamus, and specific brainstem nodes. SN is activated in response to diverse cognitive tasks and conditions, suggesting a task non-specific function , also coUnderstanding the role of the SN in modulation of the CEN and DMN networks may be critical for understanding underlying neuronal mechanisms of mental disorders. Dysfunctional “carry-over” effects from one network to another may be characteristic of brain connectivity dynamics in, e.g., schizophrenia . ManoliuDespite all research done on the dynamics of brain activity and DMN activity, we still do not know the functional role of this network and what exact role that different nodes of the DMN play for the dynamics of the network as a whole. Although the DMN was present in both conditions in the current study, there were also differences in overall DMN activity and connectivity between the two conditions. This has also been pointed out in previous studies, e.g., At the start of a BOLD run steady state was assumed after 4 frames (∼10 s) and for each run these frames were removed on a voxel-wise basis. Two frames after the start of each task block (∼5 s) were included as resting state to account for the hemodynamic delay. At the end of each task block, 6 frames (∼15 s) were excluded from the resting state data, allowing for the hemodynamic response to return to baseline” . We decided to not replicate this methodology in our study for several reasons. Firstly, including the volumes from the end of the OFF-blocks or beginning of the ON-blocks does impose the risk of confounding the intermittent resting state condition data due to participants “anticipation” for the ON-block to start and the cognitive “preparations” processes that might emerge during that time of the experiment. Following the strategy presented by A Previous study by stronger connectivity on account of data quality, or that trends in connectivity would cluster according to discrete functional networks as observed here.The OFF-block in the intermittent resting-state condition were extracted out of 17 whole brain volumes (34 s). This limits the possible number of volumes to create 4D intermittent resting-state condition data. Thus, the intermittent resting-state condition data were of relatively shorter duration than the continuous resting-state data. However, continuous resting-state data were in themselves of relatively short duration (5 min). A problem that emerges from block-fMRI experiments with relatively short resting OFF-blocks is that it limits the range of available frequencies to extract resting-state information . HoweverThe DMN network observed during OFF-blocks in the intermittent resting-state condition seems to share a similar pattern with the DMN network obtained during a continuous resting-state condition. However, there were also some differences between the conditions, mainly in frontal areas of the network. The functional connectivity analysis between DMN nodes and the whole brain volume revealed further differences between the two conditions. From inspection of hugdahl@uib.no.The data analyzed in this study is subject to the following licenses/restrictions: Due to restrictions posed by the ethics approval, data are not allowed shared other than after request to the corresponding author, and after written permission from the ethics committee. Requests to access these datasets should be directed to KH, The studies involving human participants were reviewed and approved by the Regional Committee for Medical Research Ethics in Western Norway (2014/1641/REK Vest). Written informed consent was obtained from all participants. The patients/participants provided their written informed consent to participate in this study.JB development of the fMRI tasks, data collection, analysis of the data, manuscript writing, and figure preparation. FR assisted in data analysis. KK development of fMRI tasks and data collection. LE and KH conceived and conducted the experiments. AC contributed to analysis of the data and read and commented on the manuscript. RG planned and conceived the study and conducted the experiment. All authors reviewed the manuscript.


ION/IOFF) by 1 order of magnitude (up to 108) comparedto the values measured for unpassivated nanowire. Specifically, thehBN encapsulation provided improved electrostatic top gate coupling,which is reflected in the enhanced subthreshold swing values of thedevices. For a single nanowire, an improvement up to 0.97 and 0.5V/dec in the n- and p-conduction, respectively, is observed. Due totheir dynamic switching and polarity control, RFETs boast great potentialin reducing the device count, lowering power consumption, and playinga crucial role in advanced electronic circuitry. The concept of mixed-dimensionalRFET could further strengthen its functionality, opening up new pathwaysfor future electronics.This work demonstratesthe novel concept of a mixed-dimensionalreconfigurable field effect transistor (RFET) by combining a one-dimensional(1D) channel material such as a silicon (Si) nanowire with a two-dimensional(2D) material as a gate dielectric. An RFET is an innovative devicethat can be dynamically programmed to perform as either an n- or p-FETby applying appropriate gate potentials. In this work, an insulating2D material, hexagonal boron nitride (hBN), is introduced as a gatedielectric and encapsulation layer around the nanowire in place ofa thermally grown or atomic-layer-deposited oxide. hBN flake was mechanicallyexfoliated and transferred onto a silicon nanowire-based RFET deviceusing the dry viscoelastic stamping transfer technique. The thicknessof the hBN flakes was investigated by atomic force microscopy andtransmission electron microscopy. The ambipolar transfer characteristicsof the Si-hBN RFETs with different gating architectures showed a significantimprovement in the device’s electrical parameters due to theencapsulation and passivation of the nanowire with the hBN flake.Both n- and p-type characteristics measured through the top gate exhibiteda reduction of hysteresis by 10–20 V and an increase in theon–off ratio ( Due to this property, the functional complexity of a systemcan be enhanced by these transistors without increasing the devicecount. In the most generic process, the device is based on an intrinsicSi nanowire with nickel (Ni) contact pads placed on both ends. Subsequentannealing results in the formation of silicide regions in the nanowire.Consequently, silicide-Si-silicide Schottky junctions are formed.By control of the Schottky barrier at the two ends of the nanowirewith the help of gate potentials, the type and flow of charge carrierswithin the channel can be dynamically modulated. For ambipolarity,an electrostatic potential on the back gate or a single top gate enablesthe n- or p-transport, depending on the polarity of the gate voltage.The physical downscalingof silicon-based MOSFET technology hasreached its limitations. Subsequently, the quest for alternative technologicalsolutions based on new materials and device concepts augments thedownscaling of integrated circuits. One such state-of-the-art advancementthat has been intensively researched in the past decade to improvethe functionality of nanowire field effect transistors (FETs) is calledreconfigurability.3 In ambipolar devices, both types of charge carriers takepart in the conduction in a single voltage sweep. The ambipolar RFETrealized in this