The Defective in Autoregulation (DAR) gene of Medicago truncatula encodes a protein involved in regulating nodulation and arbuscular mycorrhiza.

BACKGROUND: Legumes utilize a long-distance signaling feedback pathway, termed Autoregulation of Nodulation (AON), to regulate the establishment and maintenance of their symbiosis with rhizobia. Several proteins key to this pathway have been discovered, but the AON pathway is not completely understood. RESULTS: We report a new hypernodulating mutant, defective in autoregulation, with disruption of a gene, DAR (Medtr2g450550/MtrunA17_Chr2g0304631), previously unknown to play a role in AON. The dar-1 mutant produces ten-fold more nodules than wild type, similar to AON mutants with disrupted SUNN gene function. As in sunn mutants, suppression of nodulation by CLE peptides MtCLE12 and MtCLE13 is abolished in dar. Furthermore, dar-1 also shows increased root length colonization by an arbuscular mycorrhizal fungus, suggesting a role for DAR in autoregulation of mycorrhizal symbiosis (AOM). However, unlike SUNN which functions in the shoot to control nodulation, DAR functions in the root. CONCLUSIONS: DAR encodes a membrane protein that is a member of a small protein family in M. truncatula. Our results suggest that DAR could be involved in the subcellular transport of signals involved in symbiosis regulation, but it is not upregulated during symbiosis. DAR gene family members are also present in Arabidopsis, lycophytes, mosses, and microalgae, suggesting the AON and AOM may use pathway components common to other plants, even those that do not undergo either symbiosis.

Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker- payload.

The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.

A novel bispecific antibody drug conjugate targeting HER2 and HER3 with potent therapeutic efficacy against breast cancer.

Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. Bispecific targeting could enhance the efficacy and safety of ADC by improving its specificity, affinity and internalization. In this study we constructed a HER2/HER3-targeting bispecific ADC (BsADC) and characterized its physiochemical properties, target specificity and internalization in vitro, and assessed its anti-tumor activities in breast cancer cell lines and in animal models. The HER2/HER3-targeting BsADC had a drug to antibody ratio (DAR) of 2.89, displayed a high selectivity against the target JIMT-1 breast cancer cells in vitro, as well as a slightly higher level of internalization than HER2- or HER3-monospecific ADCs. More importantly, the bispecific ADC potently inhibited the viability of MCF7, JIMT-1, BT474, BxPC-3 and SKOV-3 cancer cells in vitro. In JIMT-1 breast cancer xenograft mice, a single injection of bispecific ADC (3 mg/kg, i.v.) significantly inhibited the tumor growth with an efficacy comparable to that caused by combined injection of HER2 and HER3-monospecific ADCs (3 mg/kg for each). Our study demonstrates that the bispecific ADC concept can be applied to development of more potent new cancer therapeutics than the monospecific ADCs.

Risk Stratification, Intention to Fast, and Outcomes of Fasting During Ramadan in People With Diabetes Presenting to a Tertiary Care Hospital.

OBJECTIVE: The objectives of this study were to evaluate the stratification of people with diabetes mellitus (DM) based on the International Diabetes Federation-Diabetes and Ramadan 2021 risk calculator into different risk categories and assess their intentions to fast and outcomes of fasting during the holy month of Ramadan. METHODS: This was a 3-month prospective study that was performed from February 9, 2023, to May 6, 2023 (6 weeks before Ramadan until 6 weeks after Ramadan), at a tertiary care hospital in Pakistan. Data regarding glycemic control, characteristics and complications of diabetes, comorbidities, and the various factors that influence fasting were gathered from patients of either sex aged 18 to 80 years with any type of diabetes. The International Diabetes Federation-Diabetes and Ramadan 2021 risk calculation and recommendation were made accordingly for each patient. RESULTS: This study comprised of 460 participants with DM, with 174 males (37.8%) and 286 females (62.2%). The risk categorization showed that 209 (45.4%), 107 (23.3%), and 144 (31.3%) of the participants were in the low-, moderate-, and high-risk categories, respectively. Of the 144 high-risk patients who fasted, 57.9% experienced hypoglycemia (P <.0001). The recommendation of fasting showed statistically significant differences with risk categories, intention to fast, hypoglycemia, type of DM, duration of DM, level of glycemic control, and days of fasting (P <.001). CONCLUSION: A statistically significant number of participants in the high-risk group who fasted experienced complications. This reiterates the importance of rigorous adherence to the medical recommendations.

