Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.

Determinants of hemoglobin level and time to default from Highly Active Antiretroviral Therapy (HAART) for adult clients living with HIV under treatment; a retrospective cohort study design.

HIV/AIDS is one of the most devastating infectious diseases affecting humankind all over the world and its impact goes beyond public health problems. This study was conducted to investigate the joint predictors of hemoglobin level and time to default from treatment for adult clients living with HIV/AIDS under HAART at the University of Gondar Comprehensive and Specialized Hospital, North-west Ethiopia. The study was conducted using a retrospective cohort design from the medical records of 403 randomly selected adult clients living with HIV whose follow-ups were from September 2015 to March 2022. Hemoglobin level was projected using Sahli's acid-hematin method. Hence, the hemoglobin tube was filled with N/10 hydrochloric acid up to 2 g % marking and the graduated tube was placed in Sahli's hemoglobin meter. The blood samples were collected using the finger-pick method, considering 22 G disposable needles. The health staff did this. From a total of 403 adult patients living with HIV/AIDS included in the current study, about 44.2% defaulted from therapy. The overall mean and median estimated survival time of adult clients under study were 44.3 and 42 months respectively. The patient's lymphocyte count (AHR = 0.7498, 95% CI: (0.7411: 0.7587), p-value < 0.01), The weight of adult patients living with HIV/AIDS (AHR = 0.9741, 95% CI: (0.9736: 0.9747), p-value = 0.012), sex of adult clients (AHR = 0.6019, 95% CI: (0.5979, 0.6059), p-value < 0.01), WHO stages III compared to Stage I (AHR = 1.4073, 95% CI: (1.3262, 1.5078), p-value < 0.01), poor adherence level (AHR = 0.2796, 95% CI: (0.2082, 0.3705) and p-value < 0.01), bedridden patients (AHR = 1.5346, 95% CI: (1.4199, 1.6495), p-value = 0.008), and opportunistic infections (AHR = 0.2237, 95% CI: (0.0248, 0.4740), p-value = 0.004) had significant effect on both hemoglobin level and time to default from treatment. Similarly, other co-morbidity conditions, disclosure status of the HIV disease, and tobacco and alcohol addiction had a significant effect on the variables of interest. The estimate of the association parameter in the slope value of Hgb level and time default was negative, indicating that the Hgb level increased as the hazard of defaulting from treatment decreased. A patient with abnormal BMI like underweight, overweight, or obese was negatively associated with the risk of anemia (lower hemoglobin level). As a recommendation, more attention should be given to those patients with abnormal BMI, patients with other co-morbidity conditions, patients with opportunistic infections, and low lymphocytes, and bedridden and ambulatory patients. Health-related education should be given to adult clients living with HIV/AIDS to be good adherents for medical treatment.

Relationship between the magnitude of haemoglobin changes and long-term mortality in patients with sepsis: a retrospective cohort study.

BACKGROUND: Sepsis is a common and severe disease with a high mortality rate in intensive care unit (ICU). The hemoglobin (HGB) level is a key parameter for oxygen supply in sepsis. Although HGB is associated with the progression of inflammation in sepsis patients, its role as a marker following sepsis treatment remains unclear. Here, we studied the correlation between early temporal changes in HGB levels and long-term mortality rates in septic patients. METHOD: In this retrospective study of data on patients with sepsis from the Medical Information Mart for Intensive Care (MIMIC) IV database, the outcome was long-term mortality. Patients were divided based on the cut-off of the HGB percentage for receiver operating characteristic (ROC) curve calculation. Kaplan-Meier (KM) survival curves and Cox proportional hazards regression models were used to analyse the associations between groups and outcomes. Propensity score matching (PSM) was used to verify the results. RESULTS: In this study, 2042 patients with sepsis and changes in HGB levels at day 4 after admission compared to day 1 were enrolled and divided into two groups: group 1 (n = 1147) for those with reduction of HGB < 7% and group 2 (n = 895) for those with dropping ≥ 7%. The long-term survival chances of sepsis with less than a 7% reduction in the proportion of HGB at day four were significantly higher than those of patients in the group with a reduction of 7% or more. After adjusting for covariates in the Cox model, the hazard ratios (HRs) with 95% confidence intervals (CIs) for long-term all-cause mortality in the group with a reduction of 7% or more were as follows: 180 days [HR = 1.41, 95% CI (1.22 to 1.63), P < 0.001]; 360 days [HR = 1.37, 95% CI (1.21 to 1.56), P < 0.001]; 540 days [HR = 1.35, 95% CI (1.20 to 1.53), P < 0.001]; 720 days [HR = 1.45, 95% CI (1.29 to 1.64), P < 0.001]. Additionally, the long-term survival rates, using Kaplan-Meier analysis, for the group with a reduction of 7% or more were lower compared to the group with less than 7% reduction at 180 days (54.3% vs. 65.3%, P < 0.001), 360 days (42.3% vs. 50.9%, P < 0.001), 540 days (40.2% vs. 48.6%, P < 0.001), and 720 days (35.5% vs. 46.1%, P < 0.001). The same trend was obtained after using PSM. CONCLUSION: A ≥ 7% decrease in HGB levels on Day 4 after admission was associated with worse long-term prognosis in sepsis patients admitted to the ICU.

Reference intervals of complete blood count parameters in the adult western Sudanese population.

BACKGROUND: A complete blood count (CBC) analysis is one of the most common conventional blood tests that physicians frequently prescribe. THE OBJECTIVE: of this study was to determine the reference intervals (RIs) of CBC parameters in the population of healthy adults living in the western Sudan region. METHODS: A cross-sectional study of healthy people residing in the western area of Sudan was carried out. We assessed the CBC RIs in samples taken from 153 individuals using an automated haematology analyser (Sysmex KX-21) and a modified Box-Cox transformation procedure to transform the data into a Gaussian distribution after eliminating outliers using the Dixon method. IBM SPSS Statistics version 25 was used to analyse the data, and t tests were employed to examine variations in the mean CBC parameters according to sex and age. P was considered significant at ≤ 0.05. RESULTS: Beyond all the other measured values, the only CBC parameters that significantly differed between the sexes were haemoglobin (HGB) and white blood cell (WBC) counts. Women were found to experience more WBC counts than men did. However, they have less HGB RIs.The male participants in our study exhibited lower WBC count RIs, a significantly lower limit, and a greater upper limit of platelet RIs than did the individuals from other nations. CONCLUSIONS: Compared with males, females had higher platelet and WBC counts and lower HGB.

Electronic Structure and Chemical Bonding of the First-, Second-, and Third-Row-Transition-Metal Monoborides: The Formation of Quadruple Bonds in RhB, RuB, and TcB.

Boron presents an important role in chemistry, biology, and materials science. Diatomic transition-metal borides (MBs) are the building blocks of many complexes and materials, and they present unique electronic structures with interesting and peculiar properties and a variety of bonding schemes which are analyzed here. In the first part of this paper, we present a review on the available experimental and theoretical studies on the first-row-transition-metal borides, i.e., ScB, TiB, VB, CrB, MnB, FeB, CoB, NiB, CuB, and ZnB; the second-row-transition-metal borides, i.e., YB, ZrB, NbB, MoB, TcB, RuB, RhB, PdB, AgB, and CdB; and the third-row-transition-metal borides, i.e., LaB, HfB, TaB, WB, ReB, OsB, IrB, PtB, AuB, and HgB. Consequently, in the second part, the second- and third-row MBs are studied via DFT calculations using the B3LYP, TPSSh, and MN15 functionals and, in some cases, via multi-reference methods, MRCISD+Q, in conjunction with the aug-cc-pVQZ-PPM/aug-cc-pVQZB basis sets. Specifically, bond distances, dissociation energies, frequencies, dipole moments, and natural NPA charges are reported. Comparisons between MB molecules along the three rows are presented, and their differences and similarities are analyzed. The bonding of the diatomic borides is also described; it is found that, apart from RhB(X1Σ+), which was just recently found to form quadruple bonds, RuB(X2Δ) and TcB(X3Σ-) also form quadruple σ2σ2π2π2 bonds in their X states. Moreover, to fill the gap existing in the current literature, here, we calculate the TcB molecule.

The role of distinct ECoG frequency features in decoding finger movement.

Objective.To identify the electrocorticography (ECoG) frequency features that encode distinct finger movement states during repeated finger flexions.Approach.We used the publicly available Stanford ECoG dataset of cue-based, repeated single finger flexions. Using linear regression, we identified the spectral features that contributed most to the encoding of movement dynamics and discriminating movement events from rest, and combined them to predict finger movement trajectories. Furthermore, we also looked into the effect of the used frequency range and the spatial distribution of the identified features.Main results.Two frequency features generate superior performance, each one for a different movement aspect: high gamma band activity distinguishes movement events from rest, whereas the local motor potential (LMP) codes for movement dynamics. Combining these two features in a finger movement decoder outperformed comparable prior work where the entire spectrum was used as the average correlation coefficient with the true trajectories increased from 0.45 to 0.5, both applied to the Stanford dataset, and erroneous predictions during rest were demoted. In addition, for the first time, our results show the influence of the upper cut-off frequency used to extract LMP, yielding a higher performance when this range is adjusted to the finger movement rate.Significance.This study shows the benefit of a detailed feature analysis prior to designing the finger movement decoder.

Determinates of anemia among Human Immune Deficiency Virus positive children on Anti-retro Viral Therapy in selected health facilities, Northwest Ethiopia: A Case-Control Study.

Even though antiretroviral therapy (ART) access for human immunodeficiency virus (HIV)-infected children increased dramatically, anaemia has continued as a challenge regardless of a cluster of differentiation (CD4) count and viral load. Hence, the present study aimed to assess the determinants of iron deficiency anaemia among children living with HIV after the initiation of ART. An institution-based unmatched case-control study was conducted among consecutively selected 712 children on HIV care from 1 September to 30 October 2022 in the Metekel zone. A pre-tested and structured data extraction checklist was used to collect the data. Data were analysed using STATA version 16 software. Binary logistic regression was used to find the association between independent variables and anaemia. The level of statistical significance was declared at a value of P < 0⋅05. A total of 712 HIV-positive children (178 cases and 534 controls) were included in this study, with a completeness rate of 98⋅8 %. In multivariable analysis, variables that have a statistically significant association with anaemia were as follows: CD4 count <350 (Adjusted Odds Ratio [AOR] 2⋅76; 95 % CI 1⋅76, 4⋅34), World Health Organization (WHO) clinical stage III (AOR 7⋅9; 95 % CI 3⋅5, 17⋅91) and stage IV (AOR 7⋅8; 95 % CI 3⋅37, 18⋅1), cotrimoxazole prophylaxis therapy (AOR 0⋅5; 95 % CI 0⋅31, 0⋅8) and mid-upper arm circumference (MUAC) ≤11⋅5 mm (AOR 2⋅1; 95 % CI 1⋅34, 3⋅28). The present study found that CD4 count, WHO clinical stage, cotrimoxazole prophylaxis therapy and MUAC were significantly associated with anaemia in children on ART. Therefore, continuous screening of anaemia and nutritional treatment is essential in these patients.

High-precision non-invasive RBC and HGB detection system based on spectral analysis.

Non-invasive blood composition analysis based on dynamic spectrum (DS) theory has gained significant attention due to its non-invasive, simple, and fast performance. However, most of the multi-wavelength photoplethysmography (PPG) detection devices used to obtain DS are composed of halogen light sources and spectrometers and cannot detect effective PPG signals in the visible light short band (400-620 nm), which limits the detection accuracy of blood components with significant absorption spectral differences in that band. Therefore, this paper designs a multi-wavelength spectral acquisition system that can measure high signal-to-noise ratio (SNR > 65 dB) PGG signals at wavelengths of 405, 430, 450, 505, 520, and 570 nm and combines this system with a halogen lamp spectrometer acquisition system for non-invasive blood component detection. Furthermore, this paper collects the DS of 272 subjects with the combined system and establishes a predictive model for DS with the content of red blood cell (RBC) and hemoglobin (HGB) components. The results show that, compared with the halogen lamp spectrometer acquisition system, the correlation coefficient (Rp) of RBC and HGB prediction model established by the combined system has increased by 0.0619 and 0.0489, respectively, and the root mean square error (RMSE) has decreased by 0.08 1e12/L and 0.85 g/L, which confirm the feasibility of the designed multi-wavelength spectrum acquisition system to enhance the accuracy of blood component detection.

Blood biomarkers as potential malnutrition screening alternatives among adult patients with cancer on treatment in oncology unit of jimma tertiary hospital: A cross-sectional analysis.

BACKGROUND: Cancer is becoming the most common global public health concern. Early malnutrition detection and treatment in patients with cancer is an important aspect of cancer management. Although Subjective global assessment (SGA) is a gold standard nutritional assessment tool, it is not routinely utilized due to it is tedious and needs patient literacy. Thus, early detection of malnutrition necessitates alternative parameters comparable with SGA. Therefore this study aims to evaluate serum albumin, Total Protein (TP), and Hemoglobin (Hgb) and their correlation with malnutrition in patients with cancer at Jimma Medical Center (JMC). METHODS: Facility based cross-sectional study was conducted from October 15 to December 15, 2021 G.C at JMC among a total of 176 adult patients with cancer selected via a systematic sampling technique. Nutritional status and behavioural data were collected using the SGA tool and a structured questionnaire. Five ml of venous blood was collected and the level of serum albumin, TP and Hgb were measured using Cobas®6000 chemistry analyzer and hematology analyzer UniCel DxH 800. Descriptive statistics, independent t-test, Pearson's correlation coefficient (r), and logistic regression analysis were implemented for analysis. RESULT: From the total of 176 study participants, 69.3% were females and the mean age was 50.1 ± 13.7 years. Based on SGA, 61.4% of the patients were malnourished. There was a significant decrease in the mean level of serum albumin, TP and Hgb in malnourished as compared to well-nourished patients. Serum albumin(r=-0.491), TP(r=-0.270), and Hgb (r=-0.451) had a significant correlation with SGA tool. Stage IV cancer AOR = 4.98 (1.23-20.07), Gastrointestinal (GI) cancer AOR = 3.39(1.29-8.88) and malnutrition AOR = 3.9(1.81-8.4) were significantly associated with hypoalbuminemia. Similarly, age of > 64 years AOR = 6.44(1.55-26.67), GI cancer AOR = 2.92(1.01-6.29) and malnutrition AOR = 3.14(1.43-6.94) were significantly associated with hypoproteinemia; and stage-IV cancer AOR = 3.94(1.11-13.35) and malnutrition AOR = 3.8(1.82-8.2) were significantly associated with low Hgb level. CONCLUSION AND RECOMMENDATION: Altered level of serum albumin, TP and Hgb was correlated with the SGA tool of malnutrition. Therefore, it is suggested to be used as an alternative or additional screening tool for prompt detection of malnutrition in adult patients with cancer.

Evaluation and Association of Hematological and Biochemical Parameters of Untreated COVID-19 Patients on the Basis of Differences in Ethnicity and Curcumin as a Possible Treatment.

BACKGROUND: CBC (complete blood count) tests, along with RPM (Renal parameters) and LFT (Liver function tests), are clinically important for coronavirus patients; