Tree-Based Reinforcement Learning for Identifying Optimal Personalized Treatment Decisions for Hand Deformity in Rheumatoid Arthritis.

BACKGROUND: Silicone metacarpophalangeal joint arthroplasty (SMPA) can reconstruct metacarpophalangeal (MCP) joint deformities in the rheumatoid hand, but patient selection criteria for the procedure remains unclear. We used statistical learning to elucidate patient selection criteria that will enhance long-term patient-reported and functional outcomes in patients with severe hand rheumatoid arthritis (RA). METHODS: This is a secondary analysis of a prospective study of 169 adults with severe hand RA (average combined ulnar deviation (UD) and extensor lag (EL) at the MCP joint ≥ 50 degrees, per finger) with one-year follow-up, conducted at three centers in the United States and England from January 1, 2004, to December 31, 2011. Primary outcomes were Michigan Hand Outcomes Questionnaire (MHQ) pain sub-score, changes in EL, UD, and Arthritis Impact Measurement Scale (AIMS2) score. A tree-based reinforcement learning (T-RL) model was used to estimate clinical decision rules for treatment. RESULTS: 132 patients (mean[SD], 61[9] years; 108[72%] female) were included in the SMPA (n=50) and non-SMPA (n=82) cohorts. To minimize EL and UD, patients should undergo SMPA. To minimize pain, patients older than 55 should undergo SMPA. To increase hand-related quality-of-life (QOL), patients with grip strength <12 kg should undergo SMPA. Estimations with imputed missing data were similar, aside from a lower grip strength (<8 kg) threshold for hand-related QOL. CONCLUSION: Unless there is significant comorbidity that precludes surgery, most patients older than 55 with severe hand RA will have improved QOL, pain, and function after SMPA. Patients with preserved grip strength may benefit from continued medical management.

Recommendations and guidance for herpes zoster vaccination for adults in Taiwan.

Herpes zoster (HZ) is a painful, vesicular, cutaneous eruption from reactivation of varicella zoster virus (VZV), which can lead to potentially debilitating complications. The lifetime risk of HZ is estimated to be 20%-30% in the general population, with an increased risk in the elderly and immunocompromised populations. The most effective strategy to prevent HZ and its complications is by vaccination. Two types of HZ vaccines, zoster vaccine live and recombinant zoster vaccine, have been approved for use. This guidance offers recommendations and suggestions for HZ vaccination in adults, aiming to reduce the disease burden of HZ and its complications. It is intended as a guide to first-line healthcare providers, but does not supersede clinical judgement when assessing risk and providing recommendations to individuals. The Working Group on Adult Immunization Practice was appointed by the Infectious Diseases Society of Taiwan (IDST) and recommendations were drafted after a full literature review, using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. The recommendations were reviewed and revised by expert review panels during a series of consensus meetings and endorsed by the IDST, Taiwan Association of Family Medicine, the Taiwanese Dermatological Association, the Taiwan Oncology Society, the Taiwan Society of Blood and Marrow Transplantation, the Transplantation Society of Taiwan, the Taiwan AIDS Society, and the Taiwan College of Rheumatology. This guidance describes the epidemiology of HZ and provides recommendations for HZ vaccination in adults with varying levels of risk, differing history of previous VZV infection and past varicella or zoster vaccinations.

Chinese version of the Tendency to Avoid Physical Activity and Sport (TAPAS) scale: testing unidimensionality, measurement invariance, concurrent validity, and known-group validity among Taiwanese youths.

