Narrative cave art in Indonesia by 51,200 years ago.

Previous dating research indicated that the Indonesian island of Sulawesi is host to some of the oldest known rock art1-3. That work was based on solution uranium-series (U-series) analysis of calcite deposits overlying rock art in the limestone caves of Maros-Pangkep, South Sulawesi1-3. Here we use a novel application of this approach-laser-ablation U-series imaging-to re-date some of the earliest cave art in this karst area and to determine the age of stylistically similar motifs at other Maros-Pangkep sites. This method provides enhanced spatial accuracy, resulting in older minimum ages for previously dated art. We show that a hunting scene from Leang Bulu' Sipong 4, which was originally dated using the previous approach to a minimum of 43,900 thousand years ago (ka)3, has a minimum age of 50.2 ± 2.2 ka, and so is at least 4,040 years older than thought. Using the imaging approach, we also assign a minimum age of 53.5 ± 2.3 ka to a newly described cave art scene at Leang Karampuang. Painted at least 51,200 years ago, this narrative composition, which depicts human-like figures interacting with a pig, is now the earliest known surviving example of representational art, and visual storytelling, in the world3. Our findings show that figurative portrayals of anthropomorphic figures and animals have a deeper origin in the history of modern human (Homo sapiens) image-making than recognized to date, as does their representation in composed scenes.

Galaxy growth in a massive halo in the first billion years of cosmic history.

According to the current understanding of cosmic structure formation, the precursors of the most massive structures in the Universe began to form shortly after the Big Bang, in regions corresponding to the largest fluctuations in the cosmic density field. Observing these structures during their period of active growth and assembly-the first few hundred million years of the Universe-is challenging because it requires surveys that are sensitive enough to detect the distant galaxies that act as signposts for these structures and wide enough to capture the rarest objects. As a result, very few such objects have been detected so far. Here we report observations of a far-infrared-luminous object at redshift 6.900 (less than 800 million years after the Big Bang) that was discovered in a wide-field survey. High-resolution imaging shows it to be a pair of extremely massive star-forming galaxies. The larger is forming stars at a rate of 2,900 solar masses per year, contains 270 billion solar masses of gas and 2.5 billion solar masses of dust, and is more massive than any other known object at a redshift of more than 6. Its rapid star formation is probably triggered by its companion galaxy at a projected separation of 8 kiloparsecs. This merging companion hosts 35 billion solar masses of stars and has a star-formation rate of 540 solar masses per year, but has an order of magnitude less gas and dust than its neighbour and physical conditions akin to those observed in lower-metallicity galaxies in the nearby Universe. These objects suggest the presence of a dark-matter halo with a mass of more than 100 billion solar masses, making it among the rarest dark-matter haloes that should exist in the Universe at this epoch.

[Randomized controlled study on the application effect of a new type of intravenous radiofrequency closed therapy system made in China and an imported system].

Objective: To compare the application effect of domestic and imported intravenous radiofrequency closure system in the treatment of primary varicose veins of lower extremities. Methods: This single-center prospective, non-inferiority randomized controlled trial was performed in the Department of Vascular Surgery, the Fourth Affiliated Hospital, Zhejiang University School of Medicine from January 2021 to January 2022. Patients with primary varicose veins of lower extremities who met the ataxation criteria were randomly assigned to the experimental group(domestic novel venous radiofrequency closure system) or the control group(imported venous radiofrequency closure system) in a ratio of 1∶1. The two groups of subjects were compared in terms of target vein closure rate, technical success rate, system operation performance, incidence of adverse events and incidence of serious adverse events(SAE) within 6 months after surgery. Quantitative data were compared by Mann-Whitney U test, and categorical data were compared by χ2 test and non-inferiority test. Results: A total of 80 subjects were included in the trial (41 in the experimental group and 39 in the control group), including 27 males and 53 females, aged (M(IQR)) 55(23) years (range:40 to 78 years). There were 48 cases of left lower limb and 32 cases of right lower limb. The technical success rate and system control performance between the groups were 100%.The incidence of adverse events (58.5% (24/41) vs. 61.5% (24/39), χ2=0.075, P=0.784), and the incidence of SAE (7.3% (3/41) vs. 5.1% (2/39), χ2=0.163, P=0.686) within 6 months after surgery in experimental group and control group had no statistical significance. There was one device-related adverse event in each of the two groups. In the experimental group, one patient developed endovenous heat-induced thrombosis after surgery and recovered after taking rivaroxaban tablets. One patient in the control group had pain in the upper right thigh for more than 1 day after operation, which was cured after using analgesic cream. No device-related SAE occurred. The venous closure rate of the experimental group was 100% (38/38) at 6 months after surgery, and that of the control group was 97.4% (37/38). The difference between the two groups was 2.63% (95%CI:-3.19 to 8.45, Z=4.865, P<0.01), and the 95%CI lower limit of the difference in target venous closure rate between two groups was greater than the non-inferiority threshold of -10.00%. Conclusion: The early application effect of the new domestic intravenous radiofrequency closure system in patients with primary varicose veins of lower extremities is in line with expectations, it is not inferior to the imported system.

