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The success behind effective project management lies in estimating the time for individual activities. In many cases, these activity times are non-deterministic. In such situations, the conventional method (project evaluation and review technique (PERT)) obtains three time estimates, which are then used to calculate the expected time. In practice, it is often difficult to get three accurate time estimates. A recent paper suggests using just two time estimates and an approximation of the normal distribution to obtain the expected time and variance for that activity. In this paper, we propose an alternate method that uses only two bits of information: the most-likely and either the optimistic or the pessimistic time. We use a lognormal approximation and experimental results to show that our method is not only better than the normal approximation, but also better than the conventional method when the underlying activity distributions are moderately or heavily right skewed. doi: 10.1057/palgrave.jors.2602204 Published online 3 May 2006 Keywords: PERT; lognormal distribution; estimation; probability

Background Caudal epidural analgesia is the most common regional anesthetic performed in infants. Dural puncture, the most common serious complication, is inversely proportional to age. Measuring the distance from the sacrococcygeal membrane to the dural sac may prevent dural puncture. This study measures the sacrococcygeal membrane to dural sac distance using ultrasound imaging to determine feasibility of imaging and obtaining measurements. Methods Sacral ultrasound imaging of 40 preterm neonates was obtained in left lateral decubitus, a typical position for caudal blockade. No punctures were made. The sacrococcygeal membrane and termination of the dural sac were visualized, and the distance measured. The spinal levels of the conus medullaris and dural sac termination were recorded. Results 20 males and 20 females former preterm neonates with an average weight (SD; range) of 1740 (290; 860-2350) g and average age (SD; range) of 35.0 (1.35; 32.2-39) weeks gestational age at the time of imaging. The average sacrococcygeal membrane to distal dural sac distance (SD; range) was 17.4 (3.1; 10.6-26.3) mm. Overall, the weights correlated positively with the distance but the coefficient of variation was large at 23%. The conus medularis terminated below the L3 level and dural sac below the S3 level in 20% and 10% of subjects respectively with hip flexion. Conclusion Ultrasound can be used to measure the sacrococcygeal membrane to dura distance in preterm neonates prior to needle insertion when performing caudal block and demonstrates large variability. Ultrasound imaging may identify patients at risk for dural puncture. When ultrasound is not available, needle insertion less than 3 mm/kg beyond the puncture of the sacrococcygeal membrane should prevent dural contact in 99.9% of neonates. [ABSTRACT FROM AUTHOR]

The purpose of this research is to measure the flexural strength of both traditional and newly modified concrete beams with kaolinite coal added. Two sets of eighteen samples each were ready for the data collection. Two sets of specimensare prepared: 18 specimens of one set using modified concrete that has been treated with kaolinite coal, and the other set of 18 specimens using traditional concrete beams. The preparation and examination of the samples involved the use of flexural strength test equipment. The beam specimen size was taken as 100 x 100 x 500mm. The SPSS software version 29 has been utilized to conduct the independent sample T-test. The statistical analysis included Levene's test for equality of variances and a t-test for equality of means to assess the flexural strength of two groups. Levene's test revealed a significant difference in variances between the groups (F=2.909, p=0.097). Subsequently, the t-test assuming equal variances indicated a highly significant difference in means (t=-16.954, df=34, p=0.000). The mean difference in flexural strength was -1.43578, with a standard error of 0.08469 and a 95% confidence interval ranging from -1.60788 to -1.26367. The t-test assuming unequal variances corroborated the significant difference in means (t=-16.954, df=29.822, p=0.000), with a consistent mean difference and confidence interval. The modified concrete beam sample with kaolinite coal added has a mean flexural strength of 4.75 N/mm2, while the standard concrete beam sample has a mean flexural strength of 2.73 N/mm2.

Abstract: Background: Necrotising enterocolitis (NEC) is one of the most common life‐threatening emergencies of the gastrointestinal tract in preterm neonates. The present study aimed to determine the efficacy of oropharyngeal colostrum with respect to reducing NEC in preterm neonates. Methods: A literature search was conducted for various randomised control trials by searching the Cochrane Central Register of Controlled Trials, PubMed, EMBASE and ongoing clinical trials. Randomised or quasi‐randomised trials comparing oropharyngeal colostrum versus placebo in neonates (birthweight ≤ 1500 g or gestational age ≤ 32 weeks) were included in the review. The methodological quality of each trial was independently reviewed by the authors. For categorical and continuous variables, typical estimates for relative risk and typical estimates for weighted mean difference were calculated, respectively. A random effect model was assumed for meta‐analysis. Results: In total, four eligible trials were included in the review. Oropharyngeal colostrum therapy was not associated with a statistically significant reduction in the incidence of NEC stage ≥2 [typical relative risk (RR) = 0.64; 95% confidence interval (CI) = 0.27–1.49], mortality from any cause (typical RR = 0.86; 95% CI = 0.15–4.80) and time to reach full feed [typical weighted mean difference (WMD) = −3.26; 95% CI = −8.87 to 2.35]. Duration of hospital stay was significantly less in the control group (typical WMD = 9.77; 95% CI = 3.96–15.59). Conclusions: The current evidence is insufficient for recommending oropharyngeal colostrum as a routine clinical practice in the prevention of NEC. We emphasise the need for large randomised controlled trials with an adequate sample size and validated clinical outcomes in preterm neonates. [ABSTRACT FROM AUTHOR]

To improve the understanding of the life history and ecology of one of Europe's most elusive fishes, the short-snouted seahorse Hippocampus hippocampus, data from wild populations in a shallow coastal lagoon in southern Portugal were analysed. The data were collected from 17 tagged seahorses on a focal-study grid as well as from >350 seahorses encountered during underwater visual surveys and a fishery-independent study using beach seines. These populations of settled juveniles and adults had a mean population density of 0·009 m−2. During the study period (2000-2004), reproduction peaked in July and August. Juveniles recruited to the lagoon at c. 66 mm standard length ( LS) and 0·5 years of age and established small home ranges (0·8 to 18·2 m2). First reproduction was estimated at 100 mm and 1 year of age. Based on a fitted von Bertalanffy model, H. hippocampus grew quickly (growth coefficient K = 0·93) to a maximum theoretical size L ∞ = 150 mm and have a maximum lifespan of c. 3·2 years. Courtship behaviours were consistent with the maintenance of pair bonds and males brooded multiple batches of young per year. Estimated annual reproductive output averaged 871 young (±632). Together these analyses provide the first life-history parameters for this species and indicate that H. hippocampus bears characteristics of opportunist and intermediate strategists. Such populations are predicted to exhibit large fluctuations in abundance, making them vulnerable to extended periods of poor recruitment. [ABSTRACT FROM AUTHOR]

Summary: Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir’s antiviral activity as much as 10-fold, while those that only inhibit Mpro do not synergize with remdesivir.