Incidence and determinants of perinatal mortality in five urban hospitals in Dar es Salaam, Tanzania: a cohort study with an embedded case-control analysis.

INTRODUCTION: Tanzania has one of the highest burdens of perinatal mortality, with a higher risk among urban versus rural women. To understand the characteristics of perinatal mortality in urban health facilities, study objectives were: I. To assess the incidence of perinatal deaths in public health facilities in Dar es Salaam and classify these into a) pre-facility stillbirths (absence of fetal heart tones on admission to the study health facilities) and b) intra-facility perinatal deaths before discharge; and II. To identify determinants of perinatal deaths by comparing each of the two groups of perinatal deaths with healthy newborns. METHODS: This was a retrospective cohort study among women who gave birth in five urban, public health facilities in Dar es Salaam. I. Incidence of perinatal death in the year 2020 was calculated based on routinely collected health facility records and the Perinatal Problem Identification Database. II. An embedded case-control study was conducted within a sub-population of singletons with birthweight ≥ 2000 g (excluding newborns with congenital malformations); pre-facility stillbirths and intra-facility perinatal deaths were compared with 'healthy newborns' (Apgar score ≥ 8 at one and ≥ 9 at five minutes and discharged home alive). Descriptive and logistic regression analyses were performed to explore the determinants of deaths. RESULTS: A total of 37,787 births were recorded in 2020. The pre-discharge perinatal death rate was 38.3 per 1,000 total births: a stillbirth rate of 27.7 per 1,000 total births and an intra-facility neonatal death rate of 10.9 per 1,000 live births. Pre-facility stillbirths accounted for 88.4% of the stillbirths. The case-control study included 2,224 women (452 pre-facility stillbirths; 287 intra-facility perinatal deaths and 1,485 controls), 99% of whom attended antenatal clinic (75% with more than three visits). Pre-facility stillbirths were associated with low birth weight (cOR 4.40; (95% CI: 3.13-6.18) and with maternal hypertension (cOR 4.72; 95% CI: 3.30-6.76). Intra-facility perinatal deaths were associated with breech presentation (aOR 40.3; 95% CI: 8.75-185.61), complications in the second stage (aOR 20.04; 95% CI: 12.02-33.41), low birth weight (aOR 5.57; 95% CI: 2.62-11.84), cervical dilation crossing the partograph's action line (aOR 4.16; 95% CI:2.29-7.56), and hypertension during intrapartum care (aOR 2.9; 95% CI 1.03-8.14), among other factors.  CONCLUSION: The perinatal death rate in the five urban hospitals was linked to gaps in the quality of antenatal and intrapartum care, in the study health facilities and in lower-level referral clinics. Urgent action is required to implement context-specific interventions and conduct implementation research to strengthen the urban referral system across the entire continuum of care from pregnancy onset to postpartum. The role of hypertensive disorders in pregnancy as a crucial determinant of perinatal deaths emphasizes the complexities of maternal-perinatal health within urban settings.

A modelling approach to compare ADC deconjugation and systemic elimination rates of individual drug-load species using native ADC LC-MS data from human plasma.

Native liquid chromatography mass spectrometry (LC-MS) is a commonly used approach for intact analysis of inter-chain cysteine conjugated antibody-drug conjugates (ADCs). Coupling native LC-MS with affinity capture provides a platform for intact ADC analysis from in vivo samples and characterisation of individual drug load species, specifically the impact of drug linker deconjugation, hydrolysis, and differential clearance in a biological system.This manuscript describes data generated from native LC-MS analysis of ADCs from human plasma, both in vitro incubations and clinical samples. It also details the pharmacokinetic (PK) model built to specifically characterise the disposition of individual drug load species from MMAE and MMAF interchain cysteine conjugated ADCs.In vitro deconjugation and hydrolysis rates were similar across both ADCs. Differential clearance of higher loaded species in vivo was pronounced for the MMAE conjugated ADC, while systemic elimination after accounting for deconjugation was similar across drug loads for the MMAF conjugated ADC. This is the first report of affinity capture native LC-MS analysis, and subsequent modelling of deconjugation, hydrolysis and clearance rates of individual drug load species using clinical data from cysteine conjugated ADCs.

The anthropometric determinants of peak expiratory flow rate among children in Dar Es Salaam, Tanzania.