[Bibliometric and visual analysis of pneumoconiosis based on Cite Space].

Objective: Through the bibliometrics analysis and visual analysis of Chinese and English literature related to pneumoconiosis through CiteSpace, to understand the research situation, research trend and hotspots of pneumoconiosis, so as to provide reference for further research. Methods: In August 2022, CNKI (China National Knowledge Infrastructure) data baseand Web of Science core collection database were used as data sources for literature retrieval. Cite Space.5.8.R3c software was used to analyze the cooperation between authors and institutions, keyword co-occurrence analysis, keyword clustering analysis and keyword emergence analysis. Results: A total of 4726 Chinese literature and 2490 English literature related to pneumoconiosis were included; The annual publication volume of Chinese literature shows a fluctuating downward trend, while the annual publication volume of English literature shows a fluctuating upward trend. The Institute of Labor Health and Occupational Disease of the Chinese Academy of Preventive Medical Sciences and the Institute of Occupational Health and Poisoning Control of the Chinese Center for Disease Control and Prevention have the highest publication volume (55 articles) in the institutional cooperation network; The National Institute for Occupational Safety and Health (NIOSH) in the United States has the highest publication volume (153 articles) in the institutional collaboration network. The results of keyword co-occurrence, clustering, and prominence analysis show that Chinese literature focuses more on clinical research on pneumoconiosis, while English literature focuses more on experimental research related to the pathogenesis of pneumoconiosis. Conclusion: In the related field of pneumoconiosis research, the experimental research and clinical research on the pathogenesis are the main research hotspots.

A sex- and site-specific relationship between body mass index and osteoarthritis: evidence from observational and genetic analyses.

OBJECTIVE: We primarily aimed to investigate whether there are phenotypic and genetic links underlying body mass index (BMI) and overall osteoarthritis (OA). We then intended to explore whether the relationships differ across sexes and sites. METHOD: We first evaluated the phenotypic association between BMI and overall OA using data from the UK Biobank. We then investigated the genetic relationship leveraging summary statistics of the hitherto largest genome-wide association studies performed for BMI and overall OA. Finally, we repeated all analyses in a sex- (female, male) and site- (knee, hip, spine) specific manner. RESULTS: Observational analysis suggested an increased hazard of diagnosed OA per 5 kg/m2 increment in BMI (hazard ratio = 1.38, 95% confidence interval (CI) = 1.37-1.39). A positive overall genetic correlation was observed for BMI and OA (rg = 0.43, P = 4.72 × 10-133), corroborated by 11 significant local signals. Cross-trait meta-analysis identified 34 pleiotropic loci shared between BMI and OA, of which seven were novel. Transcriptome-wide association study revealed 29 shared gene-tissue pairs, targeting nervous, digestive, and exo/endocrine systems. Mendelian randomization demonstrated a robust BMI-OA causal relationship (odds ratio = 1.47, 95% CI = 1.42-1.52). A similar pattern of effects was observed in sex- and site-specific analyses, with BMI affecting OA comparably in both sexes and most strongly in the knee. CONCLUSION: Our work demonstrates an intrinsic relationship underlying BMI and overall OA, reflected by a pronounced phenotypic association, significant biological pleiotropy, and a putative causal link. Stratified analysis further reveals that the effects are distinct across sites and comparable across sexes.

Liver disease among patients with psoriasis: the Malaysian Psoriasis Registry.

