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Izzeldin Elbashir,1,2 Tagwa Yousif Elsayed Yousif3 1Department of Medical Laboratory Technology, College of Applied Medical Science, Jazan University, Gizan, Saudi Arabia; 2Faculty of Post Graduate and Scientific Research, Shendi University, Shendi, Sudan; 3Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Gizan, Saudi ArabiaCorrespondence: Tagwa Yousif Elsayed Yousif, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Gizan, 45142, Saudi Arabia, Email telsayed@jazanu.edu.saBackground and Purpose: Sickle cell disease (SCD) is an inherited hemoglobin disease affecting the red cells and causing hemolytic anemia. It is a very common, endemic disease in Sudan, particularly in the central and western areas of Sudan. Sickle cell anemia (SCA) is when the patient has beta-globin gene variant (Hb S variant). In this study, we screened the co-inheritance of hemoglobin O-Arab mutation among Sudanese sickle cell disease patients.Study Population and Methods: This cross-sectional study was conducted in the Sudan-Khartoum state from November 2016 to December 2021. Blood samples were collected from a random sample of the known sickle cell disease patients of Kordofan-central Sudan origin. Study-appropriate blood samples were subjected to complete blood count (CBC), hemoglobin capillary electrophoresis (CE) and molecular laboratory investigations. Initial laboratory investigations were done in Sudan, where the DNA sequencing technique was carried out at the Egyptian National Research Center (NRC)-Cairo-Egypt.Results: The final study’s main results revealed the presence of HB O-Arab genetic mutations among Sudanese Sickle cell disease patients, which estimated to be (5%) co-inherited mutations among our study population (Hb-O Arab; (HBB):c.364G>A (p.Glu122Lys)).Conclusion: The frequency of Hb-O Arab gene mutations was determined among Sudanese sickle cell disease patients, and the results have shown a (5%) frequency of Hb-O Arab mutation. The study result is the first molecular confirmation of co-inherited Hb-O Arab/sickle cell disease clinical condition in Sudan. The results raise the importance of extended studies of other sickle variant conditions.Keywords: sickle cell anemia, molecular genetic mutation, Hb O-Arab, Hb-S disease, sickle variants

Delayed cord clamping has been shown to be beneficial in both preterm and term babies. Practice guidelines have not been consistent between centers and the practice of delayed cord clamping has not been standardized. The concept of physiologic-based cord clamping emerged into practice as well. Cord milking has different physiological effect and might be harmful in preterm babies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Caring for infants on respiratory support is a challenge in the middle-income countries, applying a protocol of targeted oxygen reduction test (tORT) guided by daily assessment of oxygen histograms is novel and practical approach. OBJECTIVE: To study the impact of tORT guided by daily assessment of oxygen histograms as a quality improvement project aiming to decrease days on oxygen support, and duration of hospital admission in preterm infants. STUDY DESIGN: A quality project conducted in neonatal intensive care units (NICU) of two hospitals, from 2017- 2018 (Epochs II). After a period of observation of a cohort of preterm Infants, 2016-2017 (Epoch I). The main aims were to reduce days on oxygen and hospital admission days. All infants in Epoch II underwent daily assessment of oxygen histograms and a trial of oxygen reduction if applicable as per a predefined protocol. Comparison was made between these two Epochs, and the primary outcome was the time to successful discontinuation of oxygen support. RESULTS: Fifty-nine infants were included; 30 underwent the protocolized tORT (Epoch II) with a median (IQR) of 4 (2–6) tORC per infant. Postanal age at presentation (time of initial tORT assessment was performed at the postnatal age of 8 (5, 13) days. Days on oxygen and total numbers of hospital days were significantly less in Epoch II. Oxygen histograms significantly improved after tORT. CONCLUSIONS: Applying tORT guided by oxygen histograms may have a significant impact on oxygen exposure and hospitalization days of patients admitted to the NICU. [ABSTRACT FROM AUTHOR]

The present study aims at examining a unique easel painting by the well-known Egyptian painter, Mahmoud Sa'id. It was painted over four years and displayed at the Agricultural Museum in Egypt. It experienced many deterioration phenomena. The study utilized some non-destructive and non-invasive analytical techniques, i.e. MA-XRF, SEM-EDX, ATR-FTIR, and GC-FID in addition to XRD and SM. Due to the case-study painting multilayers technique, the results of MA-XRF and EDX mapping and XRD patterns revealed using Ultramarine (Na,Ca)8 (AlSiO4)6 (SO4,S,Cl)2, yellow ochre (Fe2 O3 .H2O), red ochre (Fe2O3), and a mixture of graphite (C) and bone black (C,Ca5(OH)(PO4)3) as a coloring pigments in the blue, yellow, reddish brown and black samples, respectively. Moreover, Barite (BaSO4) and Zincite (ZnO) were used in the ground layer with Hydrocerussite (Pb3(CO3 )2 (OH)2) and Sphalerite (ZnS) in lightening colors. Linseed oil was asserted as the pigment binding media, while the binding media of the ground layer was not confirmed. Furthermore, fragility, brittleness, cleavages, peeling, cracks, macro cracks, stains, and ancient fault restoration were detected in the casestudy painting. Accordingly, it urgently requires treatment. [ABSTRACT FROM AUTHOR]

The urgent need to reduce greenhouse gas emissions has prompted the exploration of cleaner energy options such as renewable energy resources (RES) and electric vehicles (EVs). With the increasing use of RES and EVs, there are new opportunities and challenges for the stakeholders involved, and traditional centralized power system management methods are insufficient to handle the complexity. The energy management of photovoltaic (PV)-based parking lots is one of the challenges tackled in recent research. The main obstacle in applying previous research is the elimination of the utility objectives from the energy management models. This paper proposes an energy management framework that enables the integration of PV-based parking lots in a smart grid environment, considering the satisfaction of the utilities as a key player. The proposed framework is modeled using an optimization software package (GAMS), and the results are compared with two different cases to ensure its feasibility and effectiveness. The proposed model succeeded in taking the utilities satisfaction into account by managing the charging and discharging of the EVs.

