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OBJECTIVES:. Continuous renal replacement therapy (CRRT) and shock are both associated with high morbidity and mortality in the ICU. Adult data suggest renoprotective effects of vasopressin vs. catecholamines (norepinephrine and epinephrine). We aimed to determine whether vasopressin use during CRRT was associated with improved kidney outcomes in children and young adults. DESIGN:. Secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), a multicenter, retrospective cohort study. SETTING:. Neonatal, cardiac, PICUs at 34 centers internationally from January 1, 2015, to December 31, 2021. PATIENTS/SUBJECTS:. Patients younger than 25 years receiving CRRT for acute kidney injury and/or fluid overload and requiring vasopressors. Patients receiving vasopressin were compared with patients receiving only norepinephrine/epinephrine. The impact of timing of vasopressin relative to CRRT start was assessed by categorizing patients as: early (on or before day 0), intermediate (days 1–2), and late (days 3–7). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 1016 patients, 665 (65%) required vasopressors in the first week of CRRT. Of 665, 248 (37%) received vasopressin, 473 (71%) experienced Major Adverse Kidney Events at 90 days (MAKE-90) (death, renal replacement therapy dependence, and/or > 125% increase in serum creatinine from baseline 90 days from CRRT initiation), and 195 (29%) liberated from CRRT on the first attempt within 28 days. Receipt of vasopressin was associated with higher odds of MAKE-90 (adjusted odds ratio [aOR], 1.80; 95% CI, 1.20–2.71; p = 0.005) but not liberation success. In the vasopressin group, intermediate/late initiation was associated with higher odds of MAKE-90 (aOR, 2.67; 95% CI, 1.17–6.11; p = 0.02) compared with early initiation. CONCLUSIONS:. Nearly two-thirds of children and young adults receiving CRRT required vasopressors, including over one-third who received vasopressin. Receipt of vasopressin was associated with more MAKE-90, although earlier initiation in those who received it appears beneficial. Prospective studies are needed to understand the appropriate timing, dose, and subpopulation for use of vasopressin.

Purpose: Increasing evidence suggests that ultra-high-dose-rate (UHDR) radiation could result in similar tumor control as conventional (CONV) radiation therapy (RT) while reducing toxicity to surrounding healthy tissues. Considering that radiation toxicity to gonadal tissues can cause hormone disturbances and infertility in young patients with cancer, the purpose of this study was to assess the possible role of UHDR-RT in reducing toxicity to healthy gonads in mice compared with CONV-RT. Methods and Materials: Radiation was delivered to the abdomen or pelvis of female (8 or 16 Gy) and male (5 Gy) C57BL/6J mice, respectively, at conventional (∼0.4 Gy/s) or ultrahigh (>100 Gy/s) dose rates using an IntraOp Mobetron linear accelerator. Organ weights along with histopathology and immunostaining of irradiated gonads were used to compare toxicity between radiation modalities. Results: CONV-RT and UHDR-RT induced a similar decrease in uterine weights at both studied doses (∼50% of controls), which indicated similarly reduced ovarian follicular activity. Histologically, ovaries of CONV- and UHDR-irradiated mice exhibited a comparable lack of follicles. Weights of CONV- and UHDR-irradiated testes were reduced to ∼30% of controls, and the percentage of degenerate seminiferous tubules was also similar between radiation modalities (∼80% above controls). Pairwise comparisons of all quantitative data indicated statistical significance between irradiated (CONV or UHDR) and control groups (from P ≤ .01 to P ≤ .0001) but not between radiation modalities. Conclusions: The data presented here suggest that the short-term effects of UHDR-RT on the mouse gonads are comparable to those of CONV-RT.

BACKGROUND: The ideal method for induction of labor is still not clearly defined. Recent reports in literature have shown that oral administration of low-dose misoprostol is as effective as vaginal administration for induction of labor. The use of vaginal misoprostol in combination with Foley catheter has been shown to shorten the period of induction. However, there are limited reports on the use of oral misoprostol in combination with Foley catheter. Given the convenience of oral administration, improved compliance relative to other methods is probable. This study proposed that the combination of oral misoprostol and Foley catheter would be a better means of inducing labor. OBJECTIVE: To compare the efficacy of combined low-dose oral misoprostol and Foley catheter with oral misoprostol alone for induction of labor at term gestation. The efficacy was compared in terms of the induction-to-delivery interval and the number of women delivering vaginally within 24 hours. The second objective was to document adverse events, if any, of the 2 protocols. STUDY DESIGN: The study was conducted at a tertiary care center and included 200 patients with indication for induction, randomly allotted to either of the 2 groups: group A (a combination of Foley catheter and 25-µg misoprostol every 2 hours orally) and group B (only 25-µg misoprostol every 2 hours orally), using computer-generated random number sequence. The obstetrical and neonatal outcomes were recorded and compared between the 2 groups. Quantitative variables were compared using unpaired and paired t-tests within the groups across follow-ups. RESULTS: Group A had significantly shorter mean induction-to-active-labor interval (10.67±1.75 vs 16.28±1.69 hours), mean induction-to-full-dilation interval (11.49 vs 19.00 hours), and mean induction-to-delivery interval (16.85 vs 21.90 hours). The proportion of women delivering vaginally within 24 hours was higher in group A (76 vs 57 women). In comparing maternal side effects, the only significant difference between the 2 groups was found in postpartum hemorrhage. A 5-minute Apgar score