Hollow fiber membranes are used widely in membrane separation processes because of their high surface area to volume ratio. Several models have been developed for the hollow fiber spinning process. However, many details of the process are not well understood. In this work, the conservation of mass and momentum equations are solved for isothermal, axisymmetric hollow fiber spinning. In contrast to past work, the conservation equations are solved for both the bore and clad fluids. The two sets of equations are linked by continuity of velocity and stress across the bore--clad interface. Simulation results show an unexpected recirculation region in the bore fluid under certain operating conditions. For a given die geometry, the presence/absence and size of the recirculation region is dependent on the bore-to-clad flow rate ratio and bore-to-clad viscosity ratio. The appearance of the recirculation region leads to a more rapid decrease of both fiber outer and inner radii after die swell. The predicted changes in fiber radii are in better agreement with experimental observations than predictions from the one-dimensional thin filament analysis. [ABSTRACT FROM AUTHOR]

The E. coli protein WrbA is an FMN-dependent NAD(P)H:quinone oxidoreductase that has been implicated in oxidative defense. Three subunits of the tetrameric enzyme contribute to each of four identical, cavernous active sites that appear to accommodate NAD(P)H or various quinones, but not simultaneously, suggesting an obligate tetramer with a ping-pong mechanism in which NAD departs before oxidized quinone binds. The present work was undertaken to evaluate these suggestions and to characterize the kinetic behavior of WrbA. Steady-state kinetics results reveal that WrbA conforms to a ping-pong mechanism with respect to the constancy of the apparent Vmax to Km ratio with substrate concentration. However, the competitive/non-competitive patterns of product inhibition, though consistent with the general class of bi-substrate reactions, do not exclude a minor contribution from additional forms of the enzyme. NMR results support the presence of additional enzyme forms. Docking and energy calculations find that electron-transfer-competent binding sites for NADH and benzoquinone present severe steric overlap, consistent with the ping-pong mechanism. Unexpectedly, plots of initial velocity as a function of either NADH or benzoquinone concentration present one or two Michaelis-Menten phases depending on the temperature at which the enzyme is held prior to assay. The effect of temperature is reversible, suggesting an intramolecular conformational process. WrbA shares these and other details of its kinetic behavior with mammalian DT-diaphorase, an FAD-dependent NAD(P)H:quinone oxidoreductase. An extensive literature review reveals several other enzymes with two-plateau kinetic plots, but in no case has a molecular explanation been elucidated. Preliminary sedimentation velocity analysis of WrbA indicates a large shift in size of the multimer with temperature, suggesting that subunit assembly coupled to substrate binding may underlie the two-plateau behavior. An additional aim of this report is to bring under wider attention the apparently widespread phenomenon of two-plateau Michaelis-Menten plots.

Introduction: Achieving appropriate levels of premedication and parental separation is needed for smooth induction of anesthesia and prevention of perioperative complications. Both melatonin and midazolam are used for the premedication in children, but we do not have consensus on which premedication is superior among them., Evidence Acquisition: A systematic review of randomized controlled trials comparing the efficacy and safety of use of midazolam and melatonin as premedication in children aged 1-15 years was conducted. Patients who received drugs other than melatonin or midazolam as premedication were excluded. PubMed, Embase, Scopus, Google Scholar were searched and the last search was done in December 2022., Evidence Synthesis: Full text of ten articles with a total of 774 participants (442 melatonin, 332 midazolam) were eligible. The data extracted were synthesized after quality assessment. The outcomes appraised included: sedation, anxiety in preoperative room and during induction. Among four studies examining sedation, there were no significant differences between melatonin and midazolam (SMD=0.03, 95% CI - 0.35 to 0.40, P=0.88, I 2= 81%). There were no significant differences between melatonin and midazolam among two studies examining anxiety in pre-operative room (SMD=-0.04, 95% CI -4.58,4.50, P=0.99, I 2= 0%) and anxiety during anesthesia induction as an outcome (SMD=-1.38, 95% CI -4.81 to 2.05, P=0.43, I 2= 0%)., Conclusions: The review showed that melatonin is comparable to midazolam in achieving sedation for facilitating inhalational induction in pediatric patients. The review showed no significant difference in reduction of anxiety in the preoperative room and during induction of anesthesia when either melatonin or midazolam is used as premedicants. Heterogeneity in premedication doses, parameters assessed, outcomes measured, and scales that quantify efficacy resulted in the inconsistencies in how the medications were compared and hence resulted in difficulties in data synthesis. Future studies comparing efficacy of premedication need to consider the proposed standardizations in methodology for achieving optimal results that are a fair comparison of the two medications.

Objective: To study the effects of rapid enteral feed advancement with early feed fortification in stable very low birth weight (VLBW) infants >30 weeks gestation., Study Design: Preterm infants (N = 92) were randomized to a) rapid feed advancement-early fortification - REF group (enteral feed advanced at 25-30 ml/kg/day, fortification at 50 ml/kg/day) or b) slow feed advancement-late fortification-SLF group (feed advanced at 15-20 ml/kg/day, fortification at 100 ml/kg/day)., Results: The primary outcome-time to regain birth weight was significantly lower in REF group (9 days vs 13 days, P = 0.02). REF group reached full enteral feeds earlier (6 days vs 9 days, P = 0.001), had lower rates of sepsis (13% vs 38%, P = 0.007) and shorter hospital stay (10 days vs 15 days, P = 0.01). At one year, the median Z-scores for weight [-1.5 vs -2.2, P < 0.001] and head circumference [1.1 vs 0, P < 0.001) were significantly higher in the REF group., Conclusions: In VLBW preterm infants >30 weeks, rapid feed advancement with early fortification resulted in early postnatal regain of birth weight with positive effects on growth at one year., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Lactobacillus rhamnosus GG (LGG) is a widely used and extensively researched probiotic. Probiotic effects are considered to be strain specific. We aimed to comprehensively assess the strain-specific effects of LGG in preterm infants. A systematic review of RCTs and non-RCTs to evaluate the effect of LGG in preterm infants. We followed the Cochrane methodology, and preferred reporting items for systematic reviews (PRISMA) statement for conducting and reporting this review. We searched the Cochrane central register of controlled trials, PubMed, EMBASE and CINAHL databases till December 2023. The review was registered in PROSPERO 2022 CRD42022324933. Meta-analysis of data from RCTs that used LGG as the sole probiotic showed significantly lower risk of NEC ≥Stage II [5 RCTs, n = 851, RR:0.50 (95% CI: 0.26, 0.93), P = 0.03] in the LGG group. There was no significant difference in the risk of LOS [7 RCTs, n = 1037, RR:1.08 (95% CI 0.84, 1.39), P = 0.55], mortality [3 RCTs, n = 207, RR: 0.99 (95% CI: 0.42, 2.33), P = 0.99], time to reach full feeds [2 RCTs, n = 19, SMD = 0.11 days (95% CI: -0.22, 0.45), P = 0.51] and duration of hospital stay [3 RCTs, n = 293, SMD: -0.14 days (95% CI: -0.37 to 0.09), P = 0.23]. Meta-analysis of data from non-RCTs showed no significant effect of LGG on NEC, LOS, and mortality. RCTs showed beneficial effects of LGG when used as the sole probiotic in reducing the risk of NEC, whereas observational studies did not. Strain-specific systematic review of LGG provides important data for guiding research and clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The reinforcing nature of social interactions is necessary for the maintenance of appropriate social behavior. However, the neural substrates underlying social reward processing and how they might differ based on the sex and internal state of the animal remains unknown. It is also unclear whether these neural substrates are shared with those involved in nonsocial rewarding processing. We developed a fully automated, two choice (social-sucrose) operant assay in which mice choose between social and nonsocial rewards to directly compare the reward-related behaviors associated with two competing stimuli. We performed cellular resolution calcium imaging of medial prefrontal cortex (mPFC) neurons in male and female mice across varying states of water restriction and social isolation. We found that mPFC neurons maintain largely non-overlapping, flexible representations of social and nonsocial reward that vary with internal state in a sex-dependent manner. Additionally, optogenetic manipulation of mPFC activity during the reward period of the assay disrupted reward-seeking behavior across male and female mice. Thus, using a two choice operant assay, we have identified sex-dependent, non-overlapping neural representations of social and nonsocial reward in the mPFC that vary with internal state and that are essential for appropriate reward-seeking behavior., (© 2024. The Author(s).)