Background Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. Objectives To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma ( CTCL). Methods Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate ( RR) based on the modified Severity Weighted Assessment Tool ( mSWAT). Secondary end points included global RR, duration of response ( DOR) in skin, progression-free survival ( PFS), pruritus relief, safety and pharmacodynamic markers. Results Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six ( RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. Conclusions Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate. [ABSTRACT FROM AUTHOR]

It is increasingly recognised that biomimetic, natural polymers mimicking the extracellular matrix (ECM) have low thrombogenicity and functional motifs that regulate cell–matrix interactions, with these factors being critical for tissue engineered vascular grafts especially grafts of small diameter. Gelatin constitutes a low cost substitute of soluble collagen but gelatin scaffolds so far have shown generally low strength and suture retention strength. In this study, we have devised the fabrication of novel, electrospun, multilayer, gelatin fibre scaffolds, with controlled fibre layer orientation, and optimised gelatin crosslinking to achieve not only compliance equivalent to that of coronary artery but also for the first time strength of the wet tubular acellular scaffold (swollen with absorbed water) same as that of the tunica media of coronary artery in both circumferential and axial directions. Most importantly, for the first time for natural scaffolds and in particular gelatin, high suture retention strength was achieved in the range of 1.8–1.94 N for wet acellular scaffolds, same or better than that for fresh saphenous vein. The study presents the investigations to relate the electrospinning process parameters to the microstructural parameters of the scaffold, which are further related to the mechanical performance data of wet, crosslinked, electrospun scaffolds in both circumferential and axial tubular directions. The scaffolds exhibited excellent performance in human smooth muscle cell (SMC) proliferation, with SMCs seeded on the top surface adhering, elongating and aligning along the local fibres, migrating through the scaffold thickness and populating a transverse distance of 186 μm and 240 μm 9 days post-seeding for scaffolds of initial dry porosity of 74 and 83%, respectively. [ABSTRACT FROM AUTHOR]

This is to describe a case of a morbidly obese (BMI = 40) female with retrocaval ureter treated with laparoendoscopic single-site surgery. A JJ stent was positioned. A 2 cm umbilical access was created. A single port platform was positioned. The entire ureter was mobilized posterior to the vena cava and transected where the dilated portion ended. The distal ureter was repositioned lateral to the inferior vena cava. Anastomosis was done. A 3 mm trocar was used to assist suturing. At 4-month follow-up, CT revealed no evidence of obstruction of the right kidney and the patient was symptomless. Although challenging, in a morbidly obese patient, LESS repair for retrocaval ureter is feasible.

Abstract Background The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score ≥3, and high tumor burden by modified Groupe d’Etude des Lymphomas Folliculaires [GELF] criteria). Methods Patients aged ≥18 years with grade 1/2 FL, ≥1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naïve or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2–5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS. Results 103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade ≥3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%). Conclusions High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility. Trial registration The phase 3 LYM3001 trial is registered with ClinicalTrials.gov, with the identifier NCT00312845.

Abstract Background There is an increasing probability that the psychiatrist will, willingly or not, come into contact with mentally ill offenders in the course of their practice. There are increasing rates of violence, substance abuse and other psychiatric disorders that are of legal importance. Therefore, the aim of this work was to investigate the rates of different mental disorders in 100 court reports and to investigate the characteristics of mentally ill offenders. Methods All cases referred from different departments of the legal system to the forensic committee for assessment of legal accountability over 13-months duration were included. A specially designed form was prepared for data collection. Cases were classified into five groups: murder, robbery, financial offences, violent and simple offences and a group for other offences. Data were subjected to statistical analysis and comparisons between different groups of subjects were performed by analysis of variance (ANOVA). Results Men constituted 93% of cases. In all, 73% of offenders were younger than 40 years old. Schizophrenia cases made up 13% of the total, substance related cases constituted 56% and amphetamine cases alone made up 21%; 10% of cases were antisocial personality disorders, and 51% of cases were classified as having a low education level. Unemployment was found in 34% of cases. The final decision of the forensic committee was full responsibility in 46% of cases and partial responsibility in 11% of cases, with 33% considered non-responsible. A total of 58% of cases had had contact with psychiatric healthcare prior to the offence and in 9% of cases contact had been in the previous 12 weeks. A history of similar offences was found in 32% of cases. In all, 14% of the offences were murders, 8% were sexual crimes, and 31% were violent/simple crimes. Conclusions The ability of the legal system to detect cases was good, while the ability of the healthcare system to predict crimes and offences was weak, as 58% of cases had had previous contact with the healthcare system previously. Substance abuse, especially amphetamine abuse, played an important role.

Abstract Background A lot of studies were directed to explore the relation between drug abuse and neuropsychological functions. Some studies reported that even after a long duration of disappearance of withdrawal or intoxication symptoms, many patients have obvious deterioration of cognitive functions. The aim of this study was to explore the relationship between the substance use disorders and the executive functions. Methods Two groups were selected for this study. An experimental group consisted of 154 patients and further subdivided according to the substance used into three different subgroups: opioid, amphetamine and alcohol groups which included 49, 56 and 49 patients respectively. The control group was selected matching the experimental group in the demographic characteristics and included 100 healthy persons. Tools used were: Benton visual retention tests, color trail making test, Stroop colors-word test, symbol digit modalities test, the five dots cognitive flexibility test, and TAM verbal flexibility test. All the data were subjected to statistical analysis Results The study showed that the group of drug-dependent subjects performed significantly worse than the comparison group on all measures Also, there were significant differences among the subgroups as the alcoholic group was much worse followed by the amphetamine then the opioids groups. Patients with longer duration of dependence and multiple hospital readmissions were much worse in comparison to patients with shorter duration of dependence and less readmission. Conclusion The study confirmed that the functions of specific brain regions underlying cognitive control are significantly impaired in patients of drug addiction. This impairment was significantly related to type of substance, duration of use and number of hospitalization and may contribute to most of behavioral disturbances found in addicts and need much attention during tailoring of treatment programs.

