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This article presents a low-power (LP) area-efficient implantable neural recording system that supports high-density neural implant (HDNI) applications. The system uses a time-division multiple access method to record from 16-neural electrodes simultaneously. A least mean squares (LMSs) algorithm is used to cancel the slowly varying electrode offsets from all channels simultaneously by using a single-tap digital adaptive filter (AF). The presented technique is fabricated in 65-nm CMOS technology and achieves a per-channel area of 0.00248 mm²; 68% of which is digital circuitry (and is thus scalable with technology). The overall system consumes 3.38 μW per channel while achieving 2.6 μV ${_{{rms}}}$ of input referred noise (IRN) in 10 kHz of bandwidth. The proposed system has a noise efficiency factor (NEF) of 1.83 and is fully integrated on-chip.

Purpose Colorectal cancer is a high incidence tumor, immunotherapy has become a hot topic of research in recent years, at the same time, the dysregulation of intestinal microbiota is also gaining attention because it can lead to changes in body immunity. So, we want to explore the relationship between gut microbiota and colorectal cancer. Methods We performed 16S rRNA high-throughput sequencing of tumors and paraneoplastic tissues from 30 patients, followed by at least 5 years of follow-up. Microbiome analysis, survival analysis, and then immunohistochemistry and its correlation with microbiota were performed in 19 of these patients. Results OTU13530 and OTU17086, both representing g_Sediminibacterium, showed significant differences in normalized abundance in tumor and paraneoplastic tissues (FDR 2FC > 1). Both of them correlated with T-stage (p = 0.016, p = 0.024) and Her-2 expression (p = 0.034, p = 0.001). The former correlated with HIF expression (p = 0.017), and the latter with EGFR expression (p = 0.003). OTU3504, representing o_Myxococcales, had a correlation with patient survival (p = 0.015, HR = 28.5(1.9–425.0)), its abundance correlated with tumor neural invasion (p = 0.005) and vascular invasion (p = 0.005). Conclusion There is no statistical difference in the diversity and homogeneity of the microbiota between tumor and paraneoplastic tissues. But the abundance of some specific microbiota differed significantly between tumor and paraneoplastic tissues, and these microbiota correlated with patient survival, Her-2, HIF and other proteins expression, T-stage, neurovascular invasion and other clinical traits.

Multichannel electrophysiological sensors and stimulators—particularly those used to study the nervous system—are usually based on monolithic microelectrode arrays. However, the architecture of such arrays limits flexibility in electrode placement and scaling to a large number of nodes, especially across non-contiguous locations. Here we report wirelessly networked and powered electronic microchips that can autonomously perform neural sensing and electrical microstimulation. The microchips, which we term neurograins, have an ~1 GHz electromagnetic transcutaneous link to an external telecom hub, providing bidirectional communication and control at the individual device level. To illustrate the potential of the approach, we show that 48 neurograins can be individually addressed on a rat cortical surface and used for the acute recording of neural activity. Theoretical calculations and experimental measurements show that the link configuration could potentially be scaled to 770 neurograins using a customized time-division multiple access protocol. Wirelessly powered microchips, which have an ~1 GHz electromagnetic transcutaneous link to an external telecom hub, can be used for multichannel in vivo neural sensing, stimulation and data acquisition.

ImportanceMyopia is a global concern, but effective prevention measures remain limited. Premyopia is a refractive state in which children are at higher risk of myopia, meriting preventive interventions.ObjectiveTo assess the efficacy and safety of a repeated low-level red-light (RLRL) intervention in preventing incident myopia among children with premyopia.Design, Setting, and ParticipantsThis was a 12-month, parallel-group, school-based randomized clinical trial conducted in 10 primary schools in Shanghai, China. A total of 139 children with premyopia (defined as cycloplegic spherical equivalence refraction [SER] of −0.50 to 0.50 diopter [D] in the more myopic eye and having at least 1 parent with SER ≤−3.00 D) in grades 1 to 4 were enrolled between April 1, 2021, and June 30, 2021; the trial was completed August 31, 2022.InterventionsChildren were randomly assigned to 2 groups after grade stratification. Children in the intervention group received RLRL therapy twice per day, 5 days per week, with each session lasting 3 minutes. The intervention was conducted at school during semesters and at home during winter and summer vacations. Children in the control group continued usual activities.Main Outcomes and MeasuresThe primary outcome was the 12-month incidence rate of myopia (defined as SER ≤−0.50 D). Secondary outcomes included the changes in SER, axial length, vision function, and optical coherence tomography scan results over 12 months. Data from the more myopic eyes were analyzed. Outcomes were analyzed by means of an intention-to-treat method and per-protocol method. The intention-to-treat analysis included participants in both groups at baseline, while the per-protocol analysis included participants in the control group and those in the intervention group who were able to continue the intervention without interruption by the COVID-19 pandemic.ResultsThere were 139 children (mean [SD] age, 8.3 [1.1] years; 71 boys [51.1%]) in the intervention group and 139 children (mean [SD] age, 8.3 [1.1] years; 68 boys [48.9%]) in the control group. The 12-month incidence of myopia was 40.8% (49 of 120) in the intervention group and 61.3% (68 of 111) in the control group, a relative 33.4% reduction in incidence. For children in the intervention group who did not have treatment interruption secondary to the COVID-19 pandemic, the incidence was 28.1% (9 of 32), a relative 54.1% reduction in incidence. The RLRL intervention significantly reduced the myopic shifts in terms of axial length and SER compared with the control group (mean [SD] axial length, 0.30 [0.27] mm vs 0.47 [0.25] mm; difference, 0.17 mm [95% CI, 0.11-0.23 mm]; mean [SD] SER, –0.35 [0.54] D vs –0.76 [0.60] D; difference, –0.41 D [95% CI, –0.56 to –0.26 D]). No visual acuity or structural damage was noted on optical coherence tomography scans in the intervention group.Conclusions and RelevanceIn this randomized clinical trial, RLRL therapy was a novel and effective intervention for myopia prevention, with good user acceptability and up to 54.1% reduction in incident myopia within 12 months among children with premyopia.Trial RegistrationClinicalTrials.gov Identifier: NCT04825769

This article presents a high-dynamic-range (DR) voltage-controlled oscillator (VCO)-based front end for sensor readout applications. Unlike conventional VCO-based quantizers, which suffer from large voltage-to-frequency non-linearities, the proposed design leverages differential pulse-code modulation (DPCM) from compression theory to substantially reduce the amplitude of the signal incident to the VCO quantizer, thereby achieving an ultra-low total harmonic distortion (THD) of −112 dB. In addition, background digital gain calibration is employed to overcome gain deviation of the VCO, thus ensuring a robust design. Together with dynamic element matching (DEM), the techniques enable a high DR using only the first-order noise shaping inherent in VCO-based quantizers and a moderate $32\times $ oversampling ratio. Fabricated in 65 nm, the sensor front end consumes 3.2- $\mu \text{W}$ power and achieves an SNDR of 89 dB and a DR of 94 dB in 500 Hz of bandwidth. Together with a 1.18- $\mu \text{V}~_{\text {rms}}$ integrated input-referred noise, it achieves a noise efficiency factor (NEF) of 4 and a Schreier FoM of 171 dB.

This letter presents a voltage-controlled oscillator (VCO)-based analog-to-digital converter (ADC) for audio applications using differential pulse code modulation (DPCM) to mitigate VCO voltage-to-frequency nonlinearity. To overcome VCO gain variation, a split-ADC architecture is employed where two sub-ADCs share one calibration unit, thereby enabling a quasideterministic background gain calibration with small delay and fast convergence speed. In addition, a hybrid dynamic element matching (DEM) is employed, which offers a lower delay and a smaller in-band mismatch noise compared to the segmented-tree DEM. Fabricated in 65 nm, the ADC achieves 94.2-dB SNDR, 97.3-dB SNR, and 100.3-dB DR in 20-kHz bandwidth while dissipating 142.6-μW power, yielding a DR-based FoM of 181.8 dB.

To evaluate the relationship between ocular magnification correction and macular choroidal thickness (ChT) measurements in children, and to demonstrate when ocular magnification correction is necessary. Chinese children aged 6–9 years with various refractive statuses were included. Swept-source optical coherence tomography was used to measure macular ChT. A self-designed program was adopted to simulate ChT changes in each sector of the ETDRS grid in the macula under various simulated axial lengths (ALs). ChT measurements were not affected for all simulated ALs in over 95% of the individuals in the central fovea. In the inferior, superior, and temporal parafoveal sectors, the extent of AL that may include 95% of the individuals narrowed from approximately 22.0 mm to 27.2 mm. In the nasal parafoveal sector and inferior, superior, and temporal perifoveal sectors, the extent of AL that may include 95% of the individuals became even narrower, from approximately 22.8 mm to 26.0 mm. The narrowest extent was observed in the perifoveal nasal sector, ranging from 23.3 mm to 25.5 mm. The effect of ocular magnification was more significant in hyperopes than in myopes in the inferior parafoveal sector and temporal, superior, and nasal perifoveal sectors. During macular ChT measurements, ocular magnification correction is not necessary in the central fovea. However, ocular magnification should be corrected normally in the nasal perifoveal region and in individuals with ALs shorter than 22.8 mm or longer than 26.0 mm in the remaining macular regions.

Objective: With the continuing increase of the aged population, neurosurgeons face increasing numbers of chronic subdural haematoma (CSDH) patients using antithrombotic (AT) drugs, i.e., anticoagul...

Background Lymphangioleiomyomatosis (LAM) is a rare disease that almost exclusively affects women of reproductive age. Patients are warned of the increased risks if they become pregnant. However, information on pregnancy in patients after the diagnosis of LAM is limited. Methods Patients were collected from the LAM registry study at Peking Union Medical College Hospital, Beijing, China. Patients with a history of pregnancy after the diagnosis of LAM were included. Medical records were reviewed, and baseline information and data during and after pregnancy were collected in May 2018. Results Thirty patients with a total of 34 pregnancies after the diagnosis of LAM were included. Livebirth, spontaneous abortion and induced abortion occurred in 10, 6 and 18 pregnancies, respectively. Sirolimus treatment was common (17/34). A total of 6/10, 5/6, and 6/18 patients with livebirths, spontaneous abortions, and induced abortions respectively, had a history of sirolimus treatment. Ten pregnancies (29.4%) had LAM-associated complications during pregnancy, including the exacerbation of dyspnea in 7 patients, pneumothorax in 3 patients (2 resulting in induced abortion and 1 successful parturition), and spontaneous bleeding of renal angiomyolipomas in 2 patients (both having successful parturition). No chylothorax was found during pregnancy. There were six pregnancies in six patients (17.6%) who had a history of livebirth after sirolimus treatment for LAM (all having successful parturition and healthy infants); two of these patients reported exacerbated dyspnea after parturition compared with before pregnancy. Conclusions Patients with LAM, especially those taking sirolimus before pregnancy, were at a higher risk of spontaneous abortion. Complications such as pneumothorax, bleeding of renal angiomyolipoma, and exacerbated dyspnea during pregnancy were common. In patients without spontaneous abortion, sirolimus discontinuation before or during pregnancy did not lead to increased adverse neonatal outcomes.

Motion and stimulation artifacts encountered in wearable sensors present difficult dynamic range (DR) and linearity challenges: AFEs need to be able to resolve $\mu \mathrm{V} -$ level signals in the presence of artifacts up to 100s of mV in amplitude while maintaining linearity without saturation, such that the signal of interest can be readily recovered during post-processing. Since it is not possible to build an amplifier with appreciable gain and linearity for $ \gt 100$ mV inputs under $ \lt 1\mathrm{V}$ SoC-compatible supply, most high-DR AFEs instead incorporate an LNA into $\mathrm{a}\Delta \sum -$ based ADC-direct architecture [1] –[3]. However, as many emerging wearable devices desire single-chip integration in scaled CMOS for size and digital performance considerations, conventional $\Delta \sum$ Ms, which rely on voltage-domain building blocks, suffer from reduced intrinsic gain and headroom. Instead, time-domain quantization through VCO-based AFEs benefits from scaled CMOS and offers intrinsic $1 ^{st} -$ order noise shaping. However, the non-linear V-F conversion of conventional VCO-based AFEs makes achieving a large and linear DR difficult [1]. To address this, [3] adopts a differential pulse code modulation (DPCM) technique that enables the VCO to process only a small prediction error, V ERR , by subtracting from $V_{IN}\mathrm{a}$ digital predictor value fed through a DAC (Fig. 28.1.1 top). Maximal linearity would be achieved if the predictor was perfect, resulting in $V_{ERR},\approx 0$; however, this requires a highperformance and power-expensive DAC. Therefore, [3] truncates the predictor’s output, reducing the DAC requirements to 9b, but adding truncation error, E T . If the gain of paths P 1 and P 2 are made equal, which is enforced in [3] via a gain error calibration (GEC) circuit, E T will ideally cancel at the output. However, it is not possible to achieve perfect E T cancellation, and any residual E T will degrade SQNR, limiting the extent to which truncation can be used to relax the DAC’s resolution. In addition, GEC itself introduces power overhead.

Next-generation wearable devices will enable clinical-grade, continuous ExG (ECG, EEG, EMG, etc.) biopotential monitoring, providing medical professionals with valuable longitudinal data outside of hospital settings. These devices must be ultra-low power $(\lt 10 \mu W)$ to enable long battery life while accurately digitizing sub-kHz, $\mu V-$level ExG signals in the presence of large motion and/or stimulation artifacts $(\gt 100$ mV) with high input-impedance $(Z_{in}\gt 10M\Omega)$ to avoid signal attenuation. Achieving such performance with conventional PGA + ADC architectures is challenging due to the conflicting low-power and $\gt 90$ dB dynamic-range (DR) requirements [1]. To address this, several direct digitization analog front-ends (AFEs) have been reported [2]–[4]. While these offer wide DR, they typically have low input-impedance $(\lt 5 M\Omega)$ and/or low power-efficiency (FoM $\le 172$ dB). This paper presents a scalable $2^{nd}-$order voltage-controlled oscillator (VCO)-only $\Delta \sum$ ADC that achieves 92.3dB SNDR in a 1kHz bandwidth using a mismatch tolerant, multiphase gated-inverted ring-oscillator (GIRO) quantizer with dynamic power-scaling. The ADC uses an impedance-booster to maintain $\gt 50 M\Omega$ input-impedance over the entire bandwidth while consuming $4.25 \mu W$ during nominal operation and $5.8 \mu W$ in the presence of artifacts resulting in an FoM of 174.7dB.

Background The differential diagnosis of diffuse cystic lung disease (DCLD) is a clinical challenge. We wish to analyze the distribution of the etiology of DCLD based on data from a single lymphangioleiomyomatosis (LAM) clinic. Methods All DCLD patients at the LAM Clinic of Peking Union Medical College Hospital between January 2006 and December 2019 were analyzed. Information on the demographic, clinical, radiological, and pathological features was collected. Results A total of 1010 patients with DCLD on CT scan were evaluated. A sum of 711(70.4%) patients were diagnosed with definite or probable LAM. Other diagnoses included Birt–Hogg–Dubé syndrome (46), Sjogren's syndrome (38), pulmonary Langerhans cell histiocytosis (14), lung tumors (3), Castleman disease (2), antineutrophil cytoplasmic antibody-associated vasculitis (2), systemic lupus erythematosus (1), Marfan syndrome (1), amyloidosis (1), congenital cystic adenomatoid malformation of the lung (1), and pleuroparenchymal fibroelastosis (1). In the 38 patients diagnosed with Sjogren's syndrome, 2 were diagnosed with light-chain deposition disease, 2 were diagnosed with amyloidosis and 1 was diagnosed with lymphocytic interstitial pneumonia. One hundred and eighty-nine patients (18.7%) were undiagnosed. Lung biopsy results were available in 27 patients in the undiagnosed DCLD group but did not provide a diagnosis. Conclusion Approximately 70% of DCLD patients in our LAM clinic had LAM. The common differential diagnoses included Birt–Hogg–Dubé syndrome, Sjogren’s syndrome, and pulmonary Langerhans cell histiocytosis. Detailed clinical information and laboratory, genetic, and pathological investigations provide correct diagnoses in most patients with DCLD.

Implantable active electronic microchips are being developed as multinode in-body sensors and actuators. There is a need to develop high throughput microfabrication techniques applicable to complementary metal&ndash, oxide&ndash, semiconductor (CMOS)-based silicon electronics in order to process bare dies from a foundry to physiologically compatible implant ensembles. Post-processing of a miniature CMOS chip by usual methods is challenging as the typically sub-mm size small dies are hard to handle and not readily compatible with the standard microfabrication, e.g., photolithography. Here, we present a soft material-based, low chemical and mechanical stress, scalable microchip post-CMOS processing method that enables photolithography and electron-beam deposition on hundreds of micrometers scale dies. The technique builds on the use of a polydimethylsiloxane (PDMS) carrier substrate, in which the CMOS chips were embedded and precisely aligned, thereby enabling batch post-processing without complication from additional micromachining or chip treatments. We have demonstrated our technique with 650 &mu, m &times, 650 &mu, m and 280 &mu, 280 &mu, m chips, designed for electrophysiological neural recording and microstimulation implants by monolithic integration of patterned gold and PEDOT:PSS electrodes on the chips and assessed their electrical properties. The functionality of the post-processed chips was verified in saline, and ex vivo experiments using wireless power and data link, to demonstrate the recording and stimulation performance of the microscale electrode interfaces.