BACKGROUND: Peak expiratory flow rate (PEFR) is an important tool for assessing lung function, which can be affected by environmental and physical factors such as altitude, nutrition, genetics, age, height, and weight. Conducting a study to assess the correlation between peak expiratory flow rate and anthropometric measurements in Tanzanian schoolchildren is crucial to derive a population-specific prediction formula and further simplify respiratory health assessment. METHODS: This cross-sectional study was conducted in a single center private primary and secondary school in Dar es Salaam, Tanzania using data from an asthma screening camp. Variables of interest were height, weight, Body Mass Index (BMI) and PEFR. Independent t-test was performed to identify any differences in mean flow rate values between different ethnicities and genders. Correlation coefficients (r) were used to observe the relationship between PEFR and anthropometric measurements. A prediction equation by gender was generated using linear regression analysis. Statistical significance was set at the 5% level. All statistical data was analyzed using SPSS version 25.0. RESULTS: The study involved 260 participants with a mean age of 9.5 years. Males were 51.2% and 65% of participants were of Asian ethnicity. PEFR was not observed to differ across the different ethnic groups and genders. Height was found to have the strongest correlation coefficient of 0.745, while BMI had the weakest correlation coefficient of 0.366. The strongest correlation was found with height for females (r = 0.787), while the weakest was with body mass index for boys (r = 0.203). The derived prediction equation for males was PEFR = 279.169 (Height of Student in meters) -134.12, while the predictive equation for females was PEFR = 318.32 (Height of Student in meters) -195.69. CONCLUSION: This study found a strong correlation between PEFR and anthropometric characteristics in school children from Dar es Salaam, Tanzania. A prediction equation by gender for PEFR was developed based on anthropometric characteristics. This equation may be applied in population-based studies or situations where peak flow meters are not readily available. Further research is needed to explore how well this prediction formula performs in other Tanzanian settings and to determine other factors that may affect lung function in this population.

Does the coronal deformity angular ratio affect bracing outcome in adolescent idiopathic scoliosis?

PURPOSE: To examine if coronal deformity angular ratio (C-DAR) serves as a predictor for progression to surgical magnitude in patients with Adolescent Idiopathic Scoliosis (AIS) treated with thoracolumbar sacral orthosis (TLSO). METHODS: Patients with AIS, prescribed a full-time TLSO, Cobb angle 20-40°, Risser 0-2, who wore the brace ≥ 12.9 h and reached skeletal maturity/surgery were included retrospectively. C-DAR was defined as the Cobb angle divided by the number of vertebrae in the curve, yielding a larger value in short curves. The association between C-DAR and the risk of progression to surgical magnitude (> 45°) was assessed. Secondly, we evaluated the association between pre-treatment Cobb angle and in-brace correction on the risk of progression to > 45°. RESULTS: We included 165 patients with a mean Cobb angle of 30 ± 6°. Of these, 46/165 (28%) progressed ≥ 6° and 26/165 (16%) reached surgical magnitude at the end of treatment. C-DAR was a significant predictor for risk of progression to surgical magnitude with an OR of 1.9 (CI 1.2-2.9) per unit increase in C-DAR. A threshold value of 5.15 was established and demonstrated an OR 5.9 (CI 2.1-17.9) for curve progression to a surgical magnitude. Likewise, pre-treatment Cobb angle showed a significant OR 1.3(CI 1.2-1.4) per degree increase in Cobb, whereas in-brace % correction showed OR 0.96 (CI 0.93-0.98). CONCLUSION: C-DAR is an independent predictor for progression to a surgical magnitude in AIS patients treated with bracing. Patients with a higher C-DAR should be counseled to help set realistic expectations regarding the likelihood of curve progression despite compliance with brace wear.

Co-profiling reveals distinct patterns of genomic chromatin accessibility and gene expression in pulmonary hypertension caused by chronic hypoxia.