BACKGROUND AND OBJECTIVES: Psychosocial factors affect individuals' desire for physical activity. A newly developed instrument (Tendency to Avoid Physical Activity and Sport; TAPAS) has been designed to assess the avoidance of physical activity. Considering cultural differences could be decisive factors, the present study aimed to translate and validate the TAPAS into Chinese (Mandarin) for Taiwanese youths, and further cultural comparisons are expected. METHODS: Standard translation procedure (i.e., forward translation, back translation, and reconciliation) was used to translate the English TAPAS into the Chinese TAPAS. Following translation, 608 youths (mean [SD] age 29.10 [6.36] years; 333 [54.8%] women) participated in the study via a snowballing sampling method with an online survey. All participants completed the Chinese TAPAS and additional instruments assessing weight stigma and psychological distress. Confirmatory factor analysis (CFA) was used to examine the factor structure of the Chinese TAPAS and multigroup CFA to examine measurement invariance across gender (men vs. women) and weight status (overweight vs. non-overweight). Pearson correlations were used to examine the concurrent validity; independent t-tests between gender groups and weight status groups were used to examine the known-group validity. RESULTS: Consistent with the English version, the Chinese TAPAS was found to have a one-factor structure evidenced by CFA results. The structure was invariant across gender and weight status groups evidenced by multigroup CFA results. Concurrent validity was supported by significant associations with the related constructs assessed (r = 0.326 to 0.676; p < 0.001). Known-group validity was supported by the significant differences in TAPAS total scores between gender and weight status groups (p = 0.004 and < 0.001; Cohen's d = 0.24 and 0.48). CONCLUSION: The Chinese version of the TAPAS is a valid and reliable instrument assessing individuals' avoidance of physical activity and sports due to underlying psychosocial issues among Taiwanese youths. It is anticipated to be applied within a large Asian population, as well as cross-cultural comparisons, for further explorations in health, behavioral and epidemiological research and practice.

DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis.

Trichoderma reesei is an economically important enzyme producer with several unique meiotic features. spo11, the initiator of meiotic double-strand breaks (DSBs) in most sexual eukaryotes, is dispensable for T. reesei meiosis. T. reesei lacks the meiosis-specific recombinase Dmc1. Rad51 and Sae2, the activator of the Mre11 endonuclease complex, promote DSB repair and chromosome synapsis in wild-type and spo11Δ meiosis. DNA methyltransferases (DNMTs) perform multiple tasks in meiosis. Three DNMT genes (rid1, dim2 and dimX) differentially regulate genome-wide cytosine methylation and C:G-to-T:A hypermutations in different chromosomal regions. We have identified two types of DSBs: type I DSBs require spo11 or rid1 for initiation, whereas type II DSBs do not rely on spo11 and rid1 for initiation. rid1 (but not dim2) is essential for Rad51-mediated DSB repair and normal meiosis. rid1 and rad51 exhibit a locus heterogeneity (LH) relationship, in which LH-associated proteins often regulate interconnectivity in protein interaction networks. This LH relationship can be suppressed by deleting dim2 in a haploid rid1Δ (but not rad51Δ) parental strain, indicating that dim2 and rid1 share a redundant function that acts earlier than rad51 during early meiosis. In conclusion, our studies provide the first evidence of the involvement of DNMTs during meiotic initiation and recombination.

Association of Perinatal Cardiovascular Features with Angiotensin System Expressions in Maternal Preeclampsia.

We hypothesized and investigated whether prenatal exposure to preeclampsia (PE) would simultaneously affect perinatal cardiovascular features and angiotensin system expressions. This prospective study was composed of mother-neonate dyads with (n = 49) and without maternal preeclampsia (n = 48) in a single tertiary medical center. The neonates exposed to PE had significantly larger relative sizes for the left and right coronary arteries and a higher cord plasma level of aminopeptidase-N, which positively correlated with the maternal diastolic blood pressures and determined the relative sizes of the left and right coronary arteries, whereas the encoding aminopeptidase-N (ANPEP) mRNA level in the PE cord blood leukocytes was significantly decreased, positively correlated with the neonatal systolic blood pressures (SBPs), and negatively correlated with the cord plasma-induced endothelial vascular cell adhesion molecule-1 mRNA levels. The PE cord plasma significantly induced higher endothelial mRNA levels of angiotensin II type 1 receptor (AT1R) and AT4R, whereas in the umbilical arteries, the protein expressions of AT2R and AT4R were significantly decreased in the PE group. The endothelial AT1R mRNA level positively determined the maternal SBPs, and the AT4R mRNA level positively determined the neonatal chamber size and cardiac output. In conclusion, PE may influence perinatal angiotensin system and cardiovascular manifestations of neonates across placentae. Intriguing correlations between these two warrant further mechanistic investigation.

Brain circuits in autonomous sensory meridian response and related phenomena.