The high-throughput method based on the micron-level structure that 3D bioprinting technology offers for various environmental microbiological engineering applications is made possible by its several printing paths and precision programming control. This versatility makes it an on-demand manufacturing technology. A novel 3D manufacturing technique called 3D bioprinting may be used to precisely uptake and disperse bacteria to create microbial active substances with a variety of intricate functionalities for environmental applications. The technological challenges that the current 3D bioprinting technology must face include the mechanical properties of materials, the creation of specific bioinks to adapt to different strains, and the exploration of 4D bioprinting for intelligent applications. Therefore, this analysis delves deeply into the core technological ideas of 3D bioprinting, bioink materials, and their environmental applications. It also offers recommendations about the challenges and opportunities associated with 3D bioprinting. Combined with the present advancements in microbe enhancement technology, 3D bioprinting will provide an enabling platform for multifunctional microorganisms and facilitate the management of in situ directional responses in the environmental domain. This review highlights the applications of 3D bioprinting in the environmental monitoring and bioremediation. 3D printing in solid waste management is also discussed in detail., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Parent/caregiver-completed developmental testing (PCDT) is integral to developmental care in children; however, there is limited information on its accuracy. In this systematic review, we compared the diagnostic accuracy of PCDT with concurrently administered Bayley Scales of Infant Development for detection of developmental delay (DD) in children below 4 years of age., Methods: We searched databases PubMed, Embase, CINAHL, PsycINFO and Google Scholar until November 2023. Bivariate and multiple thresholds summary receiver operating characteristics were used to obtain the summary sensitivity and specificity with 95% CIs. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used for risk of bias assessment., Results: A total of 38 studies (31 in the meta-analysis) were included. Ages and Stages Questionnaire (ASQ) and Parent Report of Children's Abilities-Revised (PARCA-R) were the most commonly evaluated PCDTs. ASQ score >2 SD below the mean had an overall sensitivity of 0.72 (0.6, 0.82) and 0.63 (0.50, 0.75) at a median specificity of 0.89 (0.82, 0.94) and 0.81 (0.76, 0.86) for diagnosing moderate to severe DD and severe DD, respectively. PARCA- R had an overall sensitivity of 0.69 (0.51, 0.83) at median specificity of 0.75 (0.64, 0.83) for predicting severe DD. Participant selection bias and partial verification bias were found in over 50% of the studies. The certainty of evidence was low for the studied outcomes., Conclusions: The most commonly studied parental tools, ASQ and PARCA-R, have moderate to low sensitivity and moderate specificity for detecting DD in young children. High risk of bias and heterogeneity in the available data can potentially impact the interpretation of our results., Prospero Registration Number: CRD42021268629., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The salts bis(2-amino-3-methylpyridinium) fumarate dihydrate, 2C 6 H 9 N 2 + H 4 H 2 O 2 2- H 2 O (I), and 2-amino-3-methylpyridinium 5-chlorosalicylate, C 6 H 9 H 2 + (II), were synthesized from 2-amino-3-methylpyridine with fumaric acid and 5-chlorosalicylic acid, respectively. The crystal structures of these salts were characterized by single-crystal X-ray diffraction, revealing protonation in I and II by the transfer of a H atom from the acid to the pyridine base. In the crystals of both I and II, N-H...O interactions form an R 7 H 4 ClO 3 ) have been calculated and reveal that the crystal of I is more mechanically stable than II. Frontier molecular orbital (FMO) analysis predicts that the band gap energy of II (2.6577 eV) is lower compared to I (4.0035 eV). The Quantum Theory of Atoms In Molecules (QTAIM) analysis shows that the pyridinium-carboxylate N-H...O interaction present in I is stronger than the other interactions, whereas in II, the hydroxy-carboxylate O-H...O interaction is stronger than the pyridinium-carboxylate N-H...O interaction; the bond dissociation energies also confirm these results. The positive Laplacian [∇ - (II), were synthesized from 2-amino-3-methylpyridine with fumaric acid and 5-chlorosalicylic acid, respectively. The crystal structures of these salts were characterized by single-crystal X-ray diffraction, revealing protonation in I and II by the transfer of a H atom from the acid to the pyridine base. In the crystals of both I and II, N-H...O interactions form an R 2 2 (8) ring motif. Hirshfeld surface analysis distinguishes the interactions present in the crystal structures of I and II, and the two-dimensional (2D) fingerprint plot analysis shows the percentage contribution of each type of interaction in the crystal packing. The volumes of the crystal voids of I (39.65 Å 3 ) and II (118.10 Å 3 ) have been calculated and reveal that the crystal of I is more mechanically stable than II. Frontier molecular orbital (FMO) analysis predicts that the band gap energy of II (2.6577 eV) is lower compared to I (4.0035 eV). The Quantum Theory of Atoms In Molecules (QTAIM) analysis shows that the pyridinium-carboxylate N-H...O interaction present in I is stronger than the other interactions, whereas in II, the hydroxy-carboxylate O-H...O interaction is stronger than the pyridinium-carboxylate N-H...O interaction; the bond dissociation energies also confirm these results. The positive Laplacian [∇ 2 ρ(r) > 0] of these interactions shows that the interactions are of the closed shell type. An in-silico ADME (Absorption, Distribution, Metabolism and Excretion) study predicts that both salts will exhibit good pharmacokinetic properties and druglikeness.