INTRODUCTION: Aberrant gene expression is a key mechanism underlying pulmonary hypertension (PH) development. The alterations of genomic chromatin accessibility and their relationship with the aberrant gene expressions in PH are poorly understood. We used bulk Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing (RNA-seq) in pulmonary artery smooth muscle cells (PASMCs) of chronic hypoxia-exposed rats mimicking group 3 human PH. METHODS: Adult Sprague Dawley rats were commercially obtained from Hunan SJA (Hunan SJA Laboratory Animal Co., Changsha, China) and randomizedly allocated into four groups exposing to nomobaric hypoxia or normoxia for 1 or 28 days respectively. After the assessment of pulmonary hemodynamics, smooth muscle cells were isolated from intralobular arteries and simultaneously subjected to bulk Assay of ATAC-seq and RNA-seq. RESULTS: Hypoxic exposure for continuous 28-days, but not for 1-day, induced established PH phenotypes in rats. ATAC-seq revealed a major distribution of differential accessibility regions (DARs) annotated to the genome in out-of-promoter regions, following 1-day or 28-days hypoxia. 1188 DAR-associated genes and 378 differentially expressed genes (DEGs) were identified in rats after exposure to 1-day hypoxia, while 238 DAR-associated genes and 452 DEGs for 28-days hypoxia. Most of the DAR-associated genes or DEGs in 1-day did not overlap with that of 28-days hypoxia. A Pearson correlation analysis indicated no significant correlation between ATAC-seq and RNA-seq. CONCLUSIONS: The alterations in genomic chromatin accessibility and genes expression of PASMCs in the initial stage of hypoxia are distinct from the established stage of hypoxia-induced PH. The genomic differential accessibility regions may not be the main mechanisms directly underlying the differentially expressed genes observed either in the initial or established stages of PH. Thus the time-course alterations of gene expression and their possible indirect link with genomic chromatin accessibility warrant more attention in mechanistic study of pulmonary hypertension.

Incidence and predictors of post stroke seizure among adult stroke patients admitted at Felege Hiwot compressive specialized hospital, Bahir Dar, North West Ethiopia, 2021: a retrospective follow up study.

BACKGROUND: A post stroke seizure is a period of neurological dysfunction caused by abnormal neuronal activity. Seizures after a stroke have an impact on patients' lives and increase mortality in stroke patients. It also has a negative impact on the prognosis of stroke. However, there is a scarcity of literature in Ethiopia on the occurrence of post-stroke seizures. Therefore, this study aimed to assess the incidence and predictors of post-stroke seizure at Felege Hiwot compressive specialized hospital, North West Ethiopia. METHODS: An institution-based retrospective follow-up study was carried out at Felege Hiwot Compressive Specialized Hospital, North West Ethiopia from July 1, 2017 to June 30, 2021. The records of 568 stroke patients were reviewed using a random sample method. To find predictors of post-stroke seizures, we applied the log-binomial regression model. RESULT: The incidence of post-stroke seizures was 22.18%( 95% CI 18.83%-25.83%). Older age group (ARR = 2.49, 95% CI 1.33-4.69), hemorrhagic stroke (ARR = 1.99, 95% CI 1.25-3.17), surgical intervention (ARR = 1.85, 95% CI 1.22-2.81), and tramadol medication (ARR = 1.85, 95% CI 1.22-2.81) were found to be predictors of post stroke seizure. CONCLUSION: This study revealed that the incidence of post stroke seizure was high and older age, haemorrhagic type of stroke, surgical management, and use of tramadol anti-pain medication are risk factors for post-stroke seizures. Therefore, health care professionals must pay special attention and provide clinical care to patients who have risk factors for post-stroke seizure.

Proportion and associated factors of maternal complications of cesarean sections among mothers who deliver at Bahir Dar City Public Specialized Hospitals, Bahir Dar, Ethiopia.

INTRODUCTION: Cesarean delivery carries both short term and long-term maternal complications. Eventhough it's being a public burden, the proportion of complications and underlying risk factors are not studied well in our setup. This study aimed to assess the proportion and associated factors of complications of cesarean sections among mothers who delivered at Bahir Dar city public specialized hospitals, Bahir Dar, Ethiopia 2021. METHODS: A cross-sectional study was conducted at two specialized Hospitals in Bahir Dar city, Ethiopia. The sample size was 495 mothers who had cesarean section in the time period from January 1, 2020 to December 30, 2020. Checklist was used to retrieve information from the patient medical document. Study population was selected from the operation registration book. Systematic sampling was used after arranging the study frame based on date of operation. Both bivariable and multivariable logistic regression was done. In multivariable logistic regression variables with p value < 0.05 at 95% confidence interval were significantly associated with outcome variable. RESULT: Overall maternal complication rate was 44.04% (95% CI: 39.6-48.5). Living in rural setting (AOR = 4.247,95%CI: 2.765-6.522), having one or more obstetric complication (AOR = 1.913,95% CI: 1.214-3.015), cesarean section done at Second stage of labor (AOR = 4.358,95%CI: 1.841-10.317), having previous cesarean section (AOR = 3.540,95%CI: 2.121-5.910), emergency operation (AOR = 2.967,95%CI: 1.492-5.901), duration of surgery taking more than 60 min (AOR = 3.476,95%CI: 1.521-7.947) were found to be significantly associated with maternal complications. CONCLUSION: The magnitude of maternal complication of cesarean section was higher than most studies. Living in rural setting, having obstetric complications, previous cesarean scar, emergency surgeries, operation done in second stage of labor and prolonged duration of surgery are important predictors of maternal complication. Therefore, we recommend timely and adequate progress of labor evaluation, timely decision for cesarean delivery and vigilant care in post-operative period shall be conducted.