Purpose: Surgeons fixing scaphoid fractures need to be familiar with their morphological variations and their implications for safe screw placement during fixation. The purpose of this computed tomography (CT)-based study was to analyze the anatomical limits of safe screw placement for scaphoid waist fractures in the Indian population. Methods: We measured the coronal and sagittal dimensions of the scaphoid in 3 zones: proximal, waist, and distal, in CT scans of wrists with intact scaphoids obtained from 50 live subjects. In addition, we studied the curvature of the scaphoid, its longitudinal extent, and the safe placement of trajectories for different screw diameters. Results: The proximal segment had the narrowest mean coronal width of 6.39 mm, whereas the waist region had the narrowest mean sagittal width of 9.02 mm. Mean scaphoid curvature was 132.23°. Maximal bony extent of the scaphoid was significantly higher than the mean length of screw placed centrally in the mid-waist region. Conclusions: This study showed that there is a considerable amount of variation in scaphoid morphometry in Indian patients. All scaphoids capable of safely containing a single 4-mm screw or 2 parallel 1.7-mm screws coplanar in the sagittal plane. Surgeons treating these fractures should consider a CT-based analysis to plan the screw direction and length and need to be familiar with the morphometric variations of the scaphoid. Clinical relevance: The measurements and techniques in this study may be helpful in understanding morphometric variations of the scaphoid and in planning surgery for fixation of fractures around its waist region. Key words: scaphoid curvature, scaphoid morphometry, scaphoid screw, screw trajectory, waist fractures

Background: To evaluate the midterm clinical outcome, functional outcome, associated complications, and survivorship of high-flexion posterior-stabilized rotating-platform total knee arthroplasty. Methods: We prospectively analyzed 701 knees in 501 patients, who underwent total knee arthroplasty using high-flexion posterior-stabilized rotating-platform prosthesis. Patients were assessed preoperatively and postoperatively for their ability to kneel, do full squats, do half squats, and sit cross-legged by using a patient-administered questionnaire. Results: Significant improvement was seen in patient-reported outcomes at the mean follow-up of 5.5 (range, 5-7) years. Mean flexion achieved postoperatively was 135° (range, 120°-150°) from a mean preoperative flexion of 108.8° (range, 90°-120°). Ninety-five percent of patients were able to sit cross-legged, 90% were able to kneel, 70% were able to perform a half squat, and 20% were able to perform a full squat. Conclusions: Posterior-stabilized, rotating-platform, high-flexion design provides good postoperative flexion, functional outcome, and good midterm survivorship.

Content validity of the 18-item Investigator-Rated Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale IV (I-ADHD RS-IV) with adult prompts was investigated using qualitative interviews of US clinicians who had prior experience rating adults with phenylketonuria (PKU) using the I-ADHD RS-IV. Fourteen qualitative interviews were conducted to obtain key symptom experiences of adults with PKU and assessed the relevance, clarity, and administration of the I-ADHD RS-IV. Participants (n = 13, 92.9%) endorsed the inattention symptoms as key experiences by adults with PKU and endorsed the instrument as fit for purpose for adults with PKU. Participants generally reported low frequencies of occurrence for the 9 I-ADHD RS-IV hyperactivity/impulsivity items. Despite some clinicians’ concerns for the lack of patient self-awareness, the participants reported no difficulty selecting a rating on these items. This in-depth study of the content validity of the I-ADHD RS-IV provides evidence that this clinician-reported instrument captures the severity of important inattention symptoms in adults with PKU.

Adults with phenylketonuria (PKU) experience disturbances in mood. This study used qualitative and quantitative techniques to adapt the 65-item Profile of Mood States (POMS) for the assessment of key mood domains in adults with PKU. First, cognitive interviews on 58 POMS items (excluding 7 Friendliness domain items) among 15 adults and adolescents (age ≥16 years) with PKU were conducted to eliminate items poorly understood or considered irrelevant to PKU; 17 items were removed. Next, the remaining POMS items were quantitatively examined (Mokken scaling and Rasch analysis) in 115 adult patients with PKU. An additional 21 items were removed iteratively, resulting in the 20-item draft PKU-POMS. Finally, the psychometric properties of the draft PKU-POMS were examined. The instrument displayed strong psychometric properties (reliability, validity, and responsiveness) over 6 domains (Anxiety, Depression, Anger, Activity, Tiredness, and Confusion) and all items were well understood in the final cognitive interviews with 10 adults with PKU.