The accelerating pace of technological advancements necessitates specialised expertise and cutting-edge instruments to maintain competitive research in life sciences. Core facilities - collaborative laboratories equipped with state-of-the-art tools and staffed by expert personnel - are vital resources that support diverse scientific endeavours. However, their adoption in lower-income communities has been comparatively stagnant due to both financial and cultural challenges. This paper explores the perils of not supporting core facilities on national research enterprises, underscoring the need for balanced investments in discovery science and crucial infrastructure support. We explore the implications from the perspectives of funders, university leaders and lab heads. We advocate for a paradigm shift to recognise these facilities as essential components of national research efforts. Core facilities are positioned not as optional but as strategic investments that can catalyse breakthroughs, particularly in environments with limited resources., (© 2024 The Authors. Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.)

Objective: To evaluate the effect of blood sampling stewardship on transfusion requirements among infants born extremely preterm., Study Design: In this single-center, randomized controlled trial (RCT), infants born at <28 weeks of gestation and birth weight of <1000 g were randomized at 24 hours of age to two different blood sampling approaches: restricted sampling (RS) vs conventional sampling (CS). The stewardship intervention in the RS group included targeted reduction in blood sampling volume and frequency and point of care testing methods in the first 6 weeks after birth. Both groups received early recombinant erythropoietin from day three of age. Primary outcome was the rate of early red blood cell (RBC) transfusions in the first six postnatal weeks., Results: A total of 102 infants (mean gestational age: 26 weeks; birth weight: 756 g) were enrolled. Fidelity to the sampling protocol was achieved in 95% of the infants. Sampling losses in the first 6 weeks were significantly lower in the RS group (16.8 ml/kg vs 23.6 ml/kg, P < .001). The RS group had a significantly lower rate of early postnatal RBC transfusions (41% vs 73%, RR: 0.56 [0.39-0.81], P = .001). The hazard of needing a transfusion during neonatal intensive care unit (NICU) stay was reduced by 55% by RS. Mortality and neonatal morbidities were similar between the two groups., Conclusion: Minimization of blood sampling losses by approximately one-third in the first 6 weeks after birth leads to substantial reduction in the early red blood cell transfusion rate in infants born extremely preterm and weighing <1000 g at birth., Trial Registration: http://www.ctri.nic.in (CTRI/2020/01/022  964)., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose. Funding: The authors received no specific funding for this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Cerebrospinal fluid (CSF) white blood cell (WBC) count, protein, and glucose (cytochemistry) are performed to aid in the diagnosis of meningitis in young infants. However, studies have reported varying diagnostic accuracies. We assessed the diagnostic accuracy of CSF cytochemistry in infants below 90 days and determined the certainty of evidence., Study Design: We searched PubMed, Embase, Cochrane Library, Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus databases in August 2021. We included studies that evaluated the diagnostic accuracy of CSF cytochemistry compared with CSF culture, Gram stain, or polymerase chain reaction in neonates and young infants <90 days with suspected meningitis. We pooled data using the hierarchical summary receiver operator characteristic (ROC) model., Results: Of the 10,720 unique records, 16 studies were eligible for meta-analysis, with a cumulative sample size of 31,695 (15 studies) for WBC, 12,936 (11 studies) for protein, and 1,120 (4 studies) for glucose. The median (Q 1 , Q 3 ) specificities of WBC, protein, and glucose were 87 (82, 91), 89 (81, 94), and 91% (76, 99), respectively. The pooled sensitivities (95% confidence interval [CI]) at median specificity of WBC count, protein, and glucose were 90 (88, 92), 92 (89, 94), and 71% (54, 85), respectively. The area (95% CI) under ROC curves were 0.89 (0.87, 0.90), 0.87 (0.85, 0.88), and 0.81 (0.74, 0.88) for WBC, protein, and glucose, respectively. There was an unclear/high risk of bias and applicability concern in most studies. Overall certainty of the evidence was moderate. A bivariate model-based analysis to estimate the diagnostic accuracy at specific thresholds could not be conducted due to a paucity of data., Conclusion: CSF WBC and protein have good diagnostic accuracy for the diagnosis of meningitis in infants below 90 days of age. CSF glucose has good specificity but poor sensitivity. However, we could not identify enough studies to define an optimal threshold for the positivity of these tests., Key Points: · Median specificity of CSF leucocyte count, protein and glucose are similar in young infants.. · At median specificity, CSF leukocyte count and protein are more sensitive than glucose.. · Owing to inadequate data, bivariate modelling to suggest optimal diagnostic thresholds is not possible.., Competing Interests: None declared., (Thieme. All rights reserved.)

Acridines are a class of bioactive agents which exhibit high biological stability and the ability to intercalate with DNA; they have a wide range of applications. Pyridine derivatives have a wide range of biological activities. To enhance the properties of acridine and 2-amino-3-methylpyridine as the active pharmaceutical ingredient (API), 4-nitrobenzoic acid was chosen as a coformer. In the present study, a mixture of acridine and 4-nitrobenzoic acid forms the salt acridinium 4-nitrobenzoate, C 13 H 10 N + ·C 7 H 4 NO 4 - H 6 H 9 N 2 H + ·C 7 (II). In both salts, protonation takes place at the ring N atom. The crystal structure of both salts is predominantly governed by hydrogen-bond interactions. In salt I, C-H...O and N-H...O interactions form an infinite chain in the crystal, whereas in salt II, intermolecular N-H...O interactions form an eight-membered R 4 NO 4 - (II). In both salts, protonation takes place at the ring N atom. The crystal structure of both salts is predominantly governed by hydrogen-bond interactions. In salt I, C-H...O and N-H...O interactions form an infinite chain in the crystal, whereas in salt II, intermolecular N-H...O interactions form an eight-membered R 2 2 (8) ring motif. A theoretical charge-density analysis reveals the charge-density distribution of the inter- and intramolecular interactions of both salts. An in-silico ADME analysis predicts the druglikeness properties of both salts and the results confirm that both salts are potential drug candidates with good bioavailability scores and there is no violation of the Lipinski rules, which supports the druglikeness properties of both salts. However, although both salts exhibit drug-like properties, salt I has higher gastrointestinal absorption than salt II and hence it may be considered a potential drug candidate.

The optical microscope has revolutionized biology since at least the 17 th Century. Since then, it has progressed from a largely observational tool to a powerful bioanalytical platform. However, realizing its full potential to study live specimens is hindered by a daunting array of technical challenges. Here, we delve into the current state of live imaging to explore the barriers that must be overcome and the possibilities that lie ahead. We venture to envision a future where we can visualize and study everything, everywhere, all at once - from the intricate inner workings of a single cell to the dynamic interplay across entire organisms, and a world where scientists could access the necessary microscopy technologies anywhere., (© 2023. The Author(s).)

Healthcare spending in the United States is concentrated on a small percentage of individuals, with 5% of the population accounting for 50% of annual spending. Many patients among the top 5% of spenders have complex health and social needs. Care coordination interventions, often led by a multidisciplinary team consisting of nurses, community health workers and social workers, are one strategy for addressing the challenges facing such patients. Care teams strive to improve health outcomes by forging strong relationships with clients, visiting them on a regular basis, reconciling medications, arranging primary and speciality care visits, and addressing social needs such as housing instability, unemployment and insurance. In this paper, we propose a simulation algorithm that samples longitudinal patient-level encounter histories to estimate the staffing needs for a multidisciplinary care team. Our numerical results illustrate multiple uses of the algorithm for staffing under stationary and non-stationary patient enrollment rates., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Operational Research Society.)

Competing Interests: Competing interests: None declared.

Since the coronavirus disease (COVID-19) pandemic hit the globe in early 2020, we have steadily gained insight into its pathogenesis; thereby improving surveillance and preventive measures. In contrast to other respiratory viruses, neonates and young children infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have a milder clinical presentation, with only a small proportion needing hospitalization and intensive care support. With the emergence of novel variants and improved testing services, there has been a higher incidence of COVID-19 disease reported among children and neonates. Despite this, the proportion of young children with severe disease has not increased. Key mechanisms that protect young children from severe COVID-19 disease include the placental barrier, differential expression of angiotensin-converting enzyme 2 (ACE-2) receptors, immature immune response, and passive transfer of antibodies via placenta and human milk. Implementing mass vaccination programs has been a major milestone in reducing the global disease burden. However, considering the lower risk of severe COVID-19 illness in young children and the limited evidence about long-term vaccine safety, the risk-benefit balance in children under five years of age is more complex. In this review, we do not support or undermine vaccination of young children but outline current evidence and guidelines, and highlight controversies, knowledge gaps, and ethical issues related to COVID-19 vaccination in young children. Regulatory bodies should consider the individual and community benefits of vaccinating younger children in their local epidemiological setting while planning regional immunization policies.

Objective: To compare the efficacy of low dose-short course intravenous paracetamol with a conventional dose regimen for early targeted closure of patent ductus arteriosus (PDA)., Design: Single-centre, double-blinded, active controlled, randomised non-inferiority trial., Setting: Level III neonatal intensive care unit in Western India., Patients: Preterm infants <30 weeks of gestation requiring mechanical ventilation, or continuous positive airway pressure with FiO 2 ≥0.35 and diagnosed with a haemodynamically significant PDA (hsPDA) at 18-24 hours of postnatal age., Interventions: Low dose (10 mg/kg/dose 6 hourly for 72 hours) versus conventional dose (15 mg/kg/dose 6 hourly for 120 hours) intravenous paracetamol treatment., Main Outcome Measures: Comparison of the rates of ductal closure at completion of sixth postnatal day, using a prespecified non-inferiority margin of 20%., Results: A total of 102 infants were enrolled. The median gestational age and birth weight of the included infants were 26.4 weeks and 830 g. At completion of the sixth postnatal day, closure of PDA was achieved in 92% of infants in the low dose group as compared with 94% of those in the standard dose group (risk difference: -1.6%, 95% CI: -11.6% to 8.5%, p=0.38). The rates of rescue therapies, adverse effects and other neonatal morbidities were comparable in both groups., Conclusion: In very preterm infants on significant respiratory support, low dose-short course intravenous paracetamol treatment was non-inferior to a conventional dosing regime of paracetamol for closure of hsPDA in the first week of postnatal age. Larger studies with narrow margins of non-inferiority are required to confirm our findings., Trial Registration Number: CTRI/2017/10/010012., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Water quality extremes, which water quality models often struggle to predict, are a grave concern to water supply facilities. Most existing water quality models use mean error functions to maximize the predictability of water quality mean value. This paper describes a composite quantile regression neural network (CQRNN) model, which simultaneously estimates non-crossing regression quantiles by minimizing the composite quantile regression error function. This method can improve the prediction of extremes. This paper evaluates the performance of CQRNN for predicting extreme values of turbidity and total organic carbon (TOC) and compares with quantile regression (QR), linear regression (LR), and k-nearest neighbors (KNN) in an application to the Hetch Hetchy Regional Water System, which is the primary water supply for San Francisco, CA. CQRNN is superior to QR, LR, and KNN for predicting the mean trend and extremes of turbidity and TOC, especially for the non-Gaussian turbidity data. The performance of CQRNN is the most stable relative to other methods over different training sample sizes., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: A model that jointly simulates infectious diseases with common modes of transmission can serve as a decision-analytic tool to identify optimal intervention combinations for overall disease prevention. In the United States, sexually transmitted infections (STIs) are a huge economic burden, with a large fraction of the burden attributed to HIV. Data also show interactions between HIV and other sexually transmitted infections (STIs), such as higher risk of acquisition and progression of co-infections among persons with HIV compared to persons without. However, given the wide range in prevalence and incidence burdens of STIs, current compartmental or agent-based network simulation methods alone are insufficient or computationally burdensome for joint disease modeling. Further, causal factors for higher risk of coinfection could be both behavioral (i.e., compounding effects of individual behaviors, network structures, and care behaviors) and biological (i.e., presence of one disease can biologically increase the risk of another). However, the data on the fraction attributed to each are limited., Methods: We present a new mixed agent-based compartmental (MAC) framework for jointly modeling STIs. It uses a combination of a new agent-based evolving network modeling (ABENM) technique for lower-prevalence diseases and compartmental modeling for higher-prevalence diseases. As a demonstration, we applied MAC to simulate lower-prevalence HIV in the United States and a higher-prevalence hypothetical Disease 2, using a range of transmission and progression rates to generate burdens replicative of the wide range of STIs. We simulated sexual transmissions among heterosexual males, heterosexual females, and men who have sex with men (men only and men and women). Setting the biological risk of co-infection to zero, we conducted numerical analyses to evaluate the influence of behavioral factors alone on disease dynamics., Results: The contribution of behavioral factors to risk of coinfection was sensitive to disease burden, care access, and population heterogeneity and mixing. The contribution of behavioral factors was generally lower than observed risk of coinfections for the range of hypothetical prevalence studied here, suggesting potential role of biological factors, that should be investigated further specific to an STI., Conclusions: The purpose of this study is to present a new simulation technique for jointly modeling infectious diseases that have common modes of transmission but varying epidemiological features. The numerical analysis serves as proof-of-concept for the application to STIs. Interactions between diseases are influenced by behavioral factors, are sensitive to care access and population features, and are likely exacerbated by biological factors. Social and economic conditions are among key drivers of behaviors that increase STI transmission, and thus, structural interventions are a key part of behavioral interventions. Joint modeling of diseases helps comprehensively simulate behavioral and biological factors of disease interactions to evaluate the true impact of common structural interventions on overall disease prevention. The new simulation framework is especially suited to simulate behavior as a function of social determinants, and further, to identify optimal combinations of common structural and disease-specific interventions., Competing Interests: CG is also a Guest Researcher at the Division of HIV Prevention, Centers for Disease Control and Prevention. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. CG, HB, and PJH declare no other conflict of interest., (© 2022 The Authors.)