Intention to take COVID-19 vaccine and associated factors among pregnant women attending antenatal care at public health facilities in Bahir Dar city, Northwest Ethiopia.

BACKGROUND: Pregnant mothers are a risky population group for COVID-19 and pregnant mothers with COVID-19 are at increased risk of hospitalization, intensive-care unit admission, invasive ventilation support, and maternal mortality. Vaccination is an essential tool in stopping the effect of the pandemic on maternal and child health. However, there are only limited studies in Ethiopia on the intention to take the COVID-19 vaccine among pregnant women. Thus, this study aimed to assess intention to take the COVID-19 vaccine and associated factors among pregnant women in Bahir Dar city, Northwest Ethiopia. METHODS: Facility based cross-sectional study was conducted among 590 pregnant women from 23 May to 07 July 2022. The study participants were selected using a systematic sampling technique. Interviewer administrative questionnaire with epicollect5 application was used to collect the data. Both bi-variable and multivariable binary logistic regression analysis was performed. Statistical significance was defined at a 95% CI with a p-value < 0.05. RESULT: Overall, 19.8% (95% CI: 16.60-23.06%) of pregnant women intend to take the COVID-19 vaccine. Being urban residence (AOR = 3.40, 95% CI: 1.71-6.78), third trimester of gestational age (AOR = 3.11, 95% CI: 1.61-6.03), multipara (AOR = 2.30, 95% CI: 1.33-3.97), knowledge of COVID-19 vaccine (AOR = 2.33, 95% CI: 1.44-3.77) and having good attitude towards COVID-19 vaccine (AOR = 2.68, 95% CI: 1.65-4.33) were significantly associated with intention to take COVID-19 vaccine. CONCLUSION: In conclusion, the pregnant women's intention to take the COVID-19 vaccine in this study area was very low. It was significantly associated with residency, gestational age, parity, knowledge, and attitude toward the vaccine. Therefore, strengthening interventions that improve knowledge and attitude about the COVID-19 vaccine, predominantly among those primipara mothers and mothers from rural residences, may raise the intention to take it.

Uptake of retroviral pre-exposure prophylaxis and its associated factors among female sex workers, Northwest Ethiopia.

BACKGROUND: Pre-exposure prophylaxis is the use of antiretroviral medications by HIV-negative individuals to prevent infection before exposure. Ethiopia has made progress in reducing new HIV infections, but the burden remains high with ongoing challenges in prevention uptake. This study examined the utilization and factors associated with pre-exposure prophylaxis among female sex workers. METHODS: A community-based cross-sectional study design was conducted in Bahir Dar city administration among female sexual workers in 2022. The results were collected using a pre-tested and structured questionnaire. Epi data for data entry and social package for social science for analysis were used. RESULT: Overall, 15.9% (CI: 12.0-21.1) of female sexual workers received pre-exposure prophylaxis. Parents' living condition (only father alive [AOR = 0.23, 95% CI, 0.02-0.64], only mother alive [AOR = 0.31, 95% CI, 0.02-0.74]), marital status being single (AOR = 0.27, 95% CI, 0.06-0.94), having history of STI (AOR = 2.82, 95% CI, 1.60-4.77) were associated with pre-exposure prophylaxis uptake. CONCLUSION: This study showed low pre-exposure prophylaxis uptake. The study identified a history of sexually transmitted infections, marital status, and parent living conditions as significant factors. To increase pre-exposure prophylaxis uptake and reduce HIV incidence, an awareness campaign, tailored support, targeted interventions, and addressing concerns of high-risk groups are needed.

Magnitude and associated factors of acute kidney injury among preterm neonates admitted to public hospitals in Bahir Dar city, Ethiopia 2022: cross-sectional study.

BACKGROUND: Acute kidney injury is an independent risk factor for morbidity and mortality in critically ill neonates. Although the magnitude of preterm neonates is high and a major risk for acute kidney injury, there is a paucity of information regarding the magnitude and associated factors of acute kidney injury among preterm neonates in the study area. Therefore, the aim of this study was to assess magnitude and associated factors of acute kidney injury among preterm neonates admitted to public hospitals in Bahir Dar city, Ethiopia, 2022. METHODS: An institutional-based cross-sectional study was conducted among 423 preterm neonates admitted to public hospitals in Bahir Dar city from May 27 to June 27, 2022. Data were entered into Epi Data Version 4.6.0.2 transferred to Statistical Package and Service Solution version 26 for analysis. Descriptive and inferential statistics were employed. A binary logistic regression analysis was done to identify factors associated with acute kidney injury. Model fitness was checked through Hosmer-Lemeshow goodness of fit test. Variables with a p-value < 0.05 were considered as statistically significant in the multiple binary logistic regression analysis. RESULT: Out of 423 eligible, 416 neonatal charts were reviewed with a response rate of 98.3%.This study revealed that the magnitude of acute kidney injury was 18.27% (95% CI = 15-22). Very low birth weight (AOR = 3.26; 95% CI = 1.18-9.05), perinatal asphyxia (AOR = 2.84; 95%CI = 1.55-5.19), dehydration (AOR = 2.30; 95%CI = 1.29-4.09), chest compression (AOR = 3.79; 95%CI = 1.97-7.13), and pregnancy-induced hypertension (AOR = 2.17; 95%CI = 1.20-3.93) were factors significantly associated with the development of neonatal acute kidney injury. CONCLUSION: Almost one in five admitted preterm neonates developed acute kidney injury. The odds of acute kidney injury were high among neonates who were very low birth weight, perinataly asphyxiated, dehydrated, recipients of chest compression, and born to pregnancy-induced hypertensive mothers. Therefore, clinicians have to be extremely cautious and actively monitor renal function in those neonatal population in order to detect and treat acute kidney injury as early as possible.

Transition of average drug-to-antibody ratio of trastuzumab deruxtecan in systemic circulation in monkeys using a hybrid affinity capture liquid chromatography-tandem mass spectrometry.

Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate, comprising an anti-HER2 antibody at a drug-to-antibody ratio of 7-8 with the topoisomerase I inhibitor DXd. In this study, the concentrations of antibody-conjugated DXd and total antibody were determined and observed to decrease over time following intravenous administration of T-DXd to monkeys. The drug-to-antibody ratio of T-DXd also decreased in a time-dependent manner, which reached approximately 2.5 in 21 days after administration. It was suggested that antibody-conjugated DXd of T-DXd was relatively stable in vivo compared with that of other reported antibody-drug conjugates.

Spatial dispersion hot spots of contamination and human health risk assessments of PTEs in surface sediments of streams around porphyry copper mine, Iran.

This comprehensive research has been conducted to consider the distribution of PTEs in the surface sediments of a recently developed Dar-e-Allo copper mine in dependence on the potential ecological and human health risks. Field sampling was carried out discreetly at preselected sampling spots including the natural background, the streams around the mine, waste rock drainages, evaporative deposits, sediments containing Fe oxy-hydroxides and secondary phases. Distribution of target elements (Al, As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, S, Sb, Se, and Zn) showed high levels of crustal elements. As regards, Fe, Al, and S are identified to exist as the most copious elements in the earth's crust, so have the major portion of potentially toxic elements (PTEs) in the sediment concentrations. Evaluating environmental indices reflected that in general, Cu, S, and Mo have a higher quota of contamination in sedimentary systems. the pollution load index (PLI), modified contamination degree (mCd), Contamination factor (Cf), Sediment potential index (SPI), Geo-accumulation index (Igeo) and Contamination degree (Cd) confirm that sedimentary systems of mining area are heavily contaminated by PTEs and were not found within the guideline acceptable values. The potential ecological risk index (PERI) displayed a high or severe risk level for Cu with a peak in green-blue sediments containing secondary minerals. The results of total carcinogenic risk (TCRs) show that As has high toxicity level and carries a risk of carcinogenicity among children and adults. The TCRs for Cd, Cr, Ni, and Pb with carcinogenic potential are found only in children and they are classified as the prime concern elements that have serious dangers to children's public health. The results of contamination source presumed that the sources of PTEs contamination were principally geogenic along with the anthropogenic sources in the study area. Therefore, the present study has highlighted the implication of human health risks of PTEs in sedimentary systems of copper mining, also will grant advice for prime stakeholders, including mine managers, Environmental Protection Agency, the government and public organizations in connection to protecting the environment, aquatic biota and consumer's health.

Evaluation of aquifer parameters through integrated approach of geophysical investigations, pumping test analysis and Dar-Zarrouk parameters in the central part of Bari Doab, Punjab, Pakistan.

In the central part of Bari Doab in Punjab Province of Pakistan, the factors such as sporadic rainfall pattern, decrement of water in rivers, subsurface salinity and excessive mining of groundwater have badly affected the hydrogeology and recharge system of aquifer. The present research work is an endeavour to evaluate the characteristics and potential of aquifer for its future sustainable availability within the study area of central part of Bari Doab. The geophysical studies, pumping tests data, borehole logs and Dar-Zarrouk parameters were used integrally to evaluate the aquifer hydraulic and hydrologic parameters in the study area. VES technique of geophysical investigations using Schlumberger electrodes configuration was carried out at sparsely distributed 435 locations. Litho-logs and VES results altogether decipher that the subsurface alluvial succession is primarily composed of intermixed layers of sand, gravel, clay, silt and some kankar inclusions. The VES data allied with pumping test analysis of test wells in the study area were used to evaluate the aquifer hydraulic properties. Comparatively low values of discharge rate, hydraulic conductivity and transmissivity were evaluated in two wells whilst relatively higher values of these parameters were evaluated in rest of six wells. The results of hydrologic parameters also confirm the results of hydraulic parameters in the wells. Finally, the Dar-Zarrouk parameters were used for the estimation of hydraulic parameters for whole study area and the aquifer zones of relatively high and low potential were delineated.

The effect of khat cultivation on rural households' income in Bahir Dar Zuria District, Northwest Ethiopia.

The study was conducted to evaluate the effect of khat cultivation on rural households' income in the Bahir Dar Zuria district using cross-sectional data collected from 180 randomly selected respondents, and supported by focus group discussions in two districts of northwest Ethiopia. The data were analyzed by simple descriptive statistics and beta regression. Results from descriptive statistics show that khat contributes the largest (51%) of farmers' income, followed by crop sale (33%), sale of livestock and their products (9%), and off-farm and non-farm activities (7%), Empirical findings from the Beta regression model also show that farming experience, education status, the proportion of land allocated for khat cultivation, total working capital of the household, the density of khat trees planted per hectare, and participation in off-farm and non-farm activity have a significant and positive effect on the proportion of khat income of the households. On the contrary, livestock holding, total asset ownership, and access to mobile phones have a significant and negative influence on the proportion of annual khat income of the households. Hence, the cultivation of khat can have a significant effect on the improvement of rural households' income and standard of living in the districts. However, increased khat production have also serious implications on the market, water resources, and human health. Thus, policymakers need to come up together to understand and devise proper running mechanisms for these controversies of khat production in association with economic, social, and health implications.

Design, synthesis, and preclinical evaluation of a novel bifunctional macrocyclic chelator for theranostics of cancers.