Abstract Background Mental fitness for work is the ability of workers to perform their work without risks for themselves or others. Mental fitness was a neglected area of practice and research. Mental ill health at work seems to be rising as a cause of disablement. Psychiatrists who may have had no experience in relating mental health to working conditions are increasingly being asked to undertake these examinations. This research was done to explore the relationship of mental ill health and fitness to work and to recognize the differences between fit and unfit mentally ill patients. Methods This study was cross sectional one. All cases referred to Al-Amal complex for assessment of mental fitness during a period of 12 months were included. Data collected included demographic and clinical characteristics, characteristics of the work environment and data about performance at work. All data was subjected to statistical analysis. Results Total number of cases was 116, the mean age was 34.5 ± 1.4. Females were 35.3% of cases. The highly educated patients constitute 50.8% of cases. The decision of the committee was fit for regular work for 52.5%, unfit for 19.8% and modified work for 27.7%. The decision was appreciated only by 29.3% of cases. There were significant differences between fit, unfit and modified work groups. The fit group had higher level of education, less duration of illness, and better performance at work. Patients of the modified work group had more physical hazards in work environment and had more work shift and more frequent diagnosis of substance abuse. The unfit group had more duration of illness, more frequent hospitalizations, less productivity, and more diagnosis of schizophrenia. Conclusion There are many factors affecting the mental fitness the most important are the characteristics of work environment and the most serious is the overall safety of patient to self and others. A lot of ethical and legal issues should be kept in mind during such assessment as patient's rights, society's rights, and the laws applied to unfit people.

Abstract Background Little is known about how optimism/pessimism and health-related quality of life compare across cultures. Methods Three samples of pregnant women in their final trimester were recruited from China, Ghana, and the United States (U.S.). Participants completed a survey that included the Life Orientation Test - Revised (LOT-R, an optimism/pessimism measure), the Short Form 12 (SF-12, a quality of life measure), and questions addressing health and demographic factors. A three-country set was created for analysis by matching women on age, gestational age at enrollment, and number of previous pregnancies. Anovas with post-hoc pairwise comparisons were used to compare results across the cohorts. Multivariate regression analysis was used to create a model to identify those variables most strongly associated with optimism/pessimism. Results LOT-R scores varied significantly across cultures in these samples, with Ghanaian pregnant women being the most optimistic and least pessimistic and Chinese pregnant women being the least optimistic overall and the least pessimistic in subscale analysis. Four key variables predicted approximately 20% of the variance in overall optimism scores: country of origin (p = .006), working for money (p = .05); level of education (p = .002), and ever being treated for emotional issues with medication (p < .001). Quality of life scores also varied by country in these samples, with the most pronounced difference occurring in the vitality measure. U.S. pregnant women reported far lower vitality scores than both Chinese and Ghanaian pregnant women in our sample. Conclusion This research raises important questions regarding what it is about country of origin that so strongly influences optimism/pessimism among pregnant women. Further research is warranted exploring underlying conceptualization of optimism/pessimism and health related quality of life across countries.

Abstract: The interaction between menin and histone-lysine N-methyltransferase 2A (KMT2A) is a critical dependency for KMT2A- or nucleophosmin 1 (NPM1)-altered leukemias and an emerging opportunity for therapeutic development. JNJ-75276617 (bleximenib) is a novel, orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between menin and KMT2A. In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) acute myeloid leukemia (AML) cells, JNJ-75276617 inhibited the association of the menin-KMT2A complex with chromatin at target gene promoters, resulting in reduced expression of several menin-KMT2A target genes, including MEIS1 and FLT3. JNJ-75276617 displayed potent antiproliferative activity across several AML and acute lymphoblastic leukemia (ALL) cell lines and patient samples harboring KMT2A or NPM1 alterations in vitro. In xenograft models of AML and ALL, JNJ-75276617 reduced leukemic burden and provided a significant dose-dependent survival benefit accompanied by expression changes of menin-KMT2A target genes. JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice. Interestingly, JNJ-75276617 showed potent antiproliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A cocrystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903)., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Despite the growing body of literature supporting the use of point-of-care lung ultrasound (POC-LU) in neonates, its adoption in Canadian neonatal intensive care units (NICUs) remains limited. This study aimed to identify healthcare providers' perceptions and barriers to implementing POC-LU in Canadian NICUs. We conducted an electronic survey targeting neonatologists, neonatal fellows, neonatal nurse practitioners, and registered respiratory therapists in 20 Canadian NICUs. The survey comprised a 28-item questionnaire divided into four sections: (1) participants' demographics and availability of POC-LU equipment, (2) experience and interest in POC-LU learning, (3) perception of POC-LU as a diagnostic tool, and (4) barriers to POC-LU implementation in NICUs. A total of 194 participants completed the survey, with neonatologists comprising the majority (45%). Nearly half of the participants (48%) reported prior experience with POC-LU. The most prevalent indications for POC-LU use were diagnosis of pleural effusion (90%), pneumothorax (87%), and respiratory distress syndrome (76%). Participants identified the primary barrier to POC-LU adoption as the lack of trained providers available for both training and clinical integration. Notably, most respondents (87%) expressed keen interest in learning neonatal POC-LU. A subgroup analysis based on the responses collected from NICU-directors of 12 institutions yielded results consistent with those of the overall participant pool.     Conclusion: This survey underscores the perceived importance of POC-LU among NICU healthcare providers. A Canadian consensus is required to facilitate the development of widespread training programs as well as standardized clinical practice guideline for its implementation. What is Known: • In recent years, point-of-care lung ultrasound (POC-LU) has emerged as an important tool in neonatology, revolutionizing the assessment and management of critically ill infants. However, its adoption in Canadian Neonatal Intensive Care Units remains limited. What is New: • Most Canadian healthcare providers showed high level of interest in learning POC-LU techniques. Additionally, POC-LU was perceived as a useful tool for diagnosis and guiding intervention in various neonatal respiratory diseases. Nonetheless, the lack of expertise emerged as the primary barrier to its adoption and practice across different groups of participants regardless of their clinical experience level., (© 2024. Crown.)

In neonates with acute lung injury (ALI), targeting lower oxygenation saturations is suggested to limit oxygen toxicity while maintaining vital organ function. Although thresholds for cerebral autoregulation are studied for the management of premature infants, the impact of hypoxia on hemodynamics, tissue oxygen consumption and extraction is not well understood in term infants with ALI. We examined hemodynamics, cerebral autoregulation and fractional oxygen extraction, as measured by near-infrared spectroscopy (NIRS) and blood gases, in a neonatal porcine oleic acid injury model of moderate ALI. We hypothesized that in ALI animals, cerebral oxygen extraction would be increased to a greater degree than kidney or gut oxygen extraction as indicative of the brain's adaptive efforts to increase cerebral oxygen extraction at the expense of splanchnic end organs. Fifteen anesthetized, ventilated 5-day-old neonatal piglets were divided into moderate lung injury by treatment with oleic acid or control (sham injection). The degree of lung injury was quantified at baseline and after establishment of ALI by blood gases, ventilation parameters and calculated oxygenation deficit, hemodynamic indices by echocardiography and lung injury score by ultrasound. PaCO 2 was maintained constant during ventilation. Cerebral, renal and gut oxygenation was determined by NIRS during stepwise decreases in inspired oxygen from 50% to 21%, correlated with PaO 2 and PvO 2 ; changes in fractional oxygen extraction (ΔFOE) were calculated from NIRS and from regional blood gas samples. The proportion of cerebral autoregulation impairment attributable to blood pressure, and to hypoxemia, was calculated from autoregulation nomograms. ALI manifested as hypoxemia with increasing intrapulmonary shunt fraction, decreased lung compliance and increased resistance, and marked increase in lung ultrasound score. Brain, gut and renal NIRS, obtained from probes placed over the anterior skull, central abdomen and flank, respectively, correlated with concurrent SVC (brain) or IVC (gut, renal) PvO 2 and SvO 2 . Cerebral autoregulation was impaired after ALI as a function of blood pressure at all FiO 2 steps, but predominantly by hypoxemia at FiO 2 < 40%. Cerebral ΔFOE was higher in ALI animals at all FiO 2 steps. We conclude that in an animal model of neonatal ALI, cerebrovascular blood flow regulation is primarily dependent on oxygenation. There is not a defined oxygenation threshold below which cerebral autoregulation is impaired in ALI. Cerebral oxygen extraction is enhanced in ALI, reflecting compensation for exhausted cerebral autoregulation due to the degree of hypoxemia and/or hypotension, thereby protecting against tissue hypoxia.

A spectrum of critical abdominal pathological conditions that might occur in neonates and children warrants real-time point-of-care abdominal ultrasound (abdominal POCUS) assessment. Abdominal radiographs have limited value with low sensitivity and specificity in many cases and have no value in assessing abdominal organ perfusion and microcirculation (Rehan et al. in Clin Pediatr (Phila) 38(11):637-643, 1999). The advantages of abdominal POCUS include that it is non-invasive, easily available, can provide information in real-time, and can guide therapeutic intervention (such as paracentesis and urinary bladder catheterization), making it a crucial tool for use in pediatric and neonatal abdominal emergencies (Martínez Biarge et al. in J Perinat Med 32(2):190-194, 2004) and (Alexander et al. in Arch Dis Child Fetal Neonatal Ed 106(1):F96-103, 2021).  Conclusion: Abdominal POCUS is a dynamic assessment with many ultrasound markers of gut injury by two dimensions (2-D) and color Doppler (CD) compared to the abdominal X-ray; the current evidence supports the superiority of abdominal POCUS over an abdominal X-ray in emergency situations. However, it should still be considered an adjunct rather than replacing abdominal X-rays due to its limitations and operator constraints (Alexander et al. in Arch Dis Child Fetal Neonatal Ed 106(1):F96-103, 2021). What is Known: • Ultrasound is an important modality for the assessment of abdominal pathologies. What is New: • The evidence supports the superiority of abdominal POCUS over an abdominal X-ray in emergency abdominal situations in the neonatal and pediatric intensive care units., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We aimed to evaluate the impact of the registered respiratory therapist (RRT) performed point-of-care lung ultrasound (POC-LUS) on patient management in the neonatal intensive care unit (NICU)., Study Design: This is a retrospective cohort study of neonates who had RRT performed POC-LUS in two level III NICUs in Winnipeg, Manitoba, Canada. The analysis aims mainly to describe the implementation process of the POC-LUS program. The primary outcome was the prediction of the change in clinical management., Results: A total of 136 neonates underwent 171 POC-LUS studies during the study period. POC-LUS resulted in a change in clinical management following 113 POC-LUS studies (66%), while it supported continuing the same management in 58 studies (34%). The lung ultrasound severity score (LUSsc) was significantly higher in the group with worsening hypoxemic respiratory failure and on respiratory support than infants on respiratory support and stable or not on respiratory support, p  < 0.0001. LUSsc was significantly higher in infants on either noninvasive or invasive than those not on respiratory support, p -value <0.0001., Conclusion: RRT performed POC-LUS service utilization in Manitoba improved and guided the clinical management of a significant proportion of patients who received the service., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To evaluate the sensitivity and specificity of clinical, laboratory, and radiological markers and the neonatologist-performed intestinal ultrasound (NP-IUS) for treatment interventions in preterm neonates who developed necrotizing enterocolitis (NEC)., Study Design: This was a case-control study of preterm neonates < 35 weeks with a diagnostic workup for NEC. The diagnostic workup included NP-IUS performed by trained neonatologists using a standard protocol, abdominal roentgenogram (AXR), and laboratory investigations. Intestinal ultrasound (IUS) performed by two neonatologists was standardized to detect 11 injury markers. AXRs were read independently by experienced pediatric radiologists. The investigators who retrospectively interpreted the IUS were blinded to the clinical and treatment outcomes., Results: A total of 111 neonates were assessed. Fifty-four did not require intervention and formed the control group. Twenty cases were treated medically, 21 cases were treated with late surgery for stricture or adhesions, and 16 were treated with early surgery. The integrated model of cumulative severity of ultrasound markers, respiratory and hemodynamic instability, abdominal wall cellulitis, and C- reactive protein > 16 mg/L had an area under the curve (AUC) of 0.89 (95% confidence interval [CI]: 0.83-0.94%, p  < 0.0001) for diagnosing NEC requiring surgical intervention. We also investigated the utility of Bell's classification to diagnose either the need for surgery or death, and it had an AUC of 0.74 (95% CI: 0.65-0.83%, p  < 0.0001)., Conclusion: In this cohort, a combination of specific IUS markers and clinical signs of instability, abdominal wall cellulitis, plus laboratory markers were diagnostic of NEC requiring interventions., Key Points: · The diagnosis of necrotizing enterocolitis requires a combination of markers.. · The combination of specific ultrasound markers, clinical signs, and laboratory markers were diagnostic of NEC requiring intervention.. · The intestinal ultrasound performed by a trained neonatologist was the most sensitive diagnostic marker of NEC requiring surgical intervention.., Competing Interests: None declared., (Thieme. All rights reserved.)

In this systematic review and meta-analysis, we aimed to review the characteristics and outcomes of the newborns of Coronavirus disease 2019 (COVID-19) infected pregnant women. We conducted an online bibliographic search using the following electronic databases: MEDLINE via PubMed, Scopus, Web of Science, and Cochrane Central. Studies were deemed eligible if they recruited newborns from mothers with confirmed COVID-19 and reported the perinatal outcomes of neonatal COVID-19 cases. A total of 20 studies were included. Neonates born to mothers with positive COVID-19 results have been shown to have significantly lower birth weights (mean difference, MD = -48.54 g, p = 0.04), increased risks of fetal distress (odds ratio, OR = 1.76, p < 0.00001), respiratory distress (OR = 1.96, p = 0.006), premature birth (OR = 2.08, p < 0.00001), neonatal death (OR = 2.20, p = 0.004), and a lower 5-minute Apgar score (OR = 1.44, p = 0.02). Additionally, they were more likely to be admitted to the neonatal intensive care unit (NICU) (OR = 2.25, p = 0.007) and test positive for COVID-19 themselves (OR = 9.88, p = 0.03). However, other parameters, such as risks for malformations, mechanical ventilation, hypoglycemia, and sepsis, appeared to be comparable between the two groups. Maternal infection with COVID-19 during pregnancy is associated with several neonatal outcomes, some of which are adverse and others that do not show significant deviation from norms. While our meta-analysis clearly illustrates heightened risks associated with premature birth, reduced neonatal weight, and other challenges, it also emphasizes that not all neonatal outcomes can be directly attributed to maternal SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, El-Atawi et al.)

Background: The normative blood pressure values in preterm infants still not well defined during postnatal transition. We aimed to create normative blood pressure (BP) reference values in preterm infants <29 weeks gestational age recorded hourly during the postnatal transition., Methods: We included only data from hemodynamically stable newborns. Only BP values measured by umbilical arterial catheter (UAC) were included. The regression model showed that only gestational age and postnatal age in hours determine the BP., Results: We included 206 out of 547 admitted preterm infants. The BP increases with increasing gestational ages and overtime during the postnatal transition. We constructed 5 BP centile values for each gestational group. BP histograms show that the BP most of the time fluctuated between the 5th and 75th centile values, particularity during day one of life., Conclusions: The BP trend values gradually increase in stable preterm infants during the postnatal transition, and preterm infants who do not follow this trend might require hemodynamics assessment., Impact: The normative blood pressure is increasing gradually during the first 3 days after birth and is different with gestational ages. This is first normative blood pressure centile values in stable preterm infant and based on invasive blood pressure monitoring. The data enable more accurate monitoring of hemodynamics in preterm infants during postnatal transition., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Our objective is to scaffold the natural behaviors that support scientific thinking and STEM learning in children through museum exhibit design and development. Here, we describe a collaborative research-to-practice initiative called "Designing Museum Exhibits to Support the Development Scientific Thinking in Informal Learning Environments: A University-Museum-Community Partnership," in which we document natural behavior in the context of children's informal learning environments and detail our plans to translate our findings into exhibit development. This initiative is part of a long-standing university (UT Austin, Center for Applied Cognitive Science), museum (Thinkery-Austin Children's Museum), and community (Austin's Early Learner Community) partnership called Thinkery Connect. Our first aim here is to review best practices in STEM exhibit design that fosters scientific thinking. We will then describe the design of a study on exhibit signage to promote scientific thinking development. We will also discuss our plans to develop and evaluate exhibit signage in context. Our long-term objective is to deepen engagement in activities that build scientific thinking for visitors at children's museums like Thinkery, at home, and in the community., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To assess the effect of cardiovascular medications on the neurodevelopment of preterm infants, as measured by calculated cumulative time of vasoactive-inotropic score (VISct)., Methods: A retrospective study was conducted on preterm infants who developed significant hypotension defined as a mean BP more than 2SDs below the mean for GA and received treatment with duration > 6 hours for each hypotensive episode, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). The composite Bayley III was reported from the high-risk follow-up clinic for the surviving infants between 18 to 21 months corrected age., Results: VISct was significantly higher in infants with abnormal neurodevelopment. Cognitive Bayley was the most affected component with median (IQR) VISct 882.5(249,2047) versus 309(143,471) (p-value 0.012), followed by language function with VISct 786(261,1563.5), versus 343(106.75,473.75) (p-value 0.016) when those with Bayley III <85 were compared with those with normal Bayley IIIs., Conclusion: High VISct scores may have negative effect on cognitive and language neurodevelopmental outcomes.