BACKGROUND: Therapeutic options may be limited for patients with psoriasis who have concomitant liver disease (PsL). OBJECTIVES: We aimed to report the frequency of liver disease among patients with psoriasis, and describe the clinical features, treatment modalities and quality of life. METHODS: This was a multicentre cross-sectional study of patients with psoriasis notified to the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018. RESULTS: Of 21 735 patients with psoriasis, 174 (0.8%) had liver disease. The three most common liver diseases were viral hepatitis (62.1%), fatty liver (14.4%) and liver cirrhosis (10.9%). The male-to-female ratio was 3.8 : 1. Mean age (SD) of onset of psoriasis was higher in those with liver disease vs. those without [37.25 years (13.47) vs. 33.26 years (16.96), P < 0.001]. Patients with PsL, compared with those without liver disease, had a higher rate of dyslipidaemia (27.5% vs. 16.4%, P < 0.001), hypertension (33.9% vs. 23.7%, P = 0.002), diabetes mellitus (22.4% vs. 15.9%, P = 0.021) and HIV infection (5.3% vs. 0.4%, P < 0.001). Those with PsL were also more likely than those without liver disease to have severe disease [body surface area > 10% and/or Dermatology Life Quality Index (DLQI) > 10] (59.3% vs. 49.9%, P = 0.027), psoriatic arthropathy (21.1% vs. 13.0%, P = 0.002) and nail involvement (78.2% vs. 56.1%, P < 0.001). Also significantly higher in the group with PsL were the use of phototherapy (8.4% vs. 2.6%, P < 0.001), acitretin (7.3% vs. 2.8%, P < 0.001) and ciclosporin (3.0% vs. 0.7%, P < 0.001). Mean DLQI was similar in both groups [9.69 (7.20) vs. 9.62 (6.75), P = 0.88]. CONCLUSIONS: The frequency of patients with PsL in the MPR was 0.8%. Patients with PsL were more likely to be male, had a higher rate of comorbidities, severe disease, and nail and joint involvement than those without liver disease.

The effect of recreational cannabis legalization and commercialization on substance use, mental health, and injury: a systematic review.

OBJECTIVE: To determine the effect of recreational cannabis legalization (RCL) and/or recreational cannabis commercialization (RCC) on emergency department (ED) visits, hospitalizations, and deaths due to substance use, injury, and mental health among those aged 11 years and older. METHODS: A systematic review of six electronic databases up to February 1, 2023. Original, peer-reviewed articles with interrupted time series or before and after designs were included. Four independent reviewers screened articles and assessed risk of bias. Outcomes with 'critical' risk of bias were excluded. Protocol registered on PROSPERO (# CRD42021265183). RESULTS: After screening and risk of bias assessment, 29 studies were included which examined ED visits or hospitalizations for cannabis use or alcohol (N = 10), opioid mortality (N = 3), motor vehicle fatalities or injury (N = 11), and intentional injury/mental health (N = 5). Rates or number of cannabis-related hospitalizations increased after RCL in Canada and the USA. Immediate increases in rates of cannabis-related ED visits were found after both RCL and RCC in Canada. Rates of traffic fatalities increased after RCL and RCC in certain jurisdictions in the USA. CONCLUSIONS: RCL was associated with increased rates of cannabis-related hospitalizations. RCL and/or RCC was associated with increased rates of cannabis-related ED visits, consistently shown across sex and age groups. The effect on fatal motor vehicle incidents was mixed, with observed increases found after RCL and/or RCC. The effect of RCL or RCC on opioids, alcohol, intentional injury, and mental health is not clear. These results inform population health initiatives and international jurisdictions considering RCL implementation.

[Enhance the management of cardiac arrest and improve the prognosis of the patients].

Cardiac arrest is one of the major public health problems with sudden onset, high mortality and high disability rate. The prevalence of cardiovascular disease continues to rise and the burden of cardiac arrest is increasing in China. It is of great significance to explore more effective prevention and treatment measures to improve the prognosis of patients with cardiac arrest. This article discusses the relevant progress on the treatment ability of emergency and critical cardiovascular diseases, medicines and technologies for cardiac arrest care, and registry studies of cardiac arrest, to further promote the effective improvement of key capacities at various stages of the prevention and treatment of cardiac arrest in China.

Contact sensitization to fragrance allergen: a 5-year review in the Department of Dermatology, Hospital Kuala Lumpur.