Autonomous sensory meridian response (ASMR) is characterized by a tingling sensation with a feeling of relaxation and a state of flow. We explore the neural underpinnings and comorbidities of ASMR and related phenomena with altered sensory processing. These phenomena include sensory processing sensitivity (SPS), synaesthesia, Alice in Wonderland syndrome and misophonia. The objective of this article is to uncover the shared neural substrates and distinctive features of ASMR and its counterparts. ASMR, SPS and misophonia exhibit common activations in the brain regions associated with social cognition, emotion regulation and empathy. Nevertheless, ASMR responders display reduced connectivity in the salience network (SN), while individuals with SPS exhibit increased connectivity in the SN. Furthermore, ASMR induces relaxation and temporarily reduces symptoms of depression, in contrast to SPS and misophonia, which are linked to depression. These observations lead us to propose that ASMR is a distinct phenomenon owing to its attention dispatch mechanism and its connection with emotion regulation. We suggest that increased activations in the insula, along with reduction in connectivity within the salience and default mode networks in ASMR responders, may account for their experiences of relaxation and flow states. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

Imipenem reduces the efficacy of vancomycin against Elizabethkingia species.

BACKGROUND: Elizabethkingia spp. are emerging as nosocomial pathogens causing various infections. These pathogens express resistance to a broad range of antibiotics, thus requiring antimicrobial combinations for coverage. However, possible antagonistic interactions between antibiotics have not been thoroughly explored. This study aimed to evaluate the effectiveness of antimicrobial combinations against Elizabethkingia infections, focusing on their impact on pathogenicity, including biofilm production and cell adhesion. METHODS: Double-disc diffusion, time-kill, and chequerboard assays were used for evaluating the combination effects of antibiotics against Elizabethkingia spp. We further examined the antagonistic effects of antibiotic combinations on biofilm formation and adherence to A549 human respiratory epithelial cells. Further validation of the antibiotic interactions and their implications was performed using ex vivo hamster precision-cut lung sections (PCLSs) to mimic in vivo conditions. RESULTS: Antagonistic effects were observed between cefoxitin, imipenem and amoxicillin/clavulanic acid in combination with vancomycin. The antagonism of imipenem toward vancomycin was specific to its effects on the genus Elizabethkingia. Imipenem further hampered the bactericidal effect of vancomycin and impaired its inhibition of biofilm formation and the adhesion of Elizabethkingia meningoseptica ATCC 13253 to human cells. In the ex vivo PCLS model, vancomycin exhibited dose-dependent bactericidal effects; however, the addition of imipenem also reduced the effect of vancomycin. CONCLUSIONS: Imipenem reduced the bactericidal efficacy of vancomycin against Elizabethkingia spp. and compromised its capacity to inhibit biofilm formation, thereby enhancing bacterial adhesion. Clinicians should be aware of the potential issues with the use of these antibiotic combinations when treating Elizabethkingia infections.

Injectable cross-linked hyaluronic acid hydrogels with epigallocatechin gallate loading as vitreous substitutes.

Hyaluronic acid (HA) serves as a vitreous substitute owing to its ability to mimic the physical functions of native vitreous humor. However, pure HA hydrogels alone do not provide sufficient protection against potential inflammatory risks following vitrectomy. In this study, HA was crosslinked with 1,4-butanediol diglycidyl ether (BDDE) to form HA hydrogels (HB). Subsequently, the anti-inflammatory agent epigallocatechin gallate (EGCG) was added to the hydrogel (HBE) for ophthalmic applications as a vitreous substitute. The characterization results indicated the successful preparation of HB with transparency, refractive index, and osmolality similar to those of native vitreous humor, and with good injectability. The anti-inflammatory ability of HBE was also confirmed by the reduced expression of inflammatory genes in retinal pigment epithelial cells treated with HBE compared with those treated with HB. In a New Zealand white rabbit model undergoing vitreous substitution treatment, HBE 50 (EGCG 50 µM addition) exhibited positive results at 28 days post-surgery. These outcomes included restored intraocular pressure, improved electroretinogram responses, minimal increase in corneal thickness, and no inflammation during histological examination. This study demonstrated the potential of an injectable HA-BDDE cross-linked hydrogel containing EGCG as a vitreous substitute for vitrectomy applications, offering prolonged degradation time and anti-inflammatory effects postoperatively.