Multichannel electrophysiological sensors and stimulators, especially those used for studying the nervous system, are most commonly based on monolithic microelectrode arrays. Such architecture limits the spatial flexibility of individual electrode placement, posing constraints for scaling to a large number of nodes, particularly across non-contiguous locations. We describe the design and fabrication of sub-millimeter size electronic microchips (“Neurograins”) which autonomously perform neural sensing or electrical microstimulation, with emphasis on their wireless networking and powering. An ∼1 GHz electromagnetic transcutaneous link to an external telecom hub enables bidirectional communication and control at the individual neurograin level. The link operates on a customized time division multiple access (TDMA) protocol designed to scale up to 1000 neurograins. The system is demonstrated as a cortical implant in a small animal (rat) model with anatomical limitations restricting the implant to 48 neurograins. We suggest that the neurograin approach can be generalized to overcome many scalability issues for wireless sensors and actuators as implantable microsystems.

This paper presents a VCO-based sensor front-end utilizing differential pulse-code modulation (DPCM) to substantially reduce the amplitude of the input signal to the VCO quantizer so that high linearity is achieved. Together with a background digital gain calibration and DEM, the techniques enable a high dynamic range (DR) using only 1st order noise-shaping and 32× oversampling. Fabricated in 65nm, the AFE consumes 3.2μW and achieves 1.18μV RMS input-referred noise in 500Hz BW. It also achieves an SNDR/DR/THD of 88/94/-105dB respectively with a NEF of 4 and Schreier FoM of 170dB.

This letter presents a miniaturized neural recording analog front-end (AFE) suitable for distributed sub-mm neural recording implants. Including reference generators, this AFE occupies an area of only 0.01 mm2, thanks to a mostly digital architecture with more than half of area being scalable digital logic. Implemented in 65-nm CMOS, the AFE is measured to consume 3.2 $ {\mu }\text{W}$ of power from 0.6-V supply, and achieves an input-referred noise of 2.2 $ {\mu {\mathrm{ V}}}_{\mathrm{rms}}$ over 500 Hz of bandwidth. The AFE is validated by integrating it into a neural sensing SoC with wireless power and data telemetry. In vitro experiments demonstrate reliable recording of the AFE in a fully wireless environment.

Hexarelin, a synthetic growth hormone-releasing peptide, has been proven to possess cardioprotective actions through its binding to the growth hormone secretagogue receptor (GHSR) 1a and the non-GHSR receptor CD36. However, its effect on myocardial ischemia/reperfusion (I/R) injury has not been fully clarified in vivo. We aimed to determine whether hexarelin treatment could protect cardiomyocytes from I/R injury and to examine the underlying mechanisms. In vivo hearts of male SD rats underwent 30 minutes of ischemia by left coronary artery ligation followed by reperfusion. The rats were then treated subcutaneously twice daily with hexarelin [100 μg/kg·day], ghrelin [400 μg/ kg·day], or saline for 7 days. Echocardiography, malondialdehyde detection, and histochemical staining were performed after treatment. In addition, Western blot was used to examine the expression levels of IL-1β, IL-1Ra, and IL-1RI. Our study showed that hexarelin treatment improved cardiac systolic function, decreased malondialdehyde production, and increased the number of surviving cardiomyocytes. The beneficial effects of hexarelin treatment were slightly superior to those of equimolar ghrelin treatment. We meanwhile confirmed that hexarelin induced down-regulation of IL-1β expression and up-regulation of IL-1Ra expression in I/R myocardium, which could be neutralized by the GHSR antagonist [D-Lys3]-growth hormone releasing peptide-6 ([D-Lys3]-GHRP-6). These findings suggest that hexarelin protects in vivo cardiomyocytes from I/R injury partly by modification of the IL-1 signaling pathway through the activation of cardiac GHSR1a receptors.

1. Anthocyanins are a subgroup of flavonoids responsible for the blue, purple and red color of many fruits, flowers and leaves. Consumption of foods rich in anthocyanins is associated with a reduced risk of cardiovascular disease and cancer. Most food intervention studies employ once or twice per day dose schedules. 2. The current study demonstrated that plasma concentrations of cyanidin-3-galactoside and cyanidin-3-xyloside, the two major components of saskatoon berries, were significantly increased following three consecutive saskatoon berry supplements 4 hours apart. This accumulation is due to the residual concentrations of anthocyanins at the time of second and third supplements. 3. Accumulation was especially pronounced for peonidin-3-glucoside and peonidin-3-galactoside, the methylated metabolites of cyanidin-3-glucoside and cyanidin-3-galactoside, respectively. Little or no accumulation was observed for cyanidin-3-arabinoside and cyanidin-3-glucoside, two other components of saskatoon berries, possibly due to their short half-lives. 4. Thus, taking anthocyanin supplements with every meal would provide higher plasma concentrations for some anthocyanins and their metabolites than the once or twice-a-day dose regimens.