PURPOSE: This study was to design and synthesize a novel bifunctional chelator, named Dar, primarily validated by conjugating to tumor targeting motifs, labeled with radiometals, and performed preclinical evaluation of tumor imaging and cancer therapy in murine tumor models. METHOD: The designed Dar was synthesized and characterized by X-ray crystallography, 1H/13C NMR, and mass spectrometry. Dar-PSMA-617 was conjugated and radiolabeled with 68Ga, 177Lu, and 89Zr. The in vivo behavior of 68 Ga/89Zr-labeled Dar-PSMA-617 were evaluated using micro-PET imaging and biodistribution from image quantitation and tissue radioactivity counting, with 68Ga/89Zr-labeled NOTA/DOTA/DFO-PSMA-617 analogs as controls, respectively. The [177Lu]-Dar-PSMA-617, with [177Lu]-DOTA-PSMA-617 as control, was evaluated in competitive cell uptake, tumor cell internalization, and efflux studies. The treatment efficacy of [177Lu]Lu-Dar-PSMA-617, with [177Lu]Lu-DOTA-PSMA-617 as control, was evaluated in PSMA-positive LNCaP tumor-bearing mice. In addition, the ability of Dar for radiolabeling nanobody was tested by conjugating Dar to KN035 nanobody. The resultant [89Zr]Zr-Dar-KN035 nanobody, with [89Zr]Zr-DFO-KN035 as control, was evaluated by micro-PET imaging and biodistribution in a mouse model bearing MC38&MC38-hPD-L1 colon cancer. RESULTS: 68Ga, 89Zr, and 177Lu-radiolabeled Dar-PSMA-617 complexes were able to be produced under mild condition with high radiochemical yield and purity successfully. [177Lu]Lu-Dar-PSMA-617 had higher cellular uptake yet similar internalization and efflux properties in LNCaP cells, as compared to [177Lu]Lu-DOTA-PSMA-617. Micro-PET images demonstrated significantly higher tumor uptake of [68Ga]Ga-Dar-PSMA-617, than that of the analog [68Ga]Ga-DOTA-PSMA-617. The tumor uptake values of [68Ga]Ga-Dar-PSMA-617 at multiple time points are comparable to that of [68Ga]Ga-NOTA-PSMA-617, although a higher and persistently prolonged kidney retention was resulted in during the study period. The Dar chelator can also successfully mediate the radiolabeling with 89Zr, while the resultant [89Zr]Zr-Dar-PSMA-617 demonstrated a similar biodistribution with [89Zr]Zr-DFO-PSMA-617 measured at 96 h p.i. The treatment with [177Lu]Lu-Dar-PSMA-617 significantly inhibited the tumor growth, showing much better efficacy than that of [177Lu]Lu-DOTA-PSMA-617 at the same injected radioactivity and mass dose. Dar was covalently linked to KN035 nanobody and enabled radiolabeling with 89Zr in high yield and radiochemical purity at room temperature. The resultant [89Zr]Zr-Dar-KN035, with [89Zr]Zr-DFO-KN035 as control, demonstrated superior tumor uptake and detection capability in PET imaging studies. CONCLUSION: The Dar, as a novel bifunctional chelator for medicating the labeling of radiometals onto tumor targeting carriers, was successfully synthesized and chemically characterized. Test radiolabeling, on PSMA-617 and a nanobody as tool targeting molecule carriers, demonstrated the Dar has potential as a universal bifunctional chelator for radiolabeling various radiometals (at least 68Ga, 177Lu, and 89Zr tested) commonly used for clinical imaging and therapy. Using a novel Dar chelator results in altered in vivo behavior of the carriers even though labeled with the same nuclide. This capability makes Dar an alternative to the existing choices for radiolabeling new carrier molecules with various radiometals, especially the radiometals with large radius.

Antimicrobial usage in cattle and poultry production in Dar es Salaam, Tanzania: pattern and quantity.

BACKGROUND: Antimicrobials are extensively used in cattle and poultry production in Tanzania. However, there is dearth of information on its quantitative use. A questionnaire-based cross-sectional study was conducted from August to September 2019 in randomly selected poultry and small-scale dairy farms, in three districts of Dar es Salaam City eastern, Tanzania, to assess the practice and quantify antimicrobial use. Descriptive and statistical analyses were performed at a confidence interval of 95%. The ratio of Used Daily Dose (UDD) and Defined Daily Dose (DDD) were used to determine whether the antimicrobial was overdosed or under dosed. RESULTS: A total of 51 poultry and 65 small-scale dairy farms were involved in the study. The route of antimicrobial administration was 98% orally via drinking water and 2% in feeds for poultry and for small-scale dairy farms, all through parenteral route. Seventeen types of antimicrobials comprising seven classes were recorded in poultry farms while nine belonging to six classes in the small dairy farms. Majority of the farms (poultry, 87.7% and small scale dairy, 84.3%) used antimicrobials for therapeutic purposes. About 41% of the poultry and one third (34%) of the dairy farmers' were not compliant to the drug withdrawal periods. Beta-lactams, fluoroquinolones, sulphonamides, tetracyclines and macrolides were the commonly used antimicrobials on these farms. In the poultry farms both those with records and those which relied on recall, antimicrobials were overdosed whereas in the small dairy farms, sulfadimidine, oxytetracycline and neomycin were within the appropriate dosing range (0.8-1.2). The majority (58.6%) of farmers had adequate level of practices (favorable) regarding antimicrobial use in cattle and poultry production. This was associated with the age and level of education of the cattle and poultry farmers. CONCLUSION: The study revealed a widespread misuse of antimicrobials of different types and classes in both poultry and small-scale dairy farming in Dar es Salaam, Tanzania. This result gives insight into the antimicrobial use practices and its quantification. The information obtained can guide and promote prudent use of antimicrobials among the farmers by developing mitigate strategies that reduce antimicrobial resistance risk potentials.