work is predominantly single-gated. This gate canbe either a common back gate or a fabricated top gate. The gate electrodecovers the Schottky junction region on either side of the nanowirechannel. By applying a suitable voltage on the gate, the Schottkybarrier is tuned accordingly to steer charge carriers into the channelfor current conduction. In the OFF state of the device, the presenceof both electron and hole barriers causes a limited off-current toflow, which is mainly due to high energy thermionic emission. Whena positive bias voltage is applied to the gate structure, the energyof the bands is lowered, reducing the barrier height for the electrons.This leads to the injection of electrons into the channel by tunneling,contributing to an electron current or n-type conduction taking place.Simultaneously by sweeping the gate bias voltage to a low negativepotential, the energy bands rise, reducing the barrier height forholes and promoting hole conduction. As the conduction band edge alsorises at the same time, the electrons are blocked due to the highelectron barrier height. Hence, the current is totally dominated byhole conduction only and is termed p-type conduction. The IV characteristicsof an ambipolar RFET device and the band bending at different biasvoltages are depicted in An ambipolar RFET device can be switched to its ON state by theapplication of both positive and negative voltages. This nature ofswitching on the RFET device by sweeping the gate voltage from a highpotential to a low potential is known as ambipolarity.o represents the relative permittivity of free space, κ is thedielectric constant, A is the area, and As a single-gate architecture is used for ambipolar operation,the preferred gate structure is mostly the top gate. The top gateprovides a better field effect capacitive coupling over the Schottkyjunctions and the nanowire channel than the back-gated architecture.This is due to the difference in thickness of the top gate dielectricand the buried oxide layer. The relation between the capacitance andthe thickness of the dielectric is given by the following equation4 graphene,5 silicon  transistors to achieve a high gate coupling),9 and 2D semiconductors.10 However, explorationof dielectric materials is relatively scarce.Contraryto conventional transistors, charge carrier injectionin the channel is selectively controlled at the Schottky junctions,thereby avoiding the need of having an inherently doped channel material.Tuning the Schottky barrier at both ends of the nanowire is one ofthe basic requirements for current transport in reconfigurable devices.This is achieved by electrostatic coupling and enhanced gate controlover the channel material with a proper encapsulating and passivatingdielectric material. Such transistors have been demonstrated usingdifferent channel materials such as carbon nanotubes,11 paved the way fora promising option in the field of nanoelectronics due to their stabilityat atomic thickness, high intrinsic mobility, optical transparency,and high strain limit compared to conventional semiconductors andinsulators. One such material, which has excellent insulating propertieswith a large direct band gap of about 6 eV, is hexagonal boron nitride(hBN).13 2D hBN has a structure analogous to graphenemuch like a honeycomb maze and is therefore known as “whitegraphene.” The hexagonal sublattice of hBN consists of alternatingboron and nitrogen atoms with the electron-deficient boron atoms layingdirectly above the electron-rich nitrogen atoms or vice versa in adjacentlayers.14 The asymmetry in the sublatticescauses polarized covalent bonds leading to the large band gap of hBN,making it act as an insulator. Interlayer van der Waals forces dictatethe thickness of multilayer hBN, and the mechanically exfoliated monolayeris about 0.4 nm thick.14 Atomically thinhBN has flat interfaces due to the absence of surface dangling bondsand is, therefore, resistant to oxidation. It also acts as a goodgate insulator with a dielectric constant ranging between 3 and 4(similar or comparable to that of SiO2)15 and can be even incorporated as an encapsulating layerfor the active channel material of devices to prevent degradationof relatively unstable channel materials.16 hBN is chemically stable and can withstand 1000 °C at ambientconditions, 1400 °C in vacuum, and up to 2850 °C in an inertatmosphere.14 The thermal conductivityis about 484 W m–1 K–1 for 2DhBN with an elastic constant of 220–510 N m–1 and a Young’s modulus of about 1 TPa, thus making it an excellentmaterial for flexible insulation.17The scientificexploration of 2D materials after the isolationof graphene in 2004The top-down fabricated reconfigurable devices reported in thiswork are the first of their kind to incorporate silicon nanowiresas the channel material along with 2D hBN as the gate dielectric andencapsulating layer. The focus of this work is on the developmentof the fabrication process, including structural studies of the device.Furthermore, the electrical transfer characteristics of such Si-hBNdevices are measured based on different gating architectures to showa significant improvement in SS values, reduction of hysteresis, andincrease in p and n on-currents due to the 2D encapsulation and passivation.18 The first deviceis without an hBN dielectric layer, while the second device is cappedwith a thin hBN layer. AFM analysis is performed on these two devices,and the AFM topography is shown in The initial structural characterization ofthe mixed-dimensionalRFET devices includes tapping-mode atomic force microscopy (AFM) analysis.Height profiles are extracted from multiple AFM scans to determinethe thickness of the hBN flakes. 2 layer at the bottom of the singlenanowire channel. The nanowire channel has a trapezoidal shape witha height and a width of about 20 and 25 nm, respectively. The hBNthickness is confirmed to be approximately 10 nm and is shown to coverthe nanowire channel from the top. On top of the dielectric layer,a stack of titanium (Ti) and aluminum (Al) acts as the gate electrodefor the device.For further analysis of the hBN encapsulation ofthe nanowire,cross-sectional TEM analysis is performed. 20 The presence of carbon (C) on top of the Ti and Al gate stack isdue to the protective capping layer deposited during TEM specimenpreparation. The formation of carbon with traces of silicon (Si) andoxygen (O) around the cross-section of the nanowire channel and abovethe hBN flake is mostly caused by the fabrication process of the device.Several scanning electron microscopy images were taken of the nanowiredevices before and after hBN transfer in order to characterize thedevice. Thereby, organic substances on the surface of the sample werecracked and deposited as carbon layers.The bright-field TEM image showsthe stretch of the hBN flake andthe position where it finally sits on the buried oxide layer (awayfrom the silicon nanowire channel). The structure of the top gatefollows the curvature of the hBN flake. To study the element distributionin the sectioned device, a spectrum imaging analysis based on energy-dispersiveX-ray spectroscopy (EDXS) is applied. The superposition of the correspondingelement distribution maps of the device is shown in 1.VBG) is swept between 35 and −35 V in a closed loop.Back gating the devicebefore hBN istransferred. The back gate voltage (2.VBG is swept between20 and −20 V in a closed loop.Back gating the deviceafter the transferof the hBN flake. 