INTRODUCTION: Fragrance allergy remains an important cause of contact dermatitis. We aim to describe the characteristics of patients with contact sensitisation to fragrances who underwent patch testing in the Department of Dermatology Hospital Kuala Lumpur. MATERIALS AND METHODS: This is a 5-year retrospective study of patients who developed positive reactions to fragrance allergens at the Department of Dermatology, Hospital Kuala Lumpur, Malaysia between January 2017 and December 2021. Patch tests were performed with European Baseline Series and relevant extended series. Patch test readings were recorded according to the International Contact Dermatitis Research Group recommendation. RESULTS: A total of 854 patients underwent patch test during the study period with 133 (15.6%) patients developing at least one positive reaction to fragrance allergens. The median age of patients at presentation was 40 years (range 16-79) old with 78.2% females. The most common initial presentation was hand eczema (55.6%). Other commonly involved sites include face (38.3%), leg (35.3%) and trunk (22.6%). The most frequent sensitising fragrance allergens were Fragrance Mix I (10.5%), Balsam of Peru (7.1%) and Fragrance Mix II (4.9%). Sixty patients (45%) developed positive reaction to more than one fragrance allergens. Twelve patients (9%) developed positive patch test reactions to their own products such as skincare, hair dye and hand wash. Current relevance was recorded in 96 patients (72.2 %). CONCLUSION: Contact sensitisation to fragrance allergens was detected in about 15% of our patients who underwent patch test. The most common sensitising allergens were Fragrance Mix I and II and Balsam of Peru.

Fungus isolated from dermatomycoses: a 9-month prospective study at Hospital Melaka.

INTRODUCTION: Dermatomycoses are common superficial cutaneous fungal infections which affect the skin, nails and human hairs. It affects 20 to 25% of the world population. The causative fungus varies geographically across the globe. Study on dermatomycoses is crucial to identify the aetiological fungus involved locally. The study aimed to determine the causative fungus of superficial fungal infections of the skin, nail and hair in patients presented to Hospital Melaka. METHODS: This was a prospective study conducted from 15th January 2022 till 15th October 2022 at Dermatology Clinic, Hospital Melaka. Subjects with clinical dermatomycoses were included in this study. The samples were collected from skin, nails and hairs clinically affected by tinea corporis/cruris/pedis, onychomycosis and tinea capitis respectively. A potassium hydroxide (KOH) study was performed on the sample in which the fungal hyphae/yeast positive subjects were sent for fungal culture and fungal PCR test. RESULT: A total of 222 clinical samples from skin, nails and hairs with a clinical suspicion of dermatomycoses yielded fungal hyphae/yeast in KOH. Majority of the samples were collected from skin (138, 62.2%), followed by nails (65, 29.3%) and hairs (19, 8.6%). Male to female ratio was 1.18: 1. The age ranged from 2 to 87 with the median of 55.5-yearsold. Out of 222 samples, 150 (67.6%) were fungal culture positive. From fungal culture positive samples, 87 samples were from tinea corporis, 50 samples were from onychomycoses and 13 samples were from tinea capitis. Trichophyton rubrum (39, 44.8%) was the commonest dermatophyte isolated in tinea corporis/cruris/pedis. Nondermatophyte moulds (NDM, 35, 70%) were the main fungi isolated in onychomycosis. Microsporum canis (7/53.8%) was the principal causative fungus among patients with tinea capitis. Among 150 fungal culture positive samples, 76 were fungal PCR positive. Only 38 samples consistently isolated same fungal species in both fungal culture and PCR test. CONCLUSION: Majority of tinea corporis and tinea capitis fungal culture isolated dermatophytes, especially Trichophyton rubrum and Microsporum canis, respectively. Non-dermatophyte moulds were mainly isolated in onychomycosis.

Decreased cortical bone density and mechanical strength with associated elevated bone turnover markers at peri-pubertal peak height velocity: a cross-sectional and longitudinal cohort study of 396 girls with adolescent idiopathic scoliosis.