Number and brightness (N&B) analysis is a fluorescence spectroscopy technique to quantify oligomerization of the mobile fraction of proteins. Accurate results, however, rely on a good knowledge of nonfluorescent states of the fluorescent labels, especially of fluorescent proteins, which are widely used in biology. Fluorescent proteins have been characterized for confocal, but not camera-based, N&B, which allows, in principle, faster measurements over larger areas. Here, we calibrate camera-based N&B implemented on a total internal reflection fluorescence microscope for various fluorescent proteins by determining their propensity to be fluorescent. We then apply camera-based N&B in live CHO-K1 cells to determine the oligomerization state of the epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase that is a crucial regulator of cell proliferation and survival with implications in many cancers. EGFR oligomerization in resting cells and its regulation by the plasma membrane microenvironment are still under debate. Therefore, we investigate the effects of extrinsic factors, including membrane organization, cytoskeletal structure, and ligand stimulation, and intrinsic factors, including mutations in various EGFR domains, on the receptor's oligomerization. Our results demonstrate that EGFR oligomerization increases with removal of cholesterol or sphingolipids or the disruption of GM3-EGFR interactions, indicating raft association. However, oligomerization is not significantly influenced by the cytoskeleton. Mutations in either I706/V948 residues or E685/E687/E690 residues in the kinase and juxtamembrane domains, respectively, lead to a decrease in oligomerization, indicating their necessity for EGFR dimerization. Finally, EGFR phosphorylation is oligomerization dependent, involving the extracellular domain (550-580 residues). Coupled with biochemical investigations, camera-based N&B indicates that EGFR oligomerization and phosphorylation are the outcomes of several molecular interactions involving the lipid content and structure of the cell membrane and multiple residues in the kinase, juxtamembrane, and extracellular domains., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Objective: To conduct a systematic review and meta-analysis to compare the efficacy and safety of umbilical cord milking (UCM) versus delayed cord clamping (DCC) in term and late-preterm infants., Methods: MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Clinical trial registries, and Gray literature were searched for randomized controlled trials (RCTs) comparing UCM with DCC in term and late-preterm infants for both short-term and long-term outcomes. Intact and cut UCM were compared separately with DCC using subgroup analysis. We used fixed effect model to pool the data. Random effects model was used when there was significant heterogeneity., Results: Nine studies (1632 infants) were included in the systematic review. Milking was performed on intact cord (i-UCM) in five studies ( n  = 829) and on cut cord (c-UCM) in four studies ( n  = 803). Cord milking significantly improved hemoglobin level at 48-72 h of life when compared to DCC (six studies, n  = 924, mean difference 0.36 g/dL; 95% CI: 0.19-0.53). In addition, hemoglobin level at six to eight weeks of age was also significantly higher in the studies comparing i-UCM with DCC (two studies, n  = 550: mean difference 0.16 g/dL; 95% CI: 0.06-0.27). There was no difference between the UCM group and DCC group for any other outcome. Only one study provided information on growth and hematological parameters at one year of age. Neurodevelopmental outcomes were not reported. None of the studies included non-vigorous infants. The grade of evidence was low to very low for all the outcomes studied., Conclusion: UCM is comparable to DCC in improving short-term hematological outcomes in term and late-preterm vigorous infants. Trials assessing the effect of UCM on important clinical and long-term outcomes among non-vigorous mature preterm infants are urgently required.

Objective: The study aimed to compare the efficacy and safety of two different nasal high-flow rates for primary respiratory support in preterm neonates STUDY DESIGN:  In this single-center, double-blinded randomized controlled trial, preterm neonates ≥28 weeks of gestation with respiratory distress from birth were randomized to treatment with either increased nasal flow therapy (8-10 L/min) or standard nasal flow therapy (5-7 L/min). The primary outcome of nasal high-flow therapy failure was a composite outcome defined as the need for higher respiratory support (continuous positive airway pressure [CPAP] or mechanical ventilation) or surfactant therapy., Results: A total of 212 neonates were enrolled. Nasal high-flow failure rate in the increased flow group was similar to the standard flow group (22 vs. 29%, relative risk = 0.81 [95% confidence interval: 0.57-1.15]). However, nasal flow rate escalation was significantly more common in the standard flow group (64 vs. 43%, p  = 0.004). None of the infants in the increased flow group developed air leak syndromes., Conclusion: Higher nasal flow rate (8-10 L/min) when compared with lower nasal flow rate of 5 to 7 L/min did not reduce the need for higher respiratory support (CPAP/mechanical ventilation) or surfactant therapy in moderately and late preterm neonates. However, initial flow rates of 5 L/min were not optimal for most preterm infants receiving primary nasal flow therapy., Key Points: · Use of high nasal flows (8-10 L/min) did not reduce the need for higher respiratory support in moderately and late preterm infants.. · Nasal flow rate of 5 L/min was not optimal for most preterms with respiratory distress from birth.. · Careful patient selection and optimized flow settings could enhance nasal flow success in neonates.., Competing Interests: None declared., (Thieme. All rights reserved.)

The superior colliculus is a midbrain structure that plays important roles in visually guided behaviors in mammals. Neurons in the superior colliculus receive inputs from retinal ganglion cells but how these inputs are integrated in vivo is unknown. Here, we discovered that high-density electrodes simultaneously capture the activity of retinal axons and their postsynaptic target neurons in the superior colliculus, in vivo. We show that retinal ganglion cell axons in the mouse provide a single cell precise representation of the retina as input to superior colliculus. This isomorphic mapping builds the scaffold for precise retinotopic wiring and functionally specific connection strength. Our methods are broadly applicable, which we demonstrate by recording retinal inputs in the optic tectum in zebra finches. We find common wiring rules in mice and zebra finches that provide a precise representation of the visual world encoded in retinal ganglion cells connections to neurons in retinorecipient areas., (© 2022. The Author(s).)

In primary care allocating appointments to sequential requests can result in sub-optimal scheduling. Optimal scheduling requires hiring of consultants to analyze historical patterns. Many practices focus their resources on larger problems instead of optimizing appointment schedules. We simulate simple heuristics to compare their performance with optimal schedules uncovered using offline optimization models. We use uncapacitated appointment calendars for a nationally representative heterogeneous primary care panel to meet all patients' requests. The stochastic nature of appointment requests gives a distribution for daily appointments and for the uncovered optimal capacity. The First Minimum heuristic gives near-optimal schedules and can be easily implemented in small practices using pen-and-paper, without any investment in computer-systems.