3.VTG) is swept between 10 and −10 V in a closed loop.Top gating the devices using hBN asthe gate dielectric. The top gate voltage  are appliedafter hBN transfer to avoid the dielectric breakdown of the hBN. Adrain to source voltage (VDS) of 0.5 Vis used to obtain the transfer characteristics. The device showedambipolar behavior with improved electrostatic gate coupling afterhBN transfer, which results in an enhanced SS value of the device and on–offratio (ION/IOFF) levels are enhanced after the passivation of the single nanowireby hBN and with the measurements recorded through the top gate. Thisis reflected by the modest increase in the n-type on–off ratioand 1 order of magnitude increase in the p-type ratio for the hBN-passivatedtop-gated measurements. The convention used for calculating ION and IOFF is explained in detail in the SupportingInformation . The extractedelectrical parameters of the hBN-passivated single nanowire-baseddevice with different gating schemes are listed in Lower gate voltages . Three separate measurements arecarried out at different times. The first measurement is before hBNis transferred on the nanowire, the second is after hBN is transferred,and the final measurement is after the top gate is fabricated. Forthe first two measurements (at such negligible VG), a near linear regime is exhibited with a considerable increasein the drain current (ID) after the passivationof the nanowire with hBN. For the final measurement after the topgate is fabricated, it is seen that the ID has a significant increase in current with a characteristic showingSchottky type supra linear shape. Since the top gates help in betterhBN encapsulation of the single nanowire, better dielectric passivationis expected. This might have led to superior charge carrier transportthrough the nanowire channel without the influence of the gate voltages.Simultaneously, the on-state output characteristics of the hBN ambipolardevice are also measured based on the top-gated transfer characteristics.For the n-type characteristics, VDS isvaried from 0.25 to 1 V while increasing the VTG from 0 to 10 V in steps of 1 V . For the p-type behavior, similar voltage steps are maintainedbut in a negative direction . A clear Schottky behavior is seen in both types of conductionfor high values of VDS, which providea fair conclusion to the contact properties based on the ambipolarshape of the transfer characteristics. For the hole conduction, saturationis seen for low VTG values. It is alsoto be noted that in both cases, ID increaseswith an increase in VTG. This impliesthat high VTG enables more band bendingat the Schottky junctions, leading to increased tunneling of carriers.This eventually leads to a higher current flow.The outputcharacteristics for the single nanowire-based deviceare shown in Figure S3. For both devices, the VTG is sweptin a butterfly loop while varying the VDS from 0.25 to 1 V in steps of 0.25 V. It is clearly prominent fromboth the graphs that the devices exhibit ambipolar behavior with adistinctive rise in the ION levels for both the brancheswith the increase in VDS. However, comparedto the device with 20 nm hBN as a dielectric, the one with 10 nm showshigher on-currents, lower hysteresis, and better SS. The on–offratio (ION/IOFF) levels for the 10 nm hBN device are visible for more than one decadecompared to the 20 nm hBN device. This is understandable since thinnerhBN would provide better passivation and encapsulation to the singlenanowire. This will, in turn, lead to the device exhibiting betterelectrical conduction due to reduced charge scattering. Furthermore,considering the measurements are conducted by top gating through thehBN dielectric, it is expected of the device with the thinner hBNto have a better capacitive coupling. This, in turn, improves theSS of the 10 nm hBN device compared to the 20 nm one. Finally, itis also observed that the hysteresis of the n- and p-branch is muchlower for the thinner hBN device hinting at the absence of interfacetrap states and oxide charges due to the better passivation of thenanowire. In these scenarios, it is clearly understood that the tunabilityand reconfigurability of the devices are unaltered for either thicknessof the hBN. However, the variability in thickness does play a vitalrole in enhancing the device’s electrical performance. Theseresults serve as a proof of concept that hBN can be employed as agate dielectric for one-dimensional silicon nanowire-based devices,presented for the first time to the best of our knowledge. The electrostaticcoupling can be further enhanced by improving the interface betweenhBN and the silicon nanowire. The quality, thickness, and uniformityof the hBN can also impact the device’s performance. To achievethis, a well-controlled deposition of hBN using chemical vapor deposition(CVD) or epitaxy can be employed.23 Furthermore,nanowires having smooth edges instead of sharp cuts can enable bettercontact between nanowire surfaces and hBN. Moreover, the propertiesof hBN can also be tuned, e.g., by doping or defect-induced variations.24 This attribute can be exploited to flexiblyfabricate devices to attain the desired performance.Additionally,to realize the role of the device performance basedon the hBN thickness, two hBN-passivated single nanowire-based devicesare compared. These two devices exhibit contrasting hBN thicknesses,with one measuring 10 nm and the other measuring 20 nm. The top-gatedtransfer characteristics of these two devices are obtained and areshown in the Supporting Information IOFF is dependent on the VDS value, with VG being negligible. Therefore at room temperature, with a considerable VDS and negligible VG, an adequate amount of thermally activated charge carriers can passthrough the drain-source contacts. Nonetheless, for a single nanowire,this current value is low. However, it is understandable that thearray-based device consists of 20 single nanowires in parallel. Eachof these nanowires contributes charge carriers thermionically in theoff-state, thus increasing the off-current. Furthermore, the devicemaintained the off-current when the transfer characteristics wereobtained with top gating, but the on-current was reduced. This isattributed to the weak interface between nanowire arrays and hBN . Since nanowireshave a pitch of 200 nm, hBN is seen to cover only the top part ofthe nanowires and not the sidewalls. With an increasing pitch of thenanowires, the hBN coverage of the nanowires can be expected to improveand vice versa. It is expected that for nanowire arrays with a largerdistance between the nanowires, a thinner hBN would bend in the gap.This would provide passivation and encapsulation from all three sidesof the nanowire. However, with a low pitch of 200 nm, the hBN onlysits on the top of the nanowire and does not encapsulate it like inthe case of the single nanowire-based device. Thus, although back-gatedcharacteristics improved due to the added effect of the multiple nanowires,the top gate result degraded due to weak electrostatic coupling. Thisis reflected in the SS values of these measurements is always under the set limit of 10 pA and showed minimal leakagethrough the gate dielectric. In the scope of this work, a total of18 nanowire devices are fabricated. Out of 12 are single nanowiresand 6 are nanowire array