Decreased cortical bone density and bone strength at peak height velocity (PHV) were noted in girls with adolescent idiopathic scoliosis (AIS). These findings could provide the link to the previously reported observation that low bone mineral density (BMD) could contribute as one of the prognostic factors for curve progression that mostly occurs during PHV in AIS. INTRODUCTION: As part of the studies related to aetiopathogenesis of AIS, we assessed bone qualities, bone mechanical strength and bone turnover markers (BTMs) focusing at the peri-pubertal period and PHV in AIS girls. METHODS: 396 AIS girls in two separate cohorts were studied. Skeletal maturity was assessed using the validated thumb ossification composite index (TOCI). Bone qualities and strength were evaluated with high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA). RESULTS: Cohort-A included 179 girls (11.95 ± 0.95 years old). Girls at TOCI-4 had numerically the highest height velocity (0.71 ± 0.24 cm/month) corresponding to the PHV. Subjects at TOCI-4 had lower cortical volumetric BMD (672.36 ± 39.07 mg/mm3), cortical thickness (0.68 ± 0.08 mm) and apparent modulus (1601.54 ± 243.75 N/mm2) than: (a) those at TOCI-1-3 (724.99 ± 32.09 mg/mm3 (p < 0.001), 0.79 ± 0.11 mm (p < 0.001) and 1910.88 ± 374.75 N/mm2 (p < 0.001), respectively) and (b) those at TOCI-8 (732.28 ± 53.75 mg/mm3 (p < 0.001), 0.84 ± 0.14 mm (p < 0.001), 1889.11 ± 419.37 N/mm2 (p < 0.001), respectively). Cohort-B included 217 girls (12.22 ± 0.89 years old). Subjects at TOCI-4 had higher levels of C-terminal telopeptide of type 1 collagen (1524.70 ± 271.10 pg/L) and procollagen type 1 N-terminal propeptide (941.12 ± 161.39 µg/L) than those at TOCI-8 (845.71 ± 478.55 pg/L (p < 0.001) and 370.08 ± 197.04 µg/L (p < 0.001), respectively). CONCLUSION: AIS girls had decreased cortical bone density and bone mechanical strength with elevated BTMs at PHV. Coupling of PHV with decreased cortical and FEA parameters could provide the link to the previously reported observation that low BMD could contribute as one of the prognostic factors for curve progression that mostly occurs during PHV in AIS.

Fourfold Anisotropic Magnetoresistance of L1_{0} FePt Due to Relaxation Time Anisotropy.

Experimental measurements show that the angular dependence of the anisotropic magnetoresistance (AMR) in L1_{0} ordered FePt epitaxial films on the current orientation and magnetization direction is a superposition of the corresponding dependences of twofold and fourfold symmetries. The twofold AMR exhibits a strong dependence on the current orientation, whereas the fourfold term only depends on the magnetization direction in the crystal and is independent of the current orientation. First-principles calculations reveal that the fourfold AMR arises from the relaxation time anisotropy due to the variation of the density of states near the Fermi energy under rotation of the magnetization. This relaxation time anisotropy is a universal property in ferromagnetic metals and determines other anisotropic physical properties that are observable in experiment.

Risk-Based Screening Tools to Optimise HIV Testing Services: a Systematic Review.

PURPOSE OF REVIEW: Effective ways to diagnose the remaining people living with HIV who do not know their status are a global priority. We reviewed the use of risk-based tools, a set of criteria to identify individuals who would not otherwise be tested (screen in) or excluded people from testing (screen out). RECENT FINDINGS: Recent studies suggest that there may be value in risk-based tools to improve testing efficiency (i.e. identifying those who need to be tested). However, there has not been any systematic reviews to synthesize these studies. We identified 18,238 citations, and 71 were included. The risk-based tools identified were most commonly from high-income (51%) and low HIV (<5%) prevalence countries (73%). The majority were for "screening in" (70%), with the highest performance tools related to identifying MSM with acute HIV. Screening in tools may be helpful in settings where it is not feasible or recommended to offer testing routinely. Caution is needed for screening out tools, where there is a trade-off between reducing costs of testing with missing cases of people living with HIV.

Gompertz model in COVID-19 spreading simulation.

The paper reports on application of the Gompertz model to describe the growth dynamics of COVID-19 cases during the first wave of the pandemic in different countries. Modeling has been performed for 23 countries: Australia, Austria, Belgium, Brazil, Great Britain, Germany, Denmark, Ireland, Spain, Italy, Canada, China, the Netherlands, Norway, Serbia, Turkey, France, Czech Republic, Switzerland, South Korea, USA, Mexico, and Japan. The model parameters are determined by regression analysis based on official World Health Organization data available for these countries. The comparison of the predictions given by the Gompertz model and the simple logistic model (i.e., Verhulst model) is performed allowing to conclude on the higher accuracy of the Gompertz model.

[Caution over diagnosis of preperimetric glaucoma].

Preperimetric glaucoma (PPG) refers to the earliest stage of primary open-angle glaucoma (POAG) before emergence of visual field defects. However, the existence and diagnosis of the PPG stage remains controversial. In this article, with focuses on the clinical significance of intraocular pressure measurements, the etiology classification of POAG, the value of follow-up to PPG diagnosis, the accuracy of devices and methods, and genetic factors of POAG, we point out that PPG should be carefully diagnosed in clinical practice. It is hoped that constant and deep understanding of PPG could help to reach consensus opinions, thus improving and enhancing the diagnosis and treatment of glaucoma.