The localization of many membrane proteins within cholesterol- and sphingolipid-containing microdomains is essential for proper cell signaling and function. These membrane domains, however, are too small and dynamic to be recorded, even with modern super-resolution techniques. Therefore, the association of membrane proteins with these domains can only be detected with biochemical assays that destroy the integrity of cells require pooling of many cells and take a long time to perform. Here, we present a simple membrane fluidizer-induced clustering approach to identify the phase-preference of membrane-associated molecules in individual live cells within 10-15 min. Experiments in phase-separated bilayers and live cells on molecules with known phase preference show that heptanol hyperfluidizes the membrane and stabilizes phase separation. This results in a transition from nanosized to micronsized clusters of associated molecules allowing their identification using routine microscopy techniques. Membrane fluidizer-induced clustering is an inexpensive and easy to implement method that can be conducted at large-scale and allows easy identification of protein partitioning in live cell membranes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Sepsis due to the administered probiotic strain/s is a barrier against adoption of prophylactic probiotic supplementation in preterm infants to reduce the risk of necrotising enterocolitis (NEC ≥ Stage II), all-cause mortality, late-onset sepsis, and feeding intolerance. We aimed to conduct a systematic review for reports of probiotic sepsis in preterm infants (gestation < 37 weeks). Databases including PubMed, Embase, Emcare, Cochrane Central library, and Google Scholar were searched in August 2021 and updated in Jan 2022. Probiotic sepsis was defined as positive blood/CSF culture isolating administered probiotic strain with symptoms suggestive of infection. Data collection included birth weight, gestation, comorbidities (e.g. gut surgery, NEC), presence of central venous catheters, treatment, and outcome. Literature search revealed 1569 studies. A total of 16 reports [randomised control trial (RCT): none; non-RCT: 1; case series: 8; case report: 7] involving 32 preterm infants with probiotic sepsis were included after exclusions for various reasons. Majority of the cases were born < 32 weeks' gestation. Bifidobacterium (N = 19) was the most commonly isolated organism followed by Lactobacillus (N = 10), and Saccharomyces (N = 3). A total of 25/32 cases were confirmed to be due to the administered probiotic strain on full genomic analysis. Two studies reported one neonatal death each. Twelve neonates had comorbidities. Majority were treated with antibiotics (29/32) whereas others (3/32) required antifungal treatment., Conclusion: Probiotics sepsis is relatively an uncommon event in preterm infants. Majority of the cases recovered after antibiotic or antifungal treatment. The importance of optimal surveillance and treatment of probiotic sepsis and research towards alternatives to probiotics (e.g. postbiotics) is emphasised., What Is Known: • Probiotics have been shown to reduce necrotising enterocolitis, late-onset sepsis, all-cause mortality, and time to reach full enteral feeds in preterm infants. • Despite the evidence, use of probiotics is not universal due to concerns regarding probiotic-associated sepsis in preterm infants., What Is New: • This comprehensive systematic review showed that probiotic sepsis is a relatively rare phenomenon in preterm infants. • All except one case where the diagnosis was uncertain recovered after antimicrobial therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes., Conclusion: There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings., What Is Known: • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants., What Is New: • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The proton-transfer complexes 2-amino-4-methoxy-6-methylpyrimidinium (2A4M6MP) 4-aminosalicylate (4AMSA), C 6 H 10 N 3 O + ·C 7 H 6 NO 3 - H 6 H 10 N 3 O + H 7 H 4 , II, were synthesized by slow evaporation and crystallized. The crystal structures of both I and II were determined by single-crystal X-ray structure analysis. The crystal structures of both salts exhibit O-H...O, N-H...O, N-H...N and C-H...O interactions in their crystals. The 4AMSA and 5ClSA anions in combination with the 2A4M6MP cations form distinct synthons, which are represented by the graph-set notations R 3 - , II, were synthesized by slow evaporation and crystallized. The crystal structures of both I and II were determined by single-crystal X-ray structure analysis. The crystal structures of both salts exhibit O-H...O, N-H...O, N-H...N and C-H...O interactions in their crystals. The 4AMSA and 5ClSA anions in combination with the 2A4M6MP cations form distinct synthons, which are represented by the graph-set notations R 2 2 (8), R 4 2 (8) and R 2 2 (8). Furthermore, the ΔpK a values were calculated and clearly demonstrate that 2A4M6MP is a good salt former when combined with carboxylic acids. Hirshfeld surface analysis was used to quantify the weak and strong interactions in the solid state, and energy framework calculations showed the stability of the hydrogen-bonding interactions. QTAIM (quantum theory of atoms in molecules) analysis revealed the nature of the chemical bonding in I and II, and the charge-density distribution in the intermolecular interactions in the crystal structures.

Agent-based network modeling (ABNM) simulates each person at the individual-level as agents of the simulation, and uses network generation algorithms to generate the network of contacts between individuals. ABNM are suitable for simulating individual-level dynamics of infectious diseases, especially for diseases such as HIV that spread through close contacts within intricate contact networks. However, as ABNM simulates a scaled-version of the full population, consisting of all infected and susceptible persons, they are computationally infeasible for studying certain questions in low prevalence diseases such as HIV. We present a new simulation technique, agent-based evolving network modeling (ABENM), which includes a new network generation algorithm, Evolving Contact Network Algorithm (ECNA), for generating scale-free networks. ABENM simulates only infected persons and their immediate contacts at the individual-level as agents of the simulation, and uses the ECNA for generating the contact structures between these individuals. All other susceptible persons are modeled using a compartmental modeling structure. Thus, ABENM has a hybrid agent-based and compartmental modeling structure. The ECNA uses concepts from graph theory for generating scale-free networks. Multiple social networks, including sexual partnership networks and needle sharing networks among injecting drug-users, are known to follow a scale-free network structure. Numerical results comparing ABENM with ABNM estimations for disease trajectories of hypothetical diseases transmitted on scale-free contact networks are promising for application to low prevalence diseases., (© 2021. The Author(s).)

Cortical circuits are thought to contain a large number of cell types that coordinate to produce behavior. Current in vivo methods rely on clustering of specified features of extracellular waveforms to identify putative cell types, but these capture only a small amount of variation. Here, we develop a new method ( WaveMAP ) that combines non-linear dimensionality reduction with graph clustering to identify putative cell types. We apply WaveMAP to extracellular waveforms recorded from dorsal premotor cortex of macaque monkeys performing a decision-making task. Using WaveMAP , we robustly establish eight waveform clusters and show that these clusters recapitulate previously identified narrow- and broad-spiking types while revealing previously unknown diversity within these subtypes. The eight clusters exhibited distinct laminar distributions, characteristic firing rate patterns, and decision-related dynamics. Such insights were weaker when using feature-based approaches. WaveMAP therefore provides a more nuanced understanding of the dynamics of cell types in cortical circuits., Competing Interests: EL, HB, AT, SA, MM, KS, CC No competing interests declared, (© 2021, Lee et al.)