devices. Exfoliated hBN is successfully transferredto 12 of the devices, while the top gate is fabricated on 5 of them.Out of the five top-gated single nanowire-based devices, three arenominally identical with hBN thickness varying between 10 and 15 nm.The other two devices had significantly thicker hBN gate dielectric,which led to weaker gate coupling and considerably worse device characteristics(as explained in the earlier section). On the other hand, the threedevices with thinner hBN consistently exhibited similar device performances.The electrical parameters of these nominally identical three devicesare extracted to derive the statistical analysis including the meanvalues and standard deviations (SD). This is shown in Supporting Information Table S1. Figure S6 presents the extracted electrical parameters of the three devicesalong with their resulting mean and SD values. The SD values in Figure S6a–c are relatively higher thantheir mean values. This is because the currents extracted have deviationsof a couple of orders of magnitude owing to the device-to-device variability.Since the nanowires are fabricated by a top-down approach, these devicesare robust and stable. hBN also helps to protect the devices fromthe outside environment. Therefore, over an extended period of time,the devices maintained consistent functionality and performance. Thefabrication of these 12 nanowire devices with hBN is also carriedout over different time spans. Their similar device behavior impliedthe reproducibility of the devices and the reliability of the fabricationprocess that is employed.Furthermore,a gate leakage current analysis is performed duringeach measurement step to prevent the flow of high current throughthe dielectric layer during continuous voltage scans. The repeatedflow of high currents can eventually lead to dielectric breakdownand degradation of the hBN-passivated nanowire-based devices. Themeasured leakage current analysis for hBN-passivated single nanowire-and nanowire array-based devices with different gating schemes areshown in Supporting Information 2 silicon-on-insulator (SOI) substrate.It consists of layers of silicon-insulator-silicon stacked on topof each other. The device or active top layer of the substrate consistsof 20 nm intrinsic silicon, followed by a 102 nm thick buried oxide(BOx) layer and a 775 μm p-doped Si carrier wafer. In this work,the fabrication of nanowires is based on the top-down approach, whichallows the large-scale integration of devices. The top-down approachinvolves the use of a substrate material, which is subjected to successivesubtractive procedures to ultimately achieve a nanostructure. Thedetailed process of silicon nanowire fabrication is described in ourprevious work18 and schematically shownin –2, anaperture with the size of 30 μm, and a beam area step size of2 nm. The exposure parameters are optimized according to the nanowiredimensions and were used throughout this work for patterning the appropriatenanostructures. After the exposure, the substrate is subjected toa resist development, which removes the unexposed resist.26 A SENTECH inductively coupled plasma reactiveion etching (ICP-RIE) Si 500 system is used to anisotropically transferthe HSQ pattern to the active device layer. The fabrication of sourceand drain Ni contacts at both ends of the nanowire includes a similarprocess of EBL patterning, metal deposition using a UHV e-beam evaporationsystem from BESTEC, and a lift-off process. Flash lamp annealing (FLA)is performed on the substrate after the Ni contact deposition to achievediffusion of Ni into the nanowire to form the NiSi2 phase.18 Ni silicidation in the nanowire creates a heterostructureof NiSi2–Si–NiSi2 forming twoSchottky junctions on either side. A prior study was conducted todevelop a Ni silicidation process of silicon nanowires by rapid thermalannealing (RTA).27 This study was furthercontinued to compare the results with FLA.18 The optimization of the FLA parameters with different energy densities,flash pulse durations, and various inert gas conditions was performedto achieve homogeneous Ni silicide formation in the nanowire. Theoptimum FLA treatment is obtained for the energy density of about89 J cm–2 for 6 ms in continuous nitrogen flow.The substrate material used for the fabrication of a mixed-dimensionalRFET is a 1 × 1 cm28 on a polydimethylsiloxane(PDMS) substrate (approximately1 × 1 cm2) employing commercial scotch tape. SuitablehBN flakes are then identified with the help of an optical microscopebased on their thickness, lateral dimensions, and uniformity. ThehBN flakes are transferred onto the nanowire using the dry-stampingtechnique29 by aligning the desired flakeonto the nanowire with the help of a micromanipulator setup that iscoupled to an optical microscope. The schematic of the hBN transferprocess and optical micrographs of the mixed-dimensional RFET devicesare shown in The hBN flakes are prepared using the mechanicalexfoliation techniques-corrected TITAN 80-300 microscope(FEI) operated at an accelerating voltage of 300 kV. With a TALOSF200X microscope equipped with an X-FEG electron source and a Super-XEDX detector system (FEI), high-angle annular dark-field scanningTEM (HAADF-STEM) imaging and spectrum imaging analysis based on energy-dispersiveX-ray spectroscopy (EDXS) are performed at 200 kV. Before (S)TEM analysis,the specimen mounted in a high-visibility low-background holder isplaced for 8 s into a FISCHIONE 1020 plasma cleaner to eliminate anypotential contamination. Cross-sectional TEM specimens of the mixed-dimensionalRFET devices are prepared by in situ lift-out using a Helios 5 CX-focusedion beam (FIB) device (Thermo Fisher). To protect the sample surface,a carbon cap layer is deposited beginning with electron-beam-assistedand subsequently followed by Ga-FIB-assisted precursor decomposition.Afterward, the TEM lamella is prepared using a 30 keV Ga-FIB withadapted currents. Its transfer to a 3-post copper lift-out grid (Omniprobe)is done with an EasyLift EX nanomanipulator (Thermo Fisher). To minimizesidewall damage, Ga ions with only 5 keV energy are used for the finalthinning of the TEM lamella to electron transparency. Tapping modeAFM analysis is carried out using a NANOFRAZOR SCHOLAR tool from HEIDELBERGINSTRUMENTS. For the electrical transfer characteristics measurements,a semiautomated SÜSS MICROTECH probe system PA200 connectedwith a 4200-SCS KEITHLEY INSTRUMENTS characterization system is used.Bright-field transmission electron microscopy (TEM) images arerecorded using an image-CA novel hybrid mixed-dimensional RFET concept is demonstrated byintroducing 2D hBN in nanowire-based electronics. The fabricated devicesexhibit an improvement in SS values, a reduction in hysteresis, andan enhancement of the p and n on-currents. To conclude, hBN can beused as an effective dielectric and passivating layer for one-dimensionalnanowire devices. Since the properties of the hBN can be tuned, versatiledevices can be fabricated using this robust material. However, optimizationof the device design and control over the hBN thickness is requiredfor superior device performance. This first demonstration of hBN incorporationin nanowire-based devices potentially opens up a new paradigm in semiconductorelectronics. Furthermore, system-level integration of these devicescan be achieved using CVD or epitaxy-based deposition of hBN.