Comparative analysis of mouse and human preimplantation development following POU5F1 CRISPR/Cas9 targeting reveals interspecies differences.

STUDY QUESTION: What is the role of POU class 5 homeobox 1 (POU5F1) in human preimplantation development and how does it compare with the mouse model? SUMMARY ANSWER: POU5F1 is required for successful development of mouse and human embryos to the blastocyst stage as knockout embryos exhibited a significantly lower blastocyst formation rate, accompanied by lack of inner cell mass (ICM) formation. WHAT IS KNOWN ALREADY: Clustered regularly interspaced short palindromic repeats-CRISPR associated genes (CRISPR-Cas9) has previously been used to examine the role of POU5F1 during human preimplantation development. The reported POU5F1-targeted blastocysts always retained POU5F1 expression in at least one cell, because of incomplete CRISPR-Cas9 editing. The question remains of whether the inability to obtain fully edited POU5F1-targeted blastocysts in human results from incomplete editing or the actual inability of these embryos to reach the blastocyst stage. STUDY DESIGN, SIZE, DURATION: The efficiency of CRISPR-Cas9 to induce targeted gene mutations was first optimized in the mouse model. Two CRISPR-Cas9 delivery methods were compared in the B6D2F1 strain: S-phase injection (zygote stage) (n = 135) versus metaphase II-phase (M-phase) injection (oocyte stage) (n = 23). Four control groups were included: non-injected media-control zygotes (n = 43)/oocytes (n = 48); sham-injected zygotes (n = 45)/oocytes (n = 47); Cas9-protein injected zygotes (n = 23); and Cas9 protein and scrambled guide RNA (gRNA)-injected zygotes (n = 27). Immunofluorescence analysis was performed in Pou5f1-targeted zygotes (n = 37), media control zygotes (n = 19), and sham-injected zygotes (n = 15). To assess the capacity of Pou5f1-null embryos to develop further in vitro, additional groups of Pou5f1-targeted zygotes (n = 29) and media control zygotes (n = 30) were cultured to postimplantation stages (8.5 dpf). Aiming to identify differences in developmental capacity of Pou5f1-null embryos attributed to strain variation, zygotes from a second mouse strain-B6CBA (n = 52) were targeted. Overall, the optimized methodology was applied in human oocytes following IVM (metaphase II stage) (n = 101). The control group consisted of intracytoplasmically sperm injected (ICSI) IVM oocytes (n = 33). Immunofluorescence analysis was performed in human CRISPR-injected (n = 10) and media control (n = 9) human embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS: A gRNA-Cas9 protein mixture targeting exon 2 of Pou5f1/POU5F1 was microinjected in mouse oocytes/zygotes or human IVM oocytes. Reconstructed embryos were cultured for 4 days (mouse) or 6.5 days (human) in sequential culture media. An additional group of mouse-targeted zygotes was cultured to postimplantation stages. Embryonic development was assessed daily, with detailed scoring at late blastocyst stage. Genomic editing was assessed by immunofluorescence analysis and next-generation sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Genomic analysis in mouse revealed very high editing efficiencies with 95% of the S-Phase and 100% of the M-Phase embryos containing genetic modifications, of which 89.47% in the S-Phase and 84.21% in the M-Phase group were fully edited. The developmental capacity was significantly compromised as only 46.88% embryos in the S-Phase and 19.05% in the M-Phase group reached the blastocyst stage, compared to 86.36% in control M-Phase and 90.24% in control S-Phase groups, respectively. Immunofluorescence analysis confirmed the loss of Pou5f1 expression and downregulation of the primitive marker SRY-Box transcription factor (Sox17). Our experiments confirmed the requirement of Pou5f1 expression for blastocyst development in the second B6CBA strain. Altogether, our data obtained in mouse reveal that Pou5f1 expression is essential for development to the blastocyst stage. M-Phase injection in human IVM oocytes (n = 101) similarly resulted in 88.37% of the POU5F1-targeted embryos being successfully edited. The developmental capacity of generated embryos was compromised from the eight-cell stage onwards. Only 4.55% of the microinjected embryos reached the late blastocyst stage and the embryos exhibited complete absence of ICM and an irregular trophectoderm cell layer. Loss of POU5F1 expression resulted in absence of SOX17 expression, as in mouse. Interestingly, genetic mosaicism was eliminated in a subset of targeted human embryos (9 out of 38), three of which developed into blastocysts. LIMITATIONS, REASONS FOR CAUTION: One of the major hurdles of CRISPR-Cas9 germline genome editing is the occurrence of mosaicism, which may complicate phenotypic analysis and interpretation of developmental behavior of the injected embryos. Furthermore, in this study, spare IVM human oocytes were used, which may not recapitulate the developmental behavior of in vivo matured oocytes. WIDER IMPLICATIONS OF THE FINDINGS: Comparison of developmental competency following CRISPR-Cas-mediated gene targeting in mouse and human may be influenced by the selected mouse strain. Gene targeting by CRISPR-Cas9 is subject to variable targeting efficiencies. Therefore, striving to reduce mosaicism can provide novel molecular insights into mouse and human embryogenesis. STUDY FUNDING/COMPETING INTEREST(S): The research was funded by the Ghent University Hospital and Ghent University and supported by the FWO-Vlaanderen (Flemish fund for scientific research, Grant no. G051516N), and Hercules funding (FWO.HMZ.2016.00.02.01). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Association of serum 25(OH)Vit-D levels with risk of pediatric fractures: a systematic review and meta-analysis.