Geriatric hip fractures are a challenging clinical problem throughout the world. Hip fracture services have been shown to shorten time to surgery, decrease the cost of admissions, and improve the outcomes. We instituted a geriatric hip fracture program for comanagement of these injuries by orthopedic and internal medicine teams at our hospital in India. From January 2010 till December 2011, 119 patients with a femoral neck fracture were treated with cemented modular hemiarthroplasty under this program using a cost-effective Indian implant. The cohort included 63 males and 56 females with a mean age of 70.7 years (range 55-98 years). Hypertension (n = 42) and diabetes mellitus (n = 29) were the most common comorbidities. The follow-up period ranged from 12 to 37 months with an average of 24 months. The surgery was performed within 24 hours of admission in 60.5% (n = 72) patients. The use of antiplatelet drugs was the most common reason for delay of surgery. The mean length of hospital stay was 10.4 days (range 3-24 days) with 77% (n = 92) of patients discharged within 1 week of admission. On follow-up, good to excellent Harris hip scores were seen in 88% of patients with 76% of patients returning to the preinjury ambulatory status. The mortality rate was 6% at 6 months follow-up and 10.9% at 2 years. Our study shows that a hip fracture program can be instituted in India. The program helped us in achieving the goal of early surgery, mobilization, and discharge from hospital with decreased mortality.

Aims and Background: Dentin hypersensitivity (DH) is characterized by sharp shooting pain due to exposed dentin, and the most common method for treating this pain is the occlusion of the dentinal tubules with the help of desensitizing agents. E-silver diamine fluoride (e-SDF) (Kids-e-Dental, Mumbai, India) is a commercially available 38% SDF solution in the Indian market. Despite the fact that its application for caries prevention has been proven, the fluoride (Fl) and silver (Ag) ion concentrations of e-SDF for use in treating DH have yet to be standardized. The aim of this study is to determine and compare the Fl and Ag ion concentrations released from two commercially available 38% silver diamine fluoride (SDF) solutions., Materials and Methods: The two most common commercially available 38% SDF solution brands, namely Advantage Arrest and e-SDF were used. Two drops of each of these solutions were taken in three beakers and diluted with distilled water. The Fl ion concentration was evaluated using a calibrated ion-specific electrode. The free Ag ion concentration was assessed using an atomic absorption spectrometry (AAS)., Results: Release of Ag ions shows that on days 1, 2, 5, 6, and 7, concentration (mg/L) was higher in the Advantage Arrest group but is statistically nonsignificant. On days 3 and 4, it is higher in an e-SDF group with a t -value of 1.085 and 0.243 and is statistically nonsignificant. Release of Fl ion showed that in comparison to the baseline, it was more with Advantage Arrest on days 2, 4, and 7 with a t -value of -3.766, -0.999, and 0.347 and on day 2 was statistically significant. On days 3, 5, and 6 Fl ion release from baseline was more with e-SDF in comparison with Advantage Arrest but statistically insignificant., Conclusion: The AAS analysis as well as the ion chromatography showed that the Ag and Fl ion release respectively on days 1-7 from e-SDF was similar to the one seen in the case of Advantage Arrest., Clinical Significance: This helps dentists choose among different brands of the same commercially available 38% SDF solutions depending on the cost and availability of the product., How to Cite This Article: Kamath P, Kamath P, P AN, et al. Evaluation of Fluoride and Silver Ion Concentrations in e-Silver Diamine Fluoride and Advantage Arrest: An Ion Chromatography and Atomic Absorption Spectrometer Study. Int J Clin Pediatr Dent 2024;17(10):1141-1145., Competing Interests: Source of support: Nil Conflict of interest: Dr Ashwin Rao is associated as the National Editorial Board member of this journal and this manuscript was subjected to this journal's standard review procedures, with this peer review handled independently of this editorial board member and his research group.Conflict of interest: Dr Ashwin Rao is associated as the National Editorial Board member of this journal and this manuscript was subjected to this journal's standard review procedures, with this peer review handled independently of this editorial board member and his research group., (Copyright © 2024; The Author(s).)

This paper aims to emphasize the occurrence of various emerging contaminant (EC) mixtures in natural ecosystems and highlights the primary concern arising from the unregulated release into soil and water, along with their impacts on human health. Emerging contaminant mixtures, including pharmaceuticals, personal care products, dioxins, polychlorinated biphenyls, pesticides, antibiotics, biocides, surfactants, phthalates, enteric viruses, and microplastics (MPs), are considered toxic contaminants with grave implications. MPs play a crucial role in transporting pollutants to aquatic and terrestrial ecosystems as they interact with the various components of the soil and water environments. This review summarizes that major emerging contaminants (ECs), like trimethoprim, diclofenac, sulfamethoxazole, and 17α-Ethinylestradiol, pose serious threats to public health and contribute to antimicrobial resistance. In addressing human health concerns and remediation techniques, this review critically evaluates conventional methods for removing ECs from complex matrices. The diverse physiochemical properties of surrounding environments facilitate the partitioning of ECs into sediments and other organic phases, resulting in carcinogenic, teratogenic, and estrogenic effects through active catalytic interactions and mechanisms mediated by aryl hydrocarbon receptors. The proactive toxicity of ECs mixture complexation and, in part, the yet-to-be-identified environmental mixtures of ECs represent a blind spot in current literature, necessitating conceptual frameworks for assessing the toxicity and risks with individual components and mixtures. Lastly, this review concludes with an in-depth exploration of future scopes, knowledge gaps, and challenges, emphasizing the need for a concerted effort in managing ECs and other organic pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy w /dy w ) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy 2J /dy 2J ) LAMA2-RD mouse model and the (Col6a1 -/- ) COL6-RD mouse model demonstrated decreased apoptosis., Methods: A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data., Results: Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC 0-24h ) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study., Discussion: This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations., Classification of Evidence: This study provides Class IV evidence of omigapil in a dose-finding phase 1 study., Trial Registration Information: Clinical Trials NCT01805024., Competing Interests: A.R. Foley, P. Yun, M.E. Leach, S. Neuhaus, G. Averion, Y. Hu, L.H. Hayes, S. Donkervoort, M. Jain, M. Waite, R. Parks, D.X. Bharucha-Goebel, O.H. Mayer, Y. Zou, M. Fink, J. DeCoster, C. Mendoza, C. Arévalo, and K. Cheung report no disclosures relevant to the manuscript; R. Hausmann was an employee and a shareholder of Santhera Pharmaceuticals at the time of this study; D. Petraki was an employee of Santhera Pharmaceuticals at the time of this study; C.G. Bönnemann was the site principal investigator for this study sponsored by Santhera Pharmaceuticals. Go to Neurology.org/NG for full disclosures., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Aim: To compare the sealing ability of three different materials when used as postendodontic restoration barriers to coronal microleakage in root-filled teeth., Materials and Methods: In the present study, 60 single-rooted mandibular premolars with single canals were selected. After endodontic treatment was done with protaper files, they were divided into three groups of 20 teeth each, which were restored with Zirconomer (Group I), Hi-Dense (Group II), and Surefil composite (Group III), respectively. After storing in artificial saliva for 10 days, all teeth were then immersed in Rhodamine 6G fluorescent dye. Teeth were then sectioned buccolingually in a longitudinal direction. The coronal microleakage was measured in both halves under a fluorescence microscope and images were taken with a digital camera. Data obtained from the study in the form of scoring as per specific criteria was subjected to statistical analysis., Result: Results of the study showed that the minimum amount of coronal microleakage was seen in Group II restored with Hi-Dense followed by Group III restored with Surefil Composite and the maximum amount of coronal microleakage was seen in Group I restored with Zirconomer., Conclusion: On the basis of the results of the present study, it may be concluded that Hi-Dense showed better coronal sealing ability in access cavities. Surefil composite exhibited coronal microleakage less than Zirconomer but more than Hi-Dense., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Pharmacy and Bioallied Sciences.)

Background: RYR1 -related myopathies ( RYR1 -RM) are caused by pathogenic variants in the RYR1 gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1 -RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1 -RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1 -RM., Methods: Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021., Findings: S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination., Interpretation: S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1 -RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1 -RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1 -RM., Funding: NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier., Competing Interests: E.E.M is an employee of ARMGO Pharma, Inc., during the conduct of the study; an employee of ARMGO Pharma, Inc., outside the submitted work; In addition, E.E.M has a patent US2023/0372358 pending. Y.W is an employee of ARMGO Pharma, Inc. In addition, Y.W has a patent US8853198 issued. A.R.M. is a co-founder of ARMGO Pharma Inc, chairs the Scientific Advisory Board of ARMGO Pharma Inc., and holds stock in the company. All other authors declare no conflict of interest with the research in this manuscript., (© 2024 The Author(s).)

The construction industry substantially impacts a country's economic growth and ecological progress. Due to the competitive nature of the construction business and intense rivalry between construction companies, the industry's focus is progressively becoming customer-centric. Efforts are being taken to ensure high-quality buildings are built at reasonable rates and on time. Companies are trying to ensure on-time building projects are completed within allocated budgets. This can be accomplished by ensuring minimal waste generation from various activities during the construction process. Implementing lean tools and techniques can improve work efficiency and reduce waste in the building process. This research study offers a basic understanding of lean tools and emphasizes their contribution in terms of time, effort, and sustainability. The primary purpose of this study is to present the effectiveness of the lean process for construction waste management. Through a case study, this research shows the deployment of lean tools and principles for efficient construction waste management and optimal use of building resources. The improvement in reduced waste generation and enhanced organizational resource productivity is closely monitored. The study results indicated that the lean framework could reduce waste by 25 to 50%. It is demonstrated that lean construction significantly improves construction sustainability and productivity. If it is implemented along with automation tools and circular economy concepts, more than 50% of waste reduction can be achieved. These viable initiatives are necessary to improve the performance of the Indian construction industry to achieve circularity in waste management which indirectly helps in the sustainability goals of the construction sector., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background : The angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated blood ACE is a marker for granulomatous diseases and elevated ACE expression in tissues is associated with increased risk of cardiovascular diseases. Objective and Methodology: We applied a novel approach -ACE phenotyping-to find a reason for conformationally impaired ACE in the blood of one particular donor. Similar conformationally altered ACEs were detected previously in 2-4% of the healthy population and in up to 20% of patients with uremia, and were characterized by significant increase in the rate of angiotensin I hydrolysis. Principal findings: This donor has (1) significantly increased level of endogenous ACE inhibitor in plasma with MW less than 1000; (2) increased activity toward angiotensin I; (3) M71V mutation in ABCG2 (membrane transporter for more than 200 compounds, including bilirubin). We hypothesize that this patient may also have the decreased level of free bilirubin in plasma, which normally binds to the N domain of ACE. Analysis of the local conformation of ACE in plasma of patients with Gilbert and Crigler-Najjar syndromes allowed us to speculate that binding of mAbs 1G12 and 6A12 to plasma ACE could be a natural sensor for estimation of free bilirubin level in plasma. Totally, 235 human plasma/sera samples were screened for conformational changes in soluble ACE. Conclusions/Significance: ACE phenotyping of plasma samples allows us to identify individuals with conformationally altered ACE. This type of screening has clinical significance because this conformationally altered ACE could not only result in the enhancement of the level of angiotensin II but could also serve as an indicator of free bilirubin levels.

Single cell data integration methods aim to integrate cells across data batches and modalities, and data integration tasks can be categorized into horizontal, vertical, diagonal, and mosaic integration, where mosaic integration is the most general and challenging case with few methods developed. We propose scMoMaT, a method that is able to integrate single cell multi-omics data under the mosaic integration scenario using matrix tri-factorization. During integration, scMoMaT is also able to uncover the cluster specific bio-markers across modalities. These multi-modal bio-markers are used to interpret and annotate the clusters to cell types. Moreover, scMoMaT can integrate cell batches with unequal cell type compositions. Applying scMoMaT to multiple real and simulated datasets demonstrated these features of scMoMaT and showed that scMoMaT has superior performance compared to existing methods. Specifically, we show that integrated cell embedding combined with learned bio-markers lead to cell type annotations of higher quality or resolution compared to their original annotations., (© 2023. The Author(s).)