This cross-sectional study examines contributions to decreases in racial and ethnic disparities in COVID-19 mortality among US adults from the initial wave to Omicron wave. Why did racial and ethnic disparities in COVID-19 mortality in the US decrease in the Omicron wave compared with the initial wave of the pandemic?In this cross-sectional study of 977 018 adults who died from COVID-19, 60.3% of the national decrease in disparities in COVID-19 mortality for non-Hispanic Black compared with non-Hispanic White adults between the initial and Omicron waves could be explained by increases in mortality among non-Hispanic White adults and shifts in mortality to nonmetropolitan areas, where more non-Hispanic White adults reside.This study found that racial and ethnic disparities in COVID-19 mortality decreased nationally for some groups during the first 2 years of the pandemic, but this decrease was mostly explained by increases in mortality for non-Hispanic White adults and changes in pandemic geography. Prior research has established that Hispanic and non-Hispanic Black residents in the US experienced substantially higher COVID-19 mortality rates in 2020 than non-Hispanic White residents owing to structural racism. In 2021, these disparities decreased.To assess to what extent national decreases in racial and ethnic disparities in COVID-19 mortality between the initial pandemic wave and subsequent Omicron wave reflect reductions in mortality vs other factors, such as the pandemic’s changing geography.This cross-sectional study was conducted using data from the US Centers for Disease Control and Prevention for COVID-19 deaths from March 1, 2020, through February 28, 2022, among adults aged 25 years and older residing in the US. Deaths were examined by race and ethnicity across metropolitan and nonmetropolitan areas, and the national decrease in racial and ethnic disparities between initial and Omicron waves was decomposed. Data were analyzed from June 2021 through March 2023.Metropolitan vs nonmetropolitan areas and race and ethnicity.Age-standardized death rates.There were death certificates for 977 018 US adults aged 25 years and older  that included a mention of COVID-19. The proportion of COVID-19 deaths among adults residing in nonmetropolitan areas increased from 5944 of 110 526 deaths (5.4%) during the initial wave to a peak of 40 360 of 172 515 deaths (23.4%) during the Delta wave; the proportion was 45 183 of 210 554 deaths (21.5%) during the Omicron wave. The national disparity in age-standardized COVID-19 death rates per 100 000 person-years for non-Hispanic Black compared with non-Hispanic White adults decreased from 339 to 45 deaths from the initial to Omicron wave, or by 293 deaths. After standardizing for age and racial and ethnic differences by metropolitan vs nonmetropolitan residence, increases in death rates among non-Hispanic White adults explained 120 deaths/100 000 person-years of the decrease (40.7%); 58 deaths/100 000 person-years in the decrease (19.6%) were explained by shifts in mortality to nonmetropolitan areas, where a disproportionate share of non-Hispanic White adults reside. The remaining 116 deaths/100 000 person-years in the decrease (39.6%) were explained by decreases in death rates in non-Hispanic Black adults.This study found that most of the national decrease in racial and ethnic disparities in COVID-19 mortality between the initial and Omicron waves was explained by increased mortality among non-Hispanic White adults and changes in the geographic spread of the pandemic. These findings suggest that despite media reports of a decline in disparities, there is a continued need to prioritize racial health equity in the pandemic response. Structural racism has been a key driver of national disparities throughout the pandemic.35Considerable research has documented racial and ethnic disparities in mortality during the COVID-19 pandemic in the US.14 It remains unknown if these changes were uniform across metropolitan and nonmetropolitan areas. It is also unclear to what extent decreases in disparities reflected reductions in mortality or other factors, such as changes in the geographic spread of the pandemic.Prior literature on racial and ethnic disparities in COVID-19 mortality has largely studied the first year of the pandemic. Less is known about how mortality patterns changed during the Delta and Omicron waves in the second year amid increasing vaccination rates. Nationally, racial and ethnic disparities in COVID-19 mortality decreased for some groups between 2020 and 2021.36 First, the pandemic spread to rural areas in 2021, where a higher proportion of non-Hispanic White people reside.39 Second, differences in vaccine uptake have been reported by race, ethnicity, and urbanicity.43There are multiple reasons to anticipate that pandemic geography and racial and ethnic patterns of COVID-19 mortality may have changed concurrently.In this study, we examined COVID-19 deaths among adults in the US by race and ethnicity across metropolitan and nonmetropolitan areas from March 1, 2020, to February 28, 2022. Our objective was to understand to what extent national decreases in racial and ethnic disparities in COVID-19 mortality during the first 2 years of the pandemic reflected reductions in mortality vs other factors, such as the pandemic’s changing geography.STROBE) reporting guideline for cross-sectional studies.This cross-sectional study used deidentified, publicly available data and so was exempted from review and informed consent by the Boston University Medical Center Institutional Review Board. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology  code U07.1 to identify deaths for which COVID-19 was listed anywhere on the death certificate.We used mortality data from the US Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database.14 Race and ethnicity is typically recorded on death certificates by funeral directors who are expected to collect this information from next of kin but may also rely on their own observations.45 Prior studies found that the accuracy of race and ethnicity on death certificates was high overall but lower among American Indian and Alaska Native populations.46Race and ethnicity categories were defined as Hispanic, non-Hispanic American Indian and Alaska Native, non-Hispanic Asian, non-Hispanic Black, non-Hispanic Native Hawaiian and other Pacific Islander, and non-Hispanic White to facilitate comparison with prior CDC estimates.We defined March 1, 2020, through February 28, 2021, and March 1, 2021, through February 28, 2022, as the first and second years of the pandemic, respectively. We divided this 2-year period into the initial wave , second wave , Alpha wave , Delta wave , and Omicron wave .Because death counts between 0 and 9 were suppressed, we excluded deaths among individuals aged younger than 25 years given that few deaths occurred at these ages compared with older ages. We aggregated individuals to 3 age groups  to minimize suppression.47We condensed the data’s urban and rural classifications into 3 metropolitan and nonmetropolitan categories of residence . Large metropolitan areas refer to counties in metropolitan statistical areas with a population of 1 million residents or more. Medium and small metropolitan areas refer to counties in metropolitan statistical areas with a population between 50 000 and 999 999 residents. Nonmetropolitan areas refer to all other counties.We queried COVID-19 mortality by race and ethnicity across metropolitan and nonmetropolitan categories for each pandemic year, wave, and month. To avoid substantial data suppression, we limited our monthly analyses to the 3 most populous racial and ethnic groups and included non-Hispanic Native Hawaiian and other Pacific Islander adults only in analyses of the pandemic year. Our approach to querying is presented in eAppendix 1 in 48 Race and ethnicity in the census is self-reported or reported by a member of the household. We obtained age group–specific monthly population estimates for each race and ethnicity in each metropolitan category by assuming that category-specific populations increased or decreased linearly between estimates and extrapolating for March 2020 and for August 2021 through February 2022.We used April 2020, July 2020, and July 2021 population estimates from the US Census Bureau.Death counts were imputed when values between 0 and 9 deaths were suppressed. We imputed with random