This systematic review and meta-analysis aimed to assess the utility of near-infrared spectroscopy (NIRS) in predicting the perinatal outcomes of neonates with hypoxic-ischemic encephalopathy (HIE). We conducted a literature search on Medline via PubMed, Web of Science, Scopus, and CENTRAL Library. We included studies that utilized early NIRS monitoring to study the accuracy of NIRS in predicting the perinatal outcomes of neonates with hypoxic-ischemic encephalopathy. Nine studies that met our eligibility criteria were included. These studies were published between 2012 and 2023. In this meta-analysis, no significant differences in regional cerebral oxygen saturation (cSpO2) were found between normal and abnormal groups at 12 hours (MD = 0.21, 95% CI: -6.39 to 6.82, P = 0.95) and 24 hours (MD = -1.96, 95% CI: -6.95 to 3.03, P = 0.44). However, at 48 hours, cSpO2 was significantly lower in the normal group (MD = -4.9, 95% CI: -5.91 to -3.89, P < 0.00001). At 72 hours, our analysis revealed a significant difference with lower cSpO2 in the normal group (MD = -3.0, 95% CI: -5.5 to -0.5, P = 0.02). Regarding cerebral fractional tissue oxygen extraction (FTOE), no significant differences were observed at 12 hours (MD = 0.03, 95% CI: -0.02 to 0.09, P = 0.24). After 24 hours, the normal group exhibited lower FTOE (MD = -0.03, 95% CI: -0.04 to -0.01, P < 0.001), while after 48 hours, the normal group had higher FTOE (MD = 0.07, 95% CI: 0.04 to 0.10, P < 0.0001). Early cerebral NIRS monitoring is beneficial in predicting the outcomes of HIE in term neonates. Our analysis showed that several NIRS parameters, such as regional cSpO2 and cerebral FTOE, are significantly associated with adverse outcomes in the first 72 hours of birth., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, El-Atawi et al.)

A notable decrease in conventional cigarette smoking has been witnessed on a global scale. However, this decrease has been accompanied by an equally striking global increase in the consumption of alternative tobacco products (ATPs), namely e-cigarettes and midwakh in the Arabian Gulf region. A literature review was used to outline the chemical composition of these two ATPs and review their impacts on health. The study was conducted using databases like PubMed, Google Scholar, MDPI, and WorldCat. The literature search included terms such as "e-cigarettes," "midwakh," "dokha," "heath impacts," "psychological effects," "social influences," and "cigarette smoking" with emphasis on literature from the Arabian Gulf region. Data shows that midwakh contains markedly high levels of tar, nicotine, and various compounds of notable effects on the human body. Similarly, it was found that e-cigarettes contain non-negligible amounts of nicotine and other chemical compounds that may not have been extensively investigated. Alarming reports of system-specific effects brought about by midwakh, and e-cigarette consumption, have been reported, although further research is needed to deduce the mechanism. We also discussed some of the social and psychological factors leading to their consumption within this population. Hence, this review raises questions around the safety of these two types of ATPs and encourages comprehensive studies globally and regionally., (© 2023. The Author(s).)

Background: University students are more likely to experience stress, anxiety, and depression. All these factors are regarded as psychological contributors to fibromyalgia syndrome (FMS)., Aim: To investigate the prevalence and determinants of FMS among university students and its impact on their health-related quality of life (HRQoL)., Methods: This online survey-based study involved 2146 university students who were recruited from various faculties at several Egyptian universities. The participants' demographics, medical history, academic pursuits, and sleep data were collected. To identify the existence of FMS, the 2016 updates to the 2010/2011 FMS diagnostic criteria were used. Additionally, the participants completed the Short-Form Health Survey-36 (SF-36)., Results: The mean age was 21.26 ± 2.015 years and 76% were females. Of 2146 students, 266 (12.4%) fulfilled the criteria of FMS. FMS group had a significantly lower age (p < 0.001) with predominant female gender (89.5% vs. 74.1%, p < 0.001), positive family history of FMS (8.6% vs. 3.7%, p < 0.001), previous history of traffic accident (10.2% vs. 6.8%, p = 0.045), lower level of physical activity (p = 0.002),higher time spent in study per week (p = 0.002), lower sleep time (p = 0.002), with frequent walk up (p < 0.001) and snoring (p < 0.001) during sleep. Regarding HRQoL, students with FMS had significantly lower scores than students without in all domains., Conclusion: FMS is prevalent among Egyptian university students and is linked to female gender, positive family history, lower levels of physical activity, and more time spent studying each week. FMS has a negative impact on HRQoL. Therefore, early detection and treatment are recommended., (© 2023. The Author(s).)

Central vascular access is frequently required for preterm infants. Confirmation of positioning of central line is typically on chest and abdominal radiographs; POCUS is a relatively novel diagnostic method. Misdiagnosis is the main concern limiting use of this modality. The aim of this study is to validate our standard protocol accuracy in locating the central catheter position by correlating catheter position as determined by POCUS with radiographs. Premature babies < or equal to 30 weeks gestation who had peripheral central lines or surgical lines were enrolled. Confirmation of line position by radiographs was compared to images obtained through a specific US protocol technique. The operator of US exam was blinded to the radiograph findings. All images were reviewed by two radiologists who were blinded to the radiograph findings. 35 central line placements were assessed. 22 lines were inserted in the UL, and 13 were inserted in the LL with a total of 91 ultrasound scans and radiographs. The position of the line was interpreted as normal in 79/91 scans with interpreter reliability of [Formula: see text]=0.778 (p < 0.001), sensitivity of 0.83 and specificity of 0.96, and positive predictive value of 0.77 and negative predictive value of 0.97. There was no significant difference between the ultrasound interpretation and the radiograph interpretation of UL and LL.  Conclusion: The protocol of POCUS that we propose is a reliable tool for assessing the central line positions in preterm infants. What is Known: • POCUS is a reliable tool assessing the central line positions in preterm infants. What is New: • The protocol of POCUS that we propose is a reliable tool for assessing the central line positions in preterm infants., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In December 2022, the American Academy of Pediatrics released a clinical guideline for point-of-care ultrasonography (POCUS) in the neonatal intensive care unit (NICU). The guideline outlined the development and current status of POCUS in the NICU, and summarized the key elements and implementation guidelines for successful implementation of POCUS in the NICU. This article provides an overview of the key points of the clinical guideline and analyzes the current status of POCUS in China, providing a reference for the implementation of POCUS in neonatal care in China.

Sudden unexpected clinical deterioration or cardiorespiratory instability is common in neonates and is often referred as a "crashing" neonate. The established resuscitation guidelines provide an excellent framework to stabilize and evaluate these infants, but it is primarily based upon clinical assessment only. However, clinical assessment in sick neonates is limited in identifying underlying pathophysiology. The Crashing Neonate Protocol (CNP), utilizing point-of-care ultrasound (POCUS), is specifically designed for use in neonatal emergencies. It can be applied both in term and pre-term neonates in the neonatal intensive care unit (NICU). The proposed protocol involves a stepwise systematic assessment with basic ultrasound views which can be easily learnt and reproduced with focused structured training on the use of portable ultrasonography (similar to the FAST and BLUE protocols in adult clinical practice). We conducted a literature review of the evidence-based use of POCUS in neonatal practice. We then applied stepwise voting process with a modified DELPHI strategy (electronic voting) utilizing an international expert group to prioritize recommendations. We also conducted an international survey among a group of neonatologists practicing POCUS. The lead expert authors identified a specific list of recommendations to be included in the proposed CNP. This protocol involves pre-defined steps focused on identifying the underlying etiology of clinical instability and assessing the response to intervention.Conclusion: To conclude, the newly proposed POCUS-based CNP should be used as an adjunct to the current recommendations for neonatal resuscitation and not replace them, especially in infants unresponsive to standard resuscitation steps, or where the underlying cause of deterioration remains unclear. What is known? • Point-of-care ultrasound (POCUS) is helpful in evaluation of the underlying pathophysiologic mechanisms in sick infants. What is new? • The Crashing Neonate Protocol (CNP) is proposed as an adjunct to the current recommendations for neonatal resuscitation, with pre-defined steps focused on gaining information regarding the underlying pathophysiology in unexplained "crashing" neonates. • The proposed CNP can help in targeting specific and early therapy based upon the underlying pathophysiology, and it allows assessment of the response to intervention(s) in a timely fashion., (© 2022. The Author(s).)

Automatic facial expression recognition (AFER), sometimes referred to as emotional recognition, is important for socializing. Automatic methods in the past two years faced challenges due to Covid-19 and the vital wearing of a mask. Machine learning techniques tremendously increase the amount of data processed and achieved good results in such AFER to detect emotions; however, those techniques are not designed for masked faces and thus achieved poor recognition. This paper introduces a hybrid convolutional neural network aided by a local binary pattern to extract features in an accurate way, especially for masked faces. The basic seven emotions classified into anger, happiness, sadness, surprise, contempt, disgust, and fear are to be recognized. The proposed method is applied on two datasets: the first represents CK and CK +, while the second represents M-LFW-FER. Obtained results show that emotion recognition with a face mask achieved an accuracy of 70.76% on three emotions. Results are compared to existing techniques and show significant improvement., Competing Interests: Conflict of interestAuthors declare that there is neither funding nor conflict of interest., (© The Author(s) 2023.)

Point-of-care ultrasonography (POCUS) refers to the use of portable imaging performed by the provider clinician at the bedside for diagnostic, therapeutic, and procedural purposes. POCUS could be considered an extension of the physical examination but not a substitute for diagnostic imaging. Use of POCUS in emergency situations can be lifesaving in the NICU if performed in a timely fashion for cardiac tamponade, pleural effusions, pneumothorax, etc, with potential for enhancing quality of care and improving outcomes. In the past 2 decades, POCUS has gained significant acceptance in clinical medicine in many parts of the world and in many subspecialties. Formal accredited training and certification programs are available for neonatology trainees as well as for many other subspecialties in Canada, Australia, and New Zealand. Although no formal training program or certification is available to neonatologists in Europe, POCUS is widely available to providers in NICUs. A formal institutional POCUS fellowship is now available in Canada. In the United States, many clinicians have the skills to perform POCUS and have incorporated it in their daily clinical practice. However, appropriate equipment remains limited, and many barriers exist to POCUS program implementation. Recently, the first international evidence-based POCUS guidelines for use in neonatology and pediatric critical care were published. Considering the potential benefits, a recent national survey of neonatologists confirmed that the majority of clinicians were inclined to adopt POCUS in their clinical practice if the barriers could be resolved. This technical report describes many potential POCUS applications in the NICU for diagnostic and procedural purposes., (Copyright © 2022 by the American Academy of Pediatrics.)

Fiber Bragg grating (FBG) technology has shown a mutation in developing fiber optic-based sensors because of their tiny size, high dielectric strength, distributed sensing, and immunity to high voltage and magnetic field interference. Therefore, FBG sensors significantly improve performance and accuracy in the world of measurements. The reflectivity and bandwidth are the main parameters that can dramatically affect the sensing performance and accuracy. Each industrial application has its requirements regarding the reflectivity and bandwidth of the reflected wavelength. Optimizing such problems with multi-objective functions that might t with each other based on applications' needs is a big challenge. Therefore, this paper presents an optimization method based on the nondominated sorting genetic algorithm II (NSGA-II), aiming at determining the optimum grating parameters to suit applications' needs. To sum up, the optimization process aims to convert industrial applications' requirements, including bandwidth and reflectivity, into the manufacturing setting of FBG sensors, including grating length and modulation refractive index. The method has been implemented using MATLAB and validated with other research work in the literature. Results proved the capability of the new way to determine the optimum grating parameters for fulfilling application requirements.