Aim: To determine predictors of rescue treatment among infants treated for retinopathy of prematurity and to evaluate their ocular outcomes at 18-24 months of corrected age., Methods: This is a single centre retrospective study of infants who received treatment for type 1 ROP, using laser photocoagulation or anti VEGF agents. Multivariable logistic regression was used to generate a prediction model for rescue treatment of ROP. The primary outcome was an abnormal refractive outcome by 24 months of corrected age, among infants primarily treated with laser therapy., Results: Two hundred and eight infants (including 416 eyes) who received single (n = 151) or rescue (multiple) treatments (n = 57) were included. Ninety three percent of the infants were primarily treated with laser photocoagulation. Lower gestational age, small for gestational age, early packed red blood cell transfusion (within 2 weeks of postnatal age), and presence of Zone 1 retinopathy predicted the need for rescue treatment in treated infants [area under the receiver operating characteristic curve: 0.81 (0.73-0.89)]. The incidence of abnormal refractive outcome, assessed in a total of 174 infants, was found to be significantly higher in the rescue treatment group (67% versus 21%, adjusted odds ratio: 7.56 (3.3-17.2), P < 0.001). Myopia, very high myopia and use of spectacles was significantly higher in the rescue treatment group (P < 0.001 for each)., Conclusions: Rescue treatment for ROP was associated with an increased incidence of refractive errors and requirement of spectacles by 2 years of age. Larger prospective multicentre studies are required to confirm the findings from our study.

The majority of extremely low birth weight (ELBW) neonates receive red blood cell (RBC) transfusions; at least 50% receive multiple transfusions. Anemia care bundles could be the most effective approach to reduce transfusion rates. We conducted a quality improvement non-controlled before-and-after retrospective study involving 345 ELBW infants admitted over a 5-year period in two consecutive epochs before and after implementation of an anemia care bundle in January 2017. Bundle components included (a) prophylactic subcutaneous erythropoietin twice each week (600 IU/kg/week) from day 7 through 8 weeks of age and (b) blood sampling stewardship in the first five postnatal weeks. Early postnatal blood sampling losses were significantly reduced following the implementation of the care bundle (21.2 ml/kg vs 25 ml/kg, P < 0.001). We found a 50% reduction in the rate of multiple RBC transfusions (adjusted RR 0.45, 95% CI: 0.34-0.59) and a reduced odds of necrotizing enterocolitis (NEC) (4% vs 10%, adjusted OR 0.38 (95% CI: 0.15-0.78)) among infants that received the anemia care bundle (n = 182 infants). The overall transfusion rate, number and volume of transfusions, and multiple donor exposures were also significantly reduced.Conclusion: The combination of extended subcutaneous erythropoietin administration and reduced early postnatal blood sampling was associated with a significant reduction in the rate of multiple erythrocyte transfusions and NEC in ELBW neonates. What is known: • The majority of extremely low birth weight neonates continue to require blood transfusions despite advances in standardized transfusion practices; at least 50% require multiple transfusions. • Anemia care bundles, employing a combination of anemia prevention strategies, can effectively reduce the RBC transfusion rates in ELBW infants. What is new: • A combination of extended subcutaneous erythropoietin supplementation and blood sampling stewardship practices reduced the rate of multiple RBC transfusions in ELBW neonates by 50%. • Implementation of the anemia care bundle was associated with a significant reduction in the rates of necrotizing enterocolitis.

Super-resolution microscopy and single molecule fluorescence spectroscopy require mutually exclusive experimental strategies optimizing either temporal or spatial resolution. To achieve both, we implement a GPU-supported, camera-based measurement strategy that highly resolves spatial structures (~100 nm), temporal dynamics (~2 ms), and molecular brightness from the exact same data set. Simultaneous super-resolution of spatial and temporal details leads to an improved precision in estimating the diffusion coefficient of the actin binding polypeptide Lifeact and corrects structural artefacts. Multi-parametric analysis of epidermal growth factor receptor (EGFR) and Lifeact suggests that the domain partitioning of EGFR is primarily determined by EGFR-membrane interactions, possibly sub-resolution clustering and inter-EGFR interactions but is largely independent of EGFR-actin interactions. These results demonstrate that pixel-wise cross-correlation of parameters obtained from different techniques on the same data set enables robust physicochemical parameter estimation and provides biological knowledge that cannot be obtained from sequential measurements.

Paragangliomas occurring with cyanotic heart disease is a known association. We present a case of an active paraganglioma in a child with unoperated Tetralogy of Fallot, which posed a management challenge considering the pathophysiology of both these conditions.

Objective: To conduct a systematic review and meta-analysis of the efficacy and safety of umbilical cord milking in preterm infants., Design: Randomised controlled trials comparing umbilical cord milking with delayed cord clamping/immediate cord clamping in preterm infants were identified by searching databases, clinical trial registries and reference list of relevant studies in November 2019. Fixed effects model was used to pool the data on various clinically relevant outcomes., Main Outcome Measures: Mortality and morbidities in preterm neonates., Results: Nineteen studies (2014 preterm infants) were included. Five studies (n=922) compared cord milking with delayed cord clamping, whereas 14 studies (n=1092) compared milking with immediate cord clamping. Cord milking, as opposed to delayed cord clamping, significantly increased the risk of intraventricular haemorrhage (grade III or more) (risk ratio (RR): 1.95 (95% CI 1.01 to 3.76), p=0.05). When compared with immediate cord clamping, cord milking reduced the need for packed RBC transfusions (RR:0.56 (95% CI 0.43 to 0.73), p<0.001). There was limited information on long-term neurodevelopmental outcomes. The grade of evidence was moderate or low for the various outcomes analysed., Conclusion: Umbilical cord milking, when compared with delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants, especially at lower gestational ages. Cord milking, when compared with immediate cord clamping, reduced the need for packed RBC transfusions but did not improve clinical outcomes. Hence, cord milking cannot be considered as placental transfusion strategy in preterm infants based on the currently available evidence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare the effect of self-inflating bag (SIB) vs. T-piece resuscitator (TPR) on PaCO 2 levels, when used for brief manual ventilation during administration of first dose of surfactant., Methods: Preterm neonates were randomized to receive positive pressure ventilation with either self-inflating bag or T-piece resuscitator during administration of first dose of surfactant. Arterial blood gases were obtained at baseline and 1 h after the intervention. Primary outcome was the mean change in PaCO 2 levels 1 h after the intervention., Results: Eighty neonates were enrolled (40 in each group). The drop in PaCO 2 at 1 h was significantly greater in the self inflating bag group as compared to the T-piece resuscitator group [8.96 ± 9.06 mmHg vs. 1.37 ± 9.06 mmHg, Mean difference = 7.58 mmHg, (95% CI: 3.78 to 11.4); P < 0.01]. The PaCO 2 change was also statistically significant in the subgroup of infants that required only non-invasive ventilation. The need for second dose of surfactant was higher in the self-inflating bag group [77% vs. 55%, RR - 1.41 (95% CI: 1.02 to 1.94); P = 0.03]., Conclusions: T-piece resuscitator results in smaller reduction in PaCO 2 levels compared to the self inflating bag, when used for brief manual ventilation during surfactant administration.