draws from a β distribution with α parameter of 2 and β parameter of 3 and multiplied results by 10. Imputation was limited to nonmetropolitan areas and was done only for the Hispanic population during the first month and non-Hispanic Asian population during the first and second waves.49 We standardized death rates in this study using 3 age groups  and used the overall 2020 US population as the standard population. Further details about the age-standardization procedure and our approach to calculating variance are provided in eAppendix 2 in Because racial and ethnic groups in the US have different age distributions, age standardization was necessary.The geographically standardized decrease in death rates among non-Hispanic Black or Hispanic adults in a hypothetical population in which the non-Hispanic Black or Hispanic population had the geographic distribution of a standard population.The geographically standardized increase in death rates among non-Hispanic White adults in a hypothetical population in which the non-Hispanic White population had the geographic distribution of a standard population.The change in mortality outcomes associated with shifts in where deaths occurred from metropolitan to nonmetropolitan areas, where more non-Hispanic White adults reside relative to the national geographic distribution .The change in mortality outcomes associated with shifts in the racial and ethnic population composition in metropolitan and nonmetropolitan areas, which we expected to be minor.The components sum to the national change in disparity. When expressed as percentages, the components sum to 100%. The standard population used for geographic standardization was the aggregate total of Hispanic, non-Hispanic Black, and non-Hispanic White populations, with the mean found across waves. We used the initial wave as the reference wave across all analyses for consistency. Further details about the decomposition analysis are provided in the eAppendix 3 in We decomposed the national change between the initial wave of the pandemic and the Omicron wave in the absolute disparity in age-standardized COVID-19 death rates among non-Hispanic Black compared with non-Hispanic White adults. We also decomposed the national change in disparities for Hispanic compared with non-Hispanic White adults and compared the initial wave with the second, Alpha, and Delta waves. We sought to understand the contribution of the following 4 components to national changes in disparities: 50 Data were analyzed from June 2021 through March 2023.Programming code was developed using R statistical software version 3.6.3 , and replication code is available online on GitHub.From March 1, 2020, through February 28, 2022, there were death certificates for 977 018 US adults  aged 25 years and older that included a mention of COVID-19. Among 110 526 deaths in the initial wave of the pandemic, 86 263 deaths (78.0%) occurred among adults residing in large metropolitan areas, 18 319 deaths (16.6%) in medium or small metropolitan areas, and 5944 deaths (5.4%) in nonmetropolitan areas , non-Hispanic Asian , and non-Hispanic Black  adults between initial and Delta waves . These cAt the national level, death rates were higher for non-Hispanic Black adults than non-Hispanic White adults during the initial wave of the pandemic  . This diWe sought to understand mechanisms that may have contributed to national decreases in disparities. The national disparity in age-standardized COVID-19 death rates per 100 000 person-years for non-Hispanic Black compared with non-Hispanic White adults decreased from 339 to 45 deaths, or by 293 deaths, from the initial wave to the Omicron wave . IncreasComparing the Delta wave with the initial wave, increases in geographically standardized death rates for non-Hispanic White adults and movement of mortality from metropolitan to nonmetropolitan areas also explained much of the national decrease in disparities . In the In this cross-sectional study of COVID-19 deaths in the US, we found that racial and ethnic disparities for Hispanic and non-Hispanic Black adults compared with non-Hispanic White adults decreased substantially between the initial wave of the pandemic and the Omicron wave. However, most of this reduction in disparities for non-Hispanic Black adults and all of the reduction in disparities for Hispanic adults was explained by increases in geographically standardized mortality among non-Hispanic White adults and geographic shifts of the pandemic to nonmetropolitan areas, where a disproportionate share of non-Hispanic White adults reside.51 Our work suggests that it may be premature to celebrate reductions in disparities because they did not largely represent reductions in mortality.13 In fact, over the study period, death rates increased markedly in all areas for non-Hispanic White and non-Hispanic American Indian and Alaska Native adults and in nonmetropolitan areas for most groups. Within nonmetropolitan areas, death rates were substantially higher for Hispanic, non-Hispanic American Indian and Alaska Native, and non-Hispanic Black adults during the second year of the pandemic than for non-Hispanic White adults.Our findings contrast with recent media reports suggesting that decreases in racial and ethnic disparities in COVID-19 mortality may represent improvements in public health.53 Health systems that serve rural areas, including the Indian Health Service, have long been underfunded,55 and Hispanic, non-Hispanic Black, and non-Hispanic American Indian and Alaska Native populations in rural areas report lower access to health care than the non-Hispanic White population. Prior research has further demonstrated the association of declining economic opportunity with negative outcomes in rural health,57 which was worsened in the COVID-19 pandemic.58The emergence of a rural disadvantage in COVID-19 death rates for most racial and ethnic groups during the second year of the pandemic may point to social and structural factors associated with health in rural areas. Rural populations, especially non-Hispanic Black and non-Hispanic American Indian and Alaska Native individuals, have higher rates of chronic diseases, which were associated with increased risk of dying from COVID-19.59 This may be partially associated with partisanship. Despite the effectiveness of vaccines in their association with reduced mortality, Republican voters were more vaccine hesitant than other populations and more frequently resided in rural areas.61 While vaccination delivery favored older and non-Hispanic White individuals early in the pandemic,63 the racial and ethnic gap in vaccination rates has since decreased.64 However, delivery can still improve.67 As of February 2023, Hispanic, non-Hispanic American Indian and Alaska Native, and non-Hispanic Black adults have received boosters at substantially lower rates than non-Hispanic White adults.68 Evidence-based approaches to increasing vaccine and booster uptake include partnerships with faith-based organizations, housing communities, and community organizations; mitigating barriers, such as requirements for photo identification; making vaccines available outside typical working hours; ensuring that clinics are accessible via public transportation; and centering Black and American Indian and Alaska Native officials in outreach efforts.72 Strategies in rural areas include education of community ambassadors, use of social media, and operation of mobile vaccination sites.73 The Panola Project in Alabama is 1 case study of a community leader, Dorothy Oliver, who organized her rural, predominantly Black community to get vaccinated with little government support.74 The CDC and health departments could support similar community-led efforts on a wider scale.75This rural disadvantage could also be associated with lower COVID-19 vaccination rates. As of January 2022, 61% of metropolitan residents and 48% of nonmetropolitan residents were fully vaccinated.77 Continued rent, eviction, and foreclosure moratoriums and extended unemployment benefits may reduce financial and housing insecurity.79 Economic reparations, investments in community-based safety, and funding for social programs may address social determinants of health that have been associated with mortality disparities.82 Investments in health systems that serve rural areas, including Indigenous health systems, may also help reduce high rural death rates observed for most racial and