The association between the risk of fractures and suboptimal vitamin D (Vit-D) status remains controversial in children. This meta-analysis suggested that serum 25(OH)Vit-D levels were lower in pediatric cases with fractures. 25-hydroxyvitamin D (25(OH)Vit-D) levels less than 50 nmol/L were associated with increased fracture risk in children. INTRODUCTION: This study aimed to assess the association between serum 25(OH)Vit-D and the risk of fractures in children, and to explore the sources of heterogeneity and investigate their impact on results. METHODS: Systematic review and meta-analysis were conducted for observational studies comparing serum 25(OH)Vit-D levels between fracture and non-fracture pediatric cases. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Analysis on 17 case-control and 6 cross-sectional studies (2929 fracture cases and 5000 controls) suggested that 25(OH)Vit-D was lower in fracture cases than in controls (pooled mean difference (MD) = - 3.51 nmol/L; 95% confidence interval (CI): - 5.60 to - 1.42) with a heterogeneity (I2) of 73.9%. The sensitivity analysis which merged the case-control studies that had a NOS score ≥ 4 showed a pooled MD of - 4.35 nmol/L (95% CI: - 6.64 to - 2.06) with a heterogeneity (I2) of 35.9%. Pooled odds ratio of fracture in subjects with 25(OH)Vit-D ≤ 50 nmol/L compared to subjects with 25(OH)Vit-D > 50 nmol/L was 1.29 (95% CI: 1.10 to 1.53; I2 < 1%). CONCLUSION: This study indicated that serum 25(OH)Vit-D levels were lower in pediatric patients with fractures. 25(OH)Vit-D ≤ 50 nmol/L was associated with increased fracture risk in children.

Ultrafast X-Ray Diffraction Visualization of B1-B2 Phase Transition in KCl under Shock Compression.

The classical B1(NaCl)↔B2(CsCl) transitions have been considered as a model for general structural phase transformations, and resolving corresponding phase transition mechanisms under high strain rate shock compression is critical to a fundamental understanding of phase transition dynamics. Here, we use subnanosecond synchrotron x-ray diffraction to visualize the lattice response of single-crystal KCl to planar shock compression. Complete B1-B2 orientation relations are revealed for KCl under shock compression along ⟨100⟩_{B1} and ⟨110⟩_{B1}; the orientation relations and transition mechanisms are anisotropic and can be described with the standard and modified Watanabe-Tokonami-Morimoto model, respectively, both involving interlayer sliding and intralayer ion rearrangement. The current study also establishes a paradigm for investigating solid-solid phase transitions under dynamic extremes with ultrafast synchrotron x-ray diffraction.

Application of remote online learning in oral histopathology teaching in China.