Comparing the Early Changes in Classified Higher-Order Aberrations Before and After Non-Toric and Toric Implantable Collamer Lens V4c Implantation.

PURPOSE: This study aimed to compare early changes in classified higher-order aberrations (HOAs) pre- and postsurgery in patients who received nontoric versus toric implantable collamer lenses (ICL; ICL Model V4c; STAAR Surgical, Monrovia, CA, USA). METHODS: This prospective study included 124 eyes of 64 patients: 49 eyes were treated using a nontoric implantable collamer lens (ICL), and 75 eyes were treated using a toric implantable collamer lenses (TICL). Refractive parameters and ocular aberrations were examined before and 1 month after surgery. RESULTS: At one month, the safety indices were 1.24 ± 0.17 in the ICL group and 1.20 ± 0.25 in the TICL group (p = 0.39). The efficacy indices were 1.07 ± 0.17 in the ICL group and 1.15 ± 0.26 in the TICL group (p = 0.02). The root mean square (RMS) values of whole-eye total HOAs, trefoil, corneal total HOAs, spherical aberration, and intraocular spherical aberration significantly increased postoperatively in both groups. The RMS of intraocular total HOAs in the TICL group significantly increased 1 month postoperatively. No statistically significant differences were observed in HOA changes between the ICL and TICL groups. CONCLUSIONS: The dominant increases in short-term aberrations after ICL and TICL V4c implantation were in corneal trefoil and intraocular spherical aberrations, which were related to the corneal incision and implanted lens. The HOA changes post-surgery were not statistically different between the two lens types.

Efficacy of adjunctive local periodontal treatment for type 2 diabetes mellitus patients with periodontitis: A systematic review and network meta-analysis.

OBJECTIVES: To investigate the effectiveness of different adjunctive local treatments combined with non-surgical periodontal therapy (NSPT) to reduce pocket depth (PD), gain clinical attachment level (CAL), and/or reduce glycated hemoglobin (HbA1c) in individuals with both type 2 diabetes mellitus (T2DM) and periodontitis in a systematic review and network meta-analysis. DATA SOURCES: Publications were searched in Cochrane databases, EMBASE, Google Scholar, MEDLINE, PubMed, opengrey.eu, and www. CLINICALTRIALS: gov up to May 29, 2024 with no language restriction. STUDY SELECTION: Only randomized controlled trials (RCTs) were included. Network meta-analysis utilized frequentist models. DATA: The network meta-analysis of 30 RCTs involving 1224 patients revealed that, in short-term (2-3 months) and medium-term (4-6 months), adjunctive local treatment involving statins or metformin significantly outperformed scaling and root planning (SRP) with/without additional interventions such as photodynamic and laser therapies (PDT/LT), phytotherapy, doxycycline, bisphosphonates, antibiotics, antiseptics, or placebo for reducing PD and/or gaining CAL. In the long-term (>6 months), statins yielded the most significant additional PD reduction and CAL gain, followed by antibiotics, compared to SRP with antiseptics or placebo. Only PDT/LT demonstrated significantly greater HbA1c reduction in the short term compared to SRP with/without statins, antiseptics, or placebo. CONCLUSION: This study moderately supports that adding metformin or statins locally to NSPT may enhance PD reduction and CAL gain compared to SRP with/without placebo. CLINICAL SIGNIFICANCE: Clinicians are guided to optimize adjunctive therapies, enhancing the health of patients with type 2 diabetes and periodontitis. A strategic approach is proposed to tackle systemic and oral health challenges simultaneously.

EEG coherences of the default mode network among patients comorbid with major depressive disorder and anxiety symptoms.

BACKGROUND: Higher functional connectivity within the default mode network (DMN) has been found in functional magnetic resonance imaging (fMRI) studies of major depressive disorder (MDD). We used electroencephalogram (EEG) coherence as an index of functional connectivity to examine group differences in DMN between the MDD and healthy control (HC) groups during the resting state. METHODS: MDD patients with comorbid anxiety symptoms (n = 154) and healthy controls (n = 165) completed the questionnaires of depression, anxiety, and rumination. A 19-channel EEG recording was measured under resting state for all participants. EEG coherences of the delta, theta, alpha, beta, and high beta in the anterior DMN (aDMN), posterior DMN (pDMN), aDMN-pDMN, DMN-parahippocampal gyrus (PHG), and DMN-temporal gyrus were compared between the two groups. The correlations between rumination, anxiety, and DMN coherence were examined in the MDD group. RESULTS: (1) No difference was found in the delta, theta, alpha, and beta within the DMN brain regions between the two groups; the MDD group showed higher high beta coherence within DMN brain regions than the HC group. (2) Rumination was negatively correlated with theta coherence of aDMN, and positively correlated with beta coherence of aDMN and with alpha coherence of pDMN and DMN-PHG. (3) Anxiety was positively correlated with high beta coherence of aDMN, pDMN, and DMN-PHG. CONCLUSIONS: MDD patients with comorbid anxiety symptoms exhibited hypercoherence within the DMN brain regions. Hypercoherences were related to symptoms of rumination, and anxiety may be a biomarker for MDD patients with comorbid anxiety symptoms.

Developing a Five-Minute Normative Database of Heart Rate Variability for Diagnosing Cardiac Autonomic Dysregulation for Patients with Major Depressive Disorder.

Heart rate variability (HRV) is related to cardiac vagal control and emotional regulation and an index for cardiac vagal control and cardiac autonomic activity. This study aimed to develop the Taiwan HRV normative database covering individuals aged 20 to 70 years and to assess its diagnosing validity in patients with major depressive disorder (MDD). A total of 311 healthy participants were in the HRV normative database and divided into five groups in 10-year age groups, and then the means and standard deviations of the HRV indices were calculated. We recruited 272 patients with MDD for cross-validation, compared their HRV indices with the normative database, and then converted them to Z-scores to explore the deviation of HRV in MDD patients from healthy groups. The results found a gradual decline in HRV indices with advancing age in the HC group, and females in the HC group exhibit higher cardiac vagal control and parasympathetic activity than males. Conversely, patients in the MDD group demonstrate lower HRV indices than those in the HC group, with their symptoms of depression and anxiety showing a negative correlation with HRV indices. The Taiwan HRV normative database has good psychometric characteristics of cross-validation.

Regulation of primary cilia disassembly through HUWE1-mediated TTBK2 degradation plays a crucial role in cerebellar development and medulloblastoma growth.

Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.

Resolving conjunctival prolapse following severe blepharoptosis correction: A simple sutureless direct excision technique and systematic review.

BACKGROUND: Conjunctival prolapse (CP) is an uncommon but challenging condition following maximal levator resection (MLR) and other extensive periorbital procedures. MLR extending beyond the Whitnall's ligament is frequently performed to address severe blepharoptosis with poor levator function (LF). Patients with CP may encounter symptoms such as ocular discomfort, tearing, vision impairment, persistent conjunctival chemosis, lagophthalmos, or exposure keratopathy. Typically, surgical intervention becomes necessary if conservative measures prove to be ineffective; nevertheless, there is no consensus regarding the optimal treatment approach. OBJECTIVES: This study aimed to propose a simple sutureless direct excision method and explore the surgical advancements in CP correction through a systematic review. METHODS: Patients with recurrent CP after MLR who underwent sutureless direct excision of the conjunctiva using loupe magnifiers at a tertiary hospital were included in this study. The clinical evolution and surgical results were recorded. PubMed, MEDLINE, EMBASE, and Web of Science databases were queried following The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. RESULTS: The comprehensive analysis of 1858 articles identified 88 patients from 24 studies, highlighting that blepharoptosis surgery is predominantly associated with CP (36.6%). Surgically treated CP showed a higher resolution rate compared to those managed conservatively (54.8% vs. 45.2%; p = 0.034). No relapse was observed in patients treated with sutureless direct excision of CP in long-term follow-up. CONCLUSION: We proposed a simple sutureless direct excision technique that offers a straightforward and efficient approach in treating CP, which is particularly suitable for cases requiring excision lengths >16 mm during MLR. Furthermore, stitch removal can be obviated after surgery.

Racial-Ethnic Gaps in Pandemic-Related Economic Hardship: Age Differences Among Older Adults.

OBJECTIVES: Racial-ethnic disparities in experiences of economic hardship during the pandemic are well documented in the population overall and among older adults. Existing research shows that this economic hardship was much less common at older than younger ages. Little is known about the intersection of racial-ethnic and age disparities in pandemic-related hardship in later life. This research report investigated racial-ethnic gaps in economic hardship by age group among older adults. METHODS: Data were from the 2018 and 2020 U.S. Health and Retirement Study (HRS) including the 2020 coronavirus disease 2019 module. We estimated Heckman-corrected linear probability models to examine differences in experiences of pandemic-related economic hardship in the 2020 HRS by race-ethnicity (non-Hispanic White, non-Hispanic Black, U.S.-born Hispanic, foreign-born Hispanic) across age groups (55-64, 65-74, 75+). In the multivariable analysis, we controlled for sociodemographic characteristics, participation in social programs, pre-existing health conditions and behaviors, and economic resources from the 2018 HRS. RESULTS: Experiences of economic hardship declined with age within each racial-ethnic group. Racial-ethnic gaps in hardship remained at older ages without any controls. However, when all controls were added, racial-ethnic gaps in economic hardship were eliminated for those ages 75+. Individual characteristics prior to the pandemic explained racial-ethnic differences in hardship for the oldest adults (75+) but did not explain gaps for those ages 55-74. DISCUSSION: Results point to structural factors generating new racial-ethnic gaps in pandemic-related economic hardship among those approaching retirement (ages 55-74) that did not affect the oldest adults (ages 75+).

Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion.

Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.

Enhancing antibody detection sensitivity in lateral flow immunoassays using endospores of Bacillus subtilis as signal amplifiers.

Antibody detection is the critical first step for tracking the spread of many diseases including COVID-19. Lateral flow immunoassay (LFIA) is the most commonly used method for rapid antibody detection because it is easy-to-use and inexpensive. However, LFIA has limited sensitivity when gold nanoparticles (AuNPs) are used as the signals. In this study, the endospores of Bacillus subtilis were used in combination with AuNP in a LFIA to detect antibodies. The endospores serve as a signal amplifier. The detection limit was about 10-8 M for anti-beta galactosidase antibody detection whereas the detection limit of conventional LFIA is about 10-6 M. Furthermore, the proposed methods have no additional user steps compared with the traditional LFIA. This method, therefore, improved the sensitivity 100-fold without compromising any advantages of LFIA. We believe that the proposed method will be useful for detection of antibodies against HIV, Zika virus, SARS-CoV-2, and so on.

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations.

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.

Immediate versus delayed sequential bilateral ICL implantation: A retrospective comparison of vault height and visual outcomes.

PURPOSE: To compare the visual outcomes and risks of suboptimal vault-related complications between immediate sequential bilateral ICL surgery (ISBICLS) and delayed sequential bilateral ICL surgery (DSBICLS). DESIGN: A retrospective cohort study. METHODS: Patients who underwent bilateral ICL implantation between November 2014 and December 2021 at the Eye and ENT Hospital of Fudan University (Shanghai, China) were included and divided into two groups: (1) ISBICLS: both eye surgeries performed on the same day, and (2) DSBICLS: second eye surgery performed < 7 days following the first one. Propensity score matching (PSM) was performed to compare the visual outcomes. Multivariable logistic regression models were used to estimate the odds ratios (ORs) of the suboptimal vaults. RESULTS: Finally, 10,985 eyes were included. After PSM, 204 first surgery eyes and 162 s surgery eyes with complete postoperative data were matched. The safety and efficacy indices did not statistically differ between groups (all > 1.00), except that ISBICLS first surgery eyes achieved better efficacy index than DSBICLS group (1.03 ± 0.26 vs. 1.08 ± 0.23, P = 0.034). Excessive vault was observed in eight (4.06 %) ISBICLS first eyes, one (0.50 %) DSBICLS first eye, and none in the second surgery eye in either group. An insufficient vault was observed in one second eye and one DSBICLS second eye. We found no evidence of differences in the rate of excessive vault (OR = 0.831, 95 % CI: 0.426-1.622, P = 0.588) or insufficient vault (OR = 0.609, 95 % CI:0.062-5.850, P = 0.668). CONCLUSION: ISBICLS provided safety, efficacy, and refraction predictability comparable to DSBICLS without increasing the risk of suboptimal vault-related complications.