ethnic groups.55 Finally, initiatives to diversify the physician workforce and reduce medical racism may contribute to a more equitable pandemic response.84Beyond vaccination, additional policy changes could further support racial health equity during the pandemic. Paid sick time and medical leave may ensure that essential workers are able to isolate and recover if they develop COVID-19.22 Efforts to geographically standardize COVID-19 mortality estimates early in the pandemic were criticized for decreasing the estimated magnitude of racial and ethnic disparities by controlling for structural racism that made it more likely for Hispanic and non-Hispanic Black individuals to live in urban areas, where COVID-19 death rates were higher.85 As our study found, however, death rates in rural areas exceeded those in urban areas as early as the second wave of the pandemic. This suggests that the association of geographic standardization with differences in mortality estimates changed as the pandemic progressed. While geographic standardization remains controversial as a descriptive tool, we believe it is a useful instrument to understand mechanisms associated with disparities in mortality and their changes over time. In this study, such an analysis suggested that the association of structural racism with COVID-19 mortality persists even when changes in the geographic spread of the pandemic may disguise some of its associated outcomes in national mortality statistics.This study has several limitations. First, a key limitation of our decomposition analysis was that it was not possible to fully separate racial and ethnic disparities in mortality from geography because residential segregation and other forms of structural racism are associated with where members of racial and ethnic groups live.86 Our data were accessed 11 months after the last death in our study, suggesting that these data may be nearly complete. Third, population estimates for 2022 were not available; some geographic units may have experienced population changes, and we could not account for these changes. Fourth, we used an imputation procedure to replace suppressed data; however, imputation was infrequent. Fifth, owing to constraints related to data suppression, we used 3 broader age categories rather than 10-year categories for age-standardization and did not standardize by sex. Sixth, classification of race and ethnicity on death certificates is less accurate for American Indian and Alaska Native populations.46 Thus, we may have underestimated mortality for these adults. Seventh, we did not examine death rates among non-Hispanic adults with multiracial backgrounds because prior research has identified significant heterogeneity in this population.88 Future research should use other data sources to explore important differences that may exist within this population. Eighth, our estimates of COVID-19 mortality may differ from estimates of excess mortality, which include uncounted COVID-19 deaths and deaths indirectly related to the pandemic.9 Nonmetropolitan areas and some racial and ethnic groups, such as non-Hispanic Black populations, may have a greater number of uncounted deaths.89 Understanding how undercounting of COVID-19 deaths varied throughout the pandemic is an important area for future research.Second, COVID-19 mortality data for January and February 2022 were provisional, and such mortality data are 75% complete 8 weeks after deaths occurred.In this cross-sectional study, we decomposed national decreases in racial and ethnic disparities in age-standardized COVID-19 mortality for Hispanic and non-Hispanic Black adults compared with non-Hispanic White adults over the first 2 years of the pandemic. We found that most of the decrease in disparities for non-Hispanic Black adults and all of the decrease in disparities for Hispanic adults was explained by increases in geographically standardized mortality among non-Hispanic White adults and movement of the pandemic to nonmetropolitan areas rather than reductions in mortality. While advancements toward racial and ethnic health equity have occurred, our study suggests that this work is not finished. Efforts to promote equitable booster distribution, invest in rural health systems, and address structural racism are still urgently needed.


Foot ulcers are a frequent and costly problem in people with diabetes mellitus and can lead to amputations. Prevention of these ulcers is therefore of paramount importance. Claw/hammer toe deformities are commonly seen in people with diabetes. These deformities increase the risk of ulcer development specifically at the (tip of) the toe. Percutaneous needle tenotomy of the tendon of the m. flexor digitorum longus (tendon tenotomy) can be used to reduce the severity of claw/hammer toe deformity with the goal to prevent ulcer recurrence. The main objective of this randomized controlled trial is to assess the efficacy of flexor tenotomy to prevent recurrence of toe ulcers in people with diabetes and a history of toe (pre-)ulcers. Additionally, we aim to assess interphalangeal joints (IPJ) and metatarsophalangeal joint (MTPJ) angles in a weight-bearing and non-weight-bearing position, barefoot plantar pressure during walking, cost-effectiveness and quality of life before and after the intervention and compare intervention and control study groups. Sixty-six subjects with diabetes and claw/hammer toe deformity and a recent history of (pre-)ulceration on the tip of the toe will be included and randomized between flexor tenotomy of claw/hammer toes (intervention) versus standard of care including orthosis and shoe offloading (controls) in a mono-center randomized controlled trial.NCT05228340. The forIn people with diabetic peripheral polyneuropathy, deformities of the feet are more prevalent than in people without diabetes . Common A surgical option for treating claw/hammer toe deformity is flexor tenotomy . In thisThe beneficial effects of flexor tenotomy in people with diabetes and claw/hammer toe deformity have been investigated in retrospective and prospective case series . CurrentThis randomized controlled trial aims to assess the efficacy of flexor tenotomy to prevent recurrent diabetic foot ulcers, the biomechanical and musculoskeletal changes due to the procedure, the changes in quality of life and the cost-effectiveness of the procedure.22.1The primary objective is to assess the efficacy of flexor tenotomy (intervention) versus standard of care  on the incidence of ulcer recurrence on the toes indicated for flexor tenotomy, on the adjacent toes and on the metatarsal heads. Secondary objectives are musculoskeletal changes expressed in MTPJ, PIPJ and DIPJ angles, biomechanical changes expressed in barefoot plantar pressure during walking, quality of life, the cost-effectiveness of flexor tenotomy and adverse events of the surgery.2.2This study concerns a randomized controlled trial (RCT) with a 24-month follow-up period at the out-patient clinic . Sixty-s2.3•A minimum age of 18 years•Sufficient understanding of Dutch/English language•Capable of providing informed consent•Loss of protective sensation as a result of peripheral polyneuropathy•Diabetes mellitus type 1 or 2•A minimum of 1 claw/hammer toe on either foot•A documented history of diabetic (pre-)ulcers underneath the tip of the toe in the past 5 years. Pre-ulcers include abnormalities of or damage to the nail, callus formation and hematomas.In order to be eligible to participate in this study, a participant must meet all of the following criteria.