This study's primary aim was to assess whether end-expiratory lung ultrasound severity score (expLUSsc) at Day 3 of life, the second week of life, and before weaning off nasal continuous positive airway pressure (nCPAP) can predict the weaning readiness off nCPAP trial in preterm infants. The secondary aim was to evaluate the value of adding lung tidal recruitment (LTR) to expLUSsc (expLUSsc-plus-LTR) to improve predictability. We conducted a prospective study on premature infants <33 weeks of gestation. Point-of-care lung ultrasound (POC-LUS) was performed on Day 3, the second week of life, before and after the trial off nCPAP. expLUSsc, pleural thickness, and LTR were assessed. A receiver operator curve was constructed to evaluate the ability of POC-LUS to predict the weaning readiness off nCPAP. A total of 148 studies were performed on 39 infants, of them 12 weaned off nCPAP from the first trial and 27 infants failed attempts off nCPAP. An expLUSsc cut-off 8 before the first trial of weaning off nCPAP has a sensitivity and specificity of 88% and 90%, and positive and negative predictive values of 87% and 92%, respectively, with area under the curve (AUC) was 0.87 (CI: 0.8-0.93), p < .0001. If LTR is added to an expLUSsc cut-off 8 (expLUSsc-plus-LTR) before the first trial of weaning, then sensitivity and specificity of 95% and 90%, and positive and negative predictive values of 88% and 90%, respectively, with AUC was 0.95 (CI: 0.91-0.99), p < .0001. In conclusion, this study demonstrated the ability of POC-LUS to predict the weaning readiness off nCPAP in premature infants. The use of this simple bedside noninvasive test can potentially avoid the exposure of premature infants to multiple unsuccessful weaning cycles., (© 2022 Wiley Periodicals LLC.)

Objective: To evaluate the utility of a point of care lung ultrasound (POC-LUS) on patient management in the Neonatal Intensive Care Unit (NICU)., Study Design: A retrospective cohort study of neonates who had POC-LUS from 2016 to 2020 in two-level III NICUs in Winnipeg, Manitoba, Canada. The primary outcome was the change in clinical management. The analysis aims mainly to describe the implementation process of the POC-LUS program., Results: A total of 956 neonates underwent 4076 POC-LUS studies during the study period. The number of POC-LUS studies increased significantly every year, from 316 (in 2016) to 1257 (in 2020) (p < 0.001). POC-LUS resulted in a change in clinical management following 2528 POC-LUS studies (62%), while it supported continuing the same management in 1548 studies (38%)., Conclusion: POC-LUS in Manitoba increased since its inception and led to an alteration in the clinical management in a significant proportion of patients who received the service., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Pollution of the marine environment by plastic marine debris has become one of the most pervasive threats impacting marine environments. In this study, for the first time, we evaluate the polymer types of the plastic marine debris ingested by 49 green and 14 loggerhead sea turtle strandings in the Gulf of Oman. Plastic marine debris was ingested by 73.5% of green and 42.9% of loggerhead sea turtles in this study. Overall, evidence suggested that green sea turtles from the Gulf of Oman coast of the United Arab Emirates ingested high levels of plastic marine debris, predominantly Polypropylene (PP) & Polyethylene (PE), followed by Nylon, PP-PE mixture, Polystyrene (PS), Poly vinyl chloride (PVC) and Ethylene vinyl acetate (EVA), respectively. Loggerhead sea turtles also ingested high levels of plastic marine debris, which also predominantly consisted of PP & PE, followed by PP-PE mixture, Nylon and PS. While recent studies were directed into polymer characterization of micro-plastics in aquatic life, our study focuses on macro-plastics which impose significantly greater risks., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple myeloma cells in preclinical studies., Objective: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma., Patients and Methods: To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC 50 and EC 90 values from an ex vivo cytotoxicity assay)., Results: The doses predicted to have average serum concentrations between the EC 50 and EC 90 range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC 90 . The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC 90 . All patients who responded to the RP2D of teclistamab had exposure above the maximum EC 90 in both serum and bone marrow on cycle 3, Day 1 of treatment., Conclusions: Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody's therapeutic range., Clinical Trial Registration: NCT03145181, date of registration: May 9, 2017., (© 2022. The Author(s).)

The role of autophagy in lung cancer cells exposed to waterpipe smoke (WPS) is not known. Because of the important role of autophagy in tumor resistance and progression, we investigated its relationship with WP smoking. We first showed that WPS activated autophagy, as reflected by LC3 processing, in lung cancer cell lines. The autophagy response in smokers with lung adenocarcinoma, as compared to non-smokers with lung adenocarcinoma, was investigated further using the TCGA lung adenocarcinoma bulk RNA-seq dataset with the available patient metadata on smoking status. The results, based on a machine learning classification model using Random Forest, indicate that smokers have an increase in autophagy-activating genes. Comparative analysis of lung adenocarcinoma molecular signatures in affected patients with a long-term active exposure to smoke compared to non-smoker patients indicates a higher tumor mutational burden, a higher CD8+ T-cell level and a lower dysfunction level in smokers. While the expression of the checkpoint genes tested-PD-1, PD-L1, PD-L2 and CTLA-4-remains unchanged between smokers and non-smokers, B7-1, B7-2, IDO1 and CD200R1 were found to be higher in non-smokers than smokers. Because multiple factors in the tumor microenvironment dictate the success of immunotherapy, in addition to the expression of immune checkpoint genes, our analysis explains why patients who are smokers with lung adenocarcinoma respond better to immunotherapy, even though there are no relative differences in immune checkpoint genes in the two groups. Therefore, targeting autophagy in lung adenocarcinoma patients, in combination with checkpoint inhibitor-targeted therapies or chemotherapy, should be considered in smoker patients with lung adenocarcinoma.