BACKGROUND: The aim of this study was to investigate the application of remote learning and virtual microscopy in oral histopathology teaching, a unique experience in China. The oral histopathology teaching in Nanjing Medical University has been extraordinary. MATERIAL AND METHODS: 98 third-year dental students of Grade 2016 took oral histopathology theoretical course face-to-face in 2019 (Traditional group). The 94 participants of Grade 2017 took online oral histopathology course using digital methods(E-Learning platform and Virtual Simulation Experiment Teaching Center for Dentistry) in 2020. During the practical laboratory sessions, the students in both Traditional group and Online group observed the same glass slides for morphological learning. A questionnaire survey explored students' attitudes towards the remote online learning. RESULTS: The mean Theory test scores of the Online group (80.93±12.15) were significantly higher than those of the Traditional group (73.65±8.46) (P < 0.01). The mean total scores of the Online group (82.94±10.76) were significantly higher than those of the Traditional group (77.25±7.55) (P < 0.01). The percentage of high total test score (test score > 85) of the Online group (54%) was also significantly higher than that of the Traditional group (15%) (P< 0.01). Furthermore, both remote learning and virtual microscopy courses were well accepted by students according to the questionnaire. CONCLUSIONS: This study found that remote learning and virtual technology have a positive impact on oral histopathology. The findings reveal that the application of remote online learning has enhanced oral histopathology teaching in China.

[Optimizing biopsy procedures during colposcopy and detection of high-grade cervical lesions].

Objective: To investigate the value of biopsies on diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN Ⅱ+), and optimize biopsy procedures of risk-based colposcopy practice. Methods: A prospective study was performed on 346 women referred to colposcopy following abnormal cervical cancer screening results at the First Affiliated Hospital of Nanjing Medical University, from April 2017 to December 2019. Up to 4 cervical biopsies were taken during colposcopy and each biopsy specimen was evaluated separately in histology. CIN Ⅱ+ identified by any biopsy was the reference standard of disease used to evaluate the diagnostic value of targeted biopsy and random biopsy, and to quantify the improved detection of CIN Ⅱ+ by taking multiple biopsies. Cervical cytology, HPV genotyping, and colposcopic impression were used to establish different risk strata to select various multiple biopsies procedures during colposcopy to improve accuracy and efficiency of CIN Ⅱ+ detection. Results: In total 346 women, 190 (54.9%, 190/346) cases of them were diagnosed as CIN Ⅱ+. (1) In total 346 women, 96.8% (184/190) CIN Ⅱ+ were detected by targeted biopsies, 27.9% (53/190) CIN Ⅱ+ were detected in biopsies targeted grade 1 abnormal colposcopic findings (G1) on the cervix, and 68.9% (131/190) CIN Ⅱ+ were detected in biopsies targetrd grade 2 abnormal colposcopic findings (G2) on the cervix. Colposcopy had a sensitivity of 68.9% when the biopsy threshold was G2, sensitivity increased to 96.8% when the biopsy threshold was defined to be G1. Among women with G1, adding 2 targeted biopsies to the first biopsy were sufficient to detect all CIN Ⅱ+, among women with G2, adding 1 targeted biopsy was sufficient. (2) Among 270 women, random biopsies targeted normal colposcopic findings on the cervix were performed in addition to targeted biopsies and in total 3.2% (6/190) additional CIN Ⅱ+ were detected. As the number of cervical quadrants involved by abnormal colposcopic images increased, random biopsy detected fewer CIN Ⅱ+ that would have otherwise been missed by targeted biopsies (P=0.010). (3) Women with atypical squamous cells,cannot exclude high grade squamous intraepithelial lesion (ASC-H), high grade squamous intraepithelial lesion (HSIL) or atypical glandular cell (AGC) referral cytology, HPV 16-positive, G2 were more likely to have CIN Ⅱ+(P<0.01); for those meeting only one category, the yield of CIN Ⅱ+ increased from 34.0% for one biopsy to 51.0% for two biopsies, the absolute increase in CIN Ⅱ+ yield increased from the first to the second biopsy was 17.0%, two biopsies were sufficient to detect all CIN Ⅱ+; for those meeting at least two categories, the yield of CIN Ⅱ+ increased from 90.7% for one biopsy to 92.6% for two biopsies, the absolute increase in CIN Ⅱ+ yield increased from the first to the second biopsy was 1.9%, two biopsies were sufficient to detect all CIN Ⅱ+; for those not meeting any category, the yield of CIN Ⅱ+ increased from 8.8% for one biopsy to 17.6% for two biopsies, to 23.5% for three biopsies, the absolute increase in CIN Ⅱ+ yield increased from the first to the second biopsy, from the second to the third biopsy was 8.8%, 5.9%, three biopsies were sufficient to detect all CIN Ⅱ+. Conclusions: Performing multiple targeted biopsies could improve efficiency of CIN Ⅱ+ detection. Adding random biopsies to multiple targeted biopsies showed very limited additional benefit for detection of CIN Ⅱ+. The biopsy procedures undertaken during the colposcopy visit could be modified based on various colposcopic impressions and reasons for referral.