•Open ulcer(s) on the toes•Previous participation in the study•Pregnant women•Concomitant participation in a study in which the participant is exposed to X-rays (due to the use of weight-bearing CT in this study)•Critical ischemia A potential participant who meets any of the following criteria will be excluded from participation in this study.2.4Percutaneous flexor tenotomy is a minimally invasive procedure used to treat claw/hammer toe deformity ,18,22 ThBoth the intervention group and the control group receive standard care. This includes proper wound sanitation, removing of excess callus and debridement of the ulcers by a podiatrist, evaluation of barefoot pressure measurements and in-shoe measurements of the current footwear. If necessary based on high in-shoe pressure, current footwear is adapted or new footwear is fitted by an orthopedic shoemaker and orthoses or felt are used for further off-loading.2.5All data and outcomes will be registered in a Castor EDC database . Using t2.5.1The main study outcome is ulcer recurrence on the treated toe within 2 years of follow-up. Transfer ulcers on the adjacent toes, or metatarsal heads within 2 years of follow-up will also be recorded. The formation of a claw or hammer toe in the adjacent toes will be recorded as a complication. Ulcers are defined according to the IWGDF-guideline . Partici2.5.2DIPJ, PIPJ and MTPJ angles will be measured before, and 6 and 12 months after flexor tenotomy during weight-bearing and non-weight conditions using weight-bearing CT and non-weight-bearing CT. Weight-bearing and non-weight-bearing images of both forefeet will be acquired on the Planmed Verity® CT system. This system uses cone-beam CT technology to provide 3D-images of the extremities. Subjects stand on one leg in the small bore of the weight-bearing CT scanner, with a field-of-view of approximately 13 × 16 cm. All images will be acquired subsequent to out-patient scheduled visits, therefore no additional hospital visits will be needed. In-house developed software is utilized to segment bones using region growing and manual editing where necessary ,28. The 2.5.3Dynamic barefoot pressure measurements are performed using an EMED-X pressure platform . A two-step protocol with four trials per foot and a self-selected walking speed will be used. This is a reliable method to acquire pressure data without unnecessary barefoot steps . The pre2.5.4Quality of life is measured using the EQ-5D-5L and SF-36 questionnaires at baseline, 6 months, 12 months and 24 months. The EQ-5D-5L is a validated and extensively used tool to measure Quality of Life . This qu2.5.5•Cost of the flexor tenotomy•Other costs related to prevention of recurrent ulcers prescribed at the diabetic foot rehabilitation out-patient clinic. These include: orthopedic footwear and adaptations to the footwear, felted foam, casts and orthoses•Costs of treatment of recurrent ulcers or newly formed ulcers: wound dressing, antibiotics and treatment by podiatrist at the diabetic feet rehabilitation out-patient clinic, costs of hospitalization, interventions related to ulceration (amputation) and homecare hired due to foot ulceration•Costs related to additional visits to the podiatrist, general practitioner, emergency department or the diabetic feet rehabilitation out-patient clinic due to diabetic foot ulcersWith the economic evaluation the total costs related to diabetic foot disease for all participants will be determined. These costs will be related to the effects of the treatments in the groups. The outcomes of the EQ-5D-5L and SF-36 will be used in the economic evaluation to determine cost-utility and the ulcer recurrence is used to determine cost-effectiveness. All relevant costs related to treatment will be recorded. These include.The costs will be valued using the guidelines published in the updated handbook for economic evaluation in the Netherlands . The cos2.6For our primary outcome of ulcer recurrence, we estimate 8% recurrence in 12 months in the intervention group. This is a slightly conservative estimate, given the 11% ulcer recurrence in 53 subjects during 93 weeks of follow-up following needle tenotomy as reported by Hedegaard Andersen and colleagues . In the clincalc.com .M.A.M. is supported by a personal AMC-PhD scholarship 2019. M.N. is supported by a personal The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Tibial pilon fractures are difficult to treat due to articular comminution and soft-tissue injuries caused by high-energy trauma. Open reduction and internal fixation is a commonly used method of treatment. However, it has a high risk of infection and soft-tissue complications due to the extensive detachment of soft tissue. We report on a case with a tibial pilon fracture and soft-tissue necrosis that we treated using limited internal fixation combined with a circular external fixator (LIFCEF) and reverse sural artery flap (RSAF) as part of an orthoplastic approach within the orthopedic surgery department alone, which obtained good results. A 51-year-old man was injured in a motorcycle accident and transported to a nearby hospital. X-rays at the time of injury showed tibial pilon fractures . Soft-tissue necrosis with blisters on the medial side of the lower leg (AO soft-tissue classification: IC3-MT1-NV1) was observed. In addition, the patient was referred to our hospital on day 10 of the injury. LIFCEF was chosen for treating the fracture because plate fixation was accompanied by the risk of plate exposure, soft-tissue complications, and an increased skin defect area, and RSAF was chosen to reconstruct the soft tissue defect. Four years after the surgery, the American Orthopedic Foot and Ankle Score was 92 points. X-ray alignment evaluation showed mLDTA 93° and aADTA 91°. Stage 2 arthrosis was present according to the Takakura ankle osteoarthritis classification, but the patient was able to walk without pain. Tibial pilon fractures are difficult to treat due to articular comminution and soft-tissue injuries caused by high-energy trauma. The timing and choice of treatment are crucial concerning the soft tissue. Tibial pilon fractures are relatively common, accounting for 5–7% of tibia fractures. These fractures are difficult to treat due to articular comminution and soft-tissue injuries caused by high-energy trauma . In addiWe report on a case with a tibial pilon fracture (AO Foundation/Orthopedic Trauma Association [AO/OTA] classification: AO/OTA 43c3.3) and soft-tissue necrosis (AO soft-tissue classification: IC3-MT1-NV1) that we treated using limited internal fixation combined with a circular external fixator (LIFCEF) and reverse sural artery flap (RSAF) as part of an orthoplastic approach within the orthopedic surgery department alone, which obtained good results.A 51-year-old man was injured in a motorcycle accident and transported to a nearby hospital. X-rays at the time of injury showed tibial pilon fractures  was observed , and theSurgery was performed on day 12 of the injury. First, we performed debridement of the necrotic soft tissue on the medial side. The area of soft tissue defect was 5 cm × 6 cm. We removed the medial bone fragment from the debrided area and directly visualized the joint surface , which wDuring the one-year follow-up after the surgery, the patient was able to walk without an assistive device and had a range of motion of 15° for dorsiflexion and 30° for plantar flexion at the ankle joint. X-ray evaluation showed stage 2 arthrosis according to the Takakura ankle osteoarthritis classification  [5]. FouTibial pilon fractures are difficult to treat due to comminuted fractures and soft-tissue injuries . The casTreatment for tibial pilon fracture is based on the four principles proposed by Ruedi and Allgower, including reconstruction of the fibular length, reconstruction of the joint surface, autologous bone grafting for missing articular surface bone, and buttress plate fixation for the medial side of the fracture. These principles have been reported to yield good results . HoweverThe two-staged approach involves waiting for the improvement of the soft-tissue condition, such as the appearance of wrinkles or the epithelialization of blisters, before performing ORIF. However, the soft tissue condition, the waiting period, and the choice of fixation device are left to the surgeon's discretion. In this case, LIFCEF was chosen for the treatment considering the soft-tissue injury and the planned reconstruction of the soft tissue using RSAF. Soft-tissue defect around the ankle joint is challenging for soft-tissue reconstruction due to the limited amount of skin and subcutaneous tissue and the tendency for bones and tendons to be exposed . Skin grThere have been comparative studies on the use of internal fixation versus external fixation for the definitive fixation of tibial pilon fractures with some reports showing no difference in outcomes between the two methods , and othTibial pilon fractures are difficult to treat due to articular comminution and soft-tissue injuries caused by high-energy trauma. The timing and choice of treatment are crucial concerning the soft tissue. In this case, we treated a closed tibial pilon fracture with soft-tissue necrosis on the medial side with an orthoplastic approach using an RSAF for soft-tissue reconstruction and LIFCEF that obtained a good result.