Background: High-flow fistulas related to plexiform nidi are found in 40% of large brain arteriovenous malformations (AVMs). Endovascular occlusion of intranidal fistulas before plexiform components is empirically considered safe, but potential ensuing dangerous re-routing of flow through plexiform vessels may in theory raise their rupture risk. It remains unclear whether it is safer to embolize plexiform or fistulous vessels initially. We used a novel biomathematical AVM model to compare theoretical hemodynamic changes and rupture risks on sequential embolizations of both types of nidus vessels., Methods: We computationally modeled a theoretical AVM as an electrical circuit containing a nidus consisting of a massive stochastic network ensemble comprising 1000 vessels. We sampled and individually simulated 10 000 different nidus morphologies with a fistula angioarchitecturally isolated from its adjacent plexiform nidus. We used network analysis to calculate mean intravascular pressure (P mean ) and flow rate within each nidus vessel; and Monte Carlo analysis to assess overall risks of nidus rupture when simulating sequential occlusions of vessel types in all 10 000 nidi., Results: We consistently observed lower nidus rupture risks with initial fistula occlusion in different network morphologies. Intranidal fistula occlusion simultaneously reduced P mean and flow rate within draining veins., Conclusions: Initial occlusion of AVM fistulas theoretically reduces downstream draining vessel hypertension and lowers the risk of rupture of an adjoining plexiform nidus component. This mitigates the theoretical concern that fistula occlusion may cause dangerous redistribution of hemodynamic forces into plexiform nidus vessels, and supports a clinical strategy favoring AVM fistula occlusion before plexiform nidus embolization., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: cardiac valvular diseases (CVDs) are the major cause of cardiovascular morbidity and mortality globally, with predominance of rheumatic heart disease (RHD) in developing countries. Congenital heart defects (CHD) diagnoses are delayed due to socioeconomic factors. This study aims to evaluate the post-operative surgical outcomes of CHD and valvular RHD., Methods: this study is conducted with 50 patients from Chad, operated on between 2003 and 2012. Post-operative outcomes are evaluated from 2010 to 2012., Results: with the follow-up of 19 RHD patients who underwent plasty, 8 (42.1%) had no complications, 4 (21%) presented with mild regurgitation, 7 (36.8%) required re-operation due to 6 mitral stenosis (MS) cases (mitral surface range from 0.7 to 1.2 cm 2 ) and 1 severe mitral regurgitation (MR) case. While those patients with valve replacement, 2 (50%) had no complications, 1 (25%) had mild regurgitation and 1 (25%) patient died. Two patients with aortic regurgitation (AR) that underwent annuloplasty presented with severe regurgitation. Regarding AR with valve replacement, 3 (60%) had no complications, and 2 (40%) had mild regurgitation. Among the tricuspid regurgitation (TR) patients who had plasty, 6 (85.7%) had no complications, and 1 (14.3%) had severe regurgitation. The surgical repair was curative in all CHD patients. The loss to follow-up rate was 13/50 (26%)., Conclusion: the annuloplasty on rheumatic valve disease (MR and AR) has proven to be disappointing. Plasty is debated without justified indication for AR. The outcomes of CHD, mitral and aortic valve replacement are successful., Competing Interests: The authors declare no competing interests., (Copyright: Neguemadji Ngardig Ngaba et al.)

Meniscus tears are a common orthopedic pathology and planning a single, effective treatment is challenging. The diagnosis of meniscal tears requires detailed history-taking, physical examinations, special diagnostic tests, and most likely magnetic resonance imaging (MRI) to confirm the lesion. A good understanding of the meniscal structure including vascularity, zones, function, and affected movements with associated symptoms plays a crucial role in establishing an optimal management plan. A careful assessment of the patient's characteristics, comorbidities, post-repair rehabilitation, and patient's overall function and satisfaction are also important for ideal management. While conservative management is commonly implemented and the only option for certain patients, partial meniscectomy remains to be the most performed treatment procedure. However, partial meniscectomy is no longer the first-line therapy due to the limitation of certain patient characteristics and side effects in the long run. Instead, meniscal repair has been shown to have better long-term outcomes and is therefore recommended for all tears, especially for young patients with acute traumatic lesions. Tissue engineering has been of high interest in the current research with promising therapeutic results. This review critically evaluates and compares the management of meniscal tears with surgical versus comprehensive management using the current literature., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Luvsannyam et al.)

Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present сell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues. Cell2location accounts for technical sources of variation and borrows statistical strength across locations, thereby enabling the integration of single-cell and spatial transcriptomics with higher sensitivity and resolution than existing tools. We assessed cell2location in three different tissues and show improved mapping of fine-grained cell types. In the mouse brain, we discovered fine regional astrocyte subtypes across the thalamus and hypothalamus. In the human lymph node, we spatially mapped a rare pre-germinal center B cell population. In the human gut, we resolved fine immune cell populations in lymphoid follicles. Collectively, our results present сell2location as a versatile analysis tool for mapping tissue architectures in a comprehensive manner., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Schizophrenia is a debilitating disease that presents with both positive and negative symptoms affecting cognition and emotions. Extensive studies have analyzed the different factors that contribute to the disorder. There is evidence of significant genetic etiology involving multiple genes such as dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1). There is no clear link between neurotransmitter changes and the pathophysiology of schizophrenia; however, studies have shown that subcortical dopamine dysfunction is the key mechanism. Specific regions of gray and white matter changes are observed in patients with schizophrenia; gray matter changes being more significant after the onset of psychosis. These pathological changes may be implicated in the impairment of executive functioning, attention, and working memory. The disease can be managed with pharmacological treatments based on individual patient profile, patient compliance, and disease severity. The challenge of disease management sometimes persists due to the side effects. A better understanding of the pathological processes in schizophrenia may lead to more specific and effective therapies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Luvsannyam et al.)

Bile cast nephropathy (BCN) or cholemic nephropathy (CN) is an acute renal dysfunction, including acute kidney injury (AKI) in the setting of liver injury. It is a common phenomenon in patients with liver disease and is associated with significant morbidity and mortality. CN is characterized by hemodynamic changes in the liver, kidney, systemic circulation, intratubular cast formation, and tubular epithelial cell injury. CN has been overlooked as a differential diagnosis in chronic liver disease patients due to more importance to hepatic injury. However, frequent and considerable reporting of case reports recently has further investigated this topic in the last two decades. This review determines the evidence behind the potential role of bile acids and bilirubin in acute renal dysfunction in liver injury, summarizing the implied pathophysiology risk factors, and incorporating the therapeutic mechanisms and outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Somagutta et al.)

Frailty is a complex age-related clinical condition with increased vulnerability to negative health outcomes that manifest as a multidimensional syndrome and hence, a challenge to identify at-risk populations. We aim to summarize the implementation of strategies to diagnose fragility in family practice using current evidence. We searched the PubMed and Google Scholar databases for relevant articles, using the Medical Subject Headings (MeSH) terms "Frailty," "Frailty Scales," and "Primary Health Care." All original research articles on the elderly population (65 years of age or older) published in English and the last five years were included. Frailty diagnosis has resulted in positive outcomes in the overall literature. Recent hospital admission may indicate a health problem that can end up in a negative outcome and has been often described as associated with frailty. It was also shown to affect the intensive care units' mortality, in-hospital mortality, and long-term mortality. However, multiple screening instruments have been developed and validated to improve feasibility in clinical practice. The frequent lack of agreement between frailty instruments has slowed the broad implementation of these tools. The impacts of frailty warrant an upstream, proactive, holistic, interprofessional primary care approach to its identification, assessment, and management. It is a preventable disorder; identifying elderly patients at risk in primary care can help shape appropriate care processes tailored to their needs. This literature review aims to demonstrate the importance and strategies in identifying frailty in primary care settings and assess its impact on several outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Somagutta et al.)

Statins are a class of lipid-lowering medications used worldwide by millions of people and are safe for frequent use in most patients. However, they cause necrotizing autoimmune myopathy in some patients. We reviewed case reports of 80 patients from 2010 to present diagnosed with statin-induced necrotizing autoimmune myopathy (SINAM), aiming to analyze the clinical, physiological, serologic characteristics and outcomes of SINAM. The mean age of these patients was 66 ±9.4, the majority being male (61.3%). All patients reported proximal muscle weakness, and a few had myalgias, extra muscular symptoms such as dysphagia, and pulmonary complications. Most of the patients were on atorvastatin, simvastatin, or rosuvastatin. The mean creatine kinase was 10,094.2 ±7,351.7 U/l, and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme was positive for 93.8% of patients. The majority of patients were started on steroids; other treatments were also used. Prompt cessation of statins and initiation of immunosuppressants reduced morbidity and mortality., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie.)

Multimodal data is rapidly growing in many fields of science and engineering, including single-cell biology. We introduce MultiMAP, a novel algorithm for dimensionality reduction and integration. MultiMAP can integrate any number of datasets, leverages features not present in all datasets, is not restricted to a linear mapping, allows the user to specify the influence of each dataset, and is extremely scalable to large datasets. We apply MultiMAP to single-cell transcriptomics, chromatin accessibility, methylation, and spatial data and show that it outperforms current approaches. On a new thymus dataset, we use MultiMAP to integrate cells along a temporal trajectory. This enables quantitative comparison of transcription factor expression and binding site accessibility over the course of T cell differentiation, revealing patterns of expression versus binding site opening kinetics., (© 2021. The Author(s).)

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception 1,2 , yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21)., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated ACE expression in tissues (which is generally reflected by ACE in blood) is associated with increased risk of cardiovascular diseases. Elevated ACE in blood is also a marker for granulomatous diseases., Methods: We applied our novel approach-ACE phenotyping-to characterize serum ACE in 300 unrelated patients and to establish normal values for ACE levels. ACE phenotyping includes (a) determination of ACE activity with 2 substrates (Z-Phe-His-Leu [ZPHL] and Hip-His-Leu [HHL]), (b) calculation of a ratio for hydrolysis of ZPHL and HHL, and (c) quantification of ACE immunoreactive protein levels and ACE conformation with a set of monoclonal antibodies (mAbs) to ACE., Results: Only a combination of ACE activity determination with 2 substrates and quantification of the amount of ACE immunoreactive protein with mAbs 1G12 and 9B9 allows for the unequivocal detection of the presence of ACE inhibitors in the blood. After excluding such subjects, we were able to establish normal values of ACE in healthy populations: 50%-150% from control pooled serum. This ACE phenotyping approach in screening format with special attention to outliers can also identify patients with various mutations in ACE and may help to identify the as yet unknown ACE secretase or other mechanistic details of precise regulation of ACE expression., Conclusions: ACE phenotyping is a promising new approach with potential clinical significance to advance precision medicine screening techniques by establishing different risk groups based on ACE phenotype., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Previous studies have suggested favorable outcomes of hydrocortisone, ascorbic acid (vitamin C), and thiamine (HAT) therapy in patients with sepsis. However, similar results have not been duplicated in sequential studies. This meta-analysis aimed to reevaluate the value of HAT treatment in patients with sepsis. Electronic databases were searched up until October 2020 for any studies that compared the effect of HAT versus non-HAT use in patients with sepsis. Data from 15 studies (eight randomized controlled trials [RCTs] and seven cohort studies) involving 67,349 patients were included. The results from the RCTs show no significant benefit of triple therapy on hospital mortality (risk ratio [RR], 0.99; P=0.92; I2=0%); intensive care unit (ICU) mortality (RR, 0.77; P=0.20; I2=58%); ICU length of stay (weighted mean difference [WMD], 0.11; P=0.86; I2 =37%) or hospital length of stay (WMD: 0.57; P=0.49; I2=17%), and renal replacement therapy (RR, 0.64; P=0.44; I2=39%). The delta Sequential Organ Failure Assessment (SOFA) score favored treatment after a sensitivity analysis (WMD, -0.72; P=0.01; I2=32%). However, a significant effect was noted for the duration of vasopressor use (WMD, -25.49; P<0.001; I2=46%). The results from cohort studies have also shown no significant benefit of HAT therapy on hospital mortality, ICU mortality, ICU length of stay, length of hospital stay, the delta SOFA score, the use of renal replacement therapy, or vasopressor duration. HAT therapy significantly reduced the duration of vasopressor use and improved the SOFA score but appeared not to have significant benefits in other outcomes for patients with sepsis. Further RCTs can help understand its benefit exclusively.

An elevated blood angiotensin I-converting enzyme (ACE) supports diagnosis of sarcoidosis and Gaucher disease. However, some ACE mutations increase ACE shedding, and patients with these mutations are therefore at risk of being incorrectly diagnosed with sarcoidosis because of elevated serum ACE levels. We applied a novel approach called "ACE phenotyping" to identify possible ACE mutations in 3 pulmonary clinic patients that had suspected sarcoidosis based on elevated blood ACE levels. Conformational fingerprinting of ACE indicated that these mutations may be localized in the stalk region of the protein and these were confirmed by whole exome sequencing. Index patient 1 (IP1) had a mutation (P1199L) that had been previously identified, while the other 2 patients had novel ACE mutations. IP2 had 2 mutations, T887M and N1196K (eliminating a putative glycosylation site), while IP3 had a stop codon mutation Q1124X (eliminating the transmembrane anchor). We also performed a comprehensive analysis of the existing database of all ACE mutations to estimate the proportion of mutations increasing ACE shedding. The frequency of ACE mutations resulting in increased blood ACE levels may be much higher than previously estimated. ACE phenotyping, together with whole exome sequencing, is a diagnostic approach that could prevent unnecessary invasive and/or costly diagnostic procedures, or potentially harmful treatment for patients misdiagnosed on the basis of elevated blood ACE levels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Nemaline myopathy (NM) is a rare neuromuscular condition with clinical and genetic heterogeneity. To establish disease natural history, we performed a cross-sectional study of NM, complemented by longitudinal assessment and exploration of pilot outcome measures., Methods: Fifty-seven individuals with NM were recruited at 2 family workshops, including 16 examined at both time points. Participants were evaluated by clinical history and physical examination. Functional outcome measures included the Motor Function Measure (MFM), pulmonary function tests (PFTs), myometry, goniometry, and bulbar assessments., Results: The most common clinical classification was typical congenital (54%), whereas 42% had more severe presentations. Fifty-eight percent of individuals needed mechanical support, with 26% requiring wheelchair, tracheostomy, and feeding tube. The MFM scale was performed in 44 of 57 participants and showed reduced scores in most with little floor/ceiling effect. Of the 27 individuals completing PFTs, abnormal values were observed in 65%. Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure. Genotypes included mutations in ACTA1 (18), NEB (20), and TPM2 (2). Seventeen individuals were genetically unresolved. Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype. Patients without genetic resolution had more severe disease., Conclusion: We present a comprehensive cross-sectional study of NM. Our data identify significant disabilities and support a relatively stable disease course. We identify a need for further diagnostic investigation for the genetically unresolved group. MFM, PFTs, and the slurp test were identified as promising outcome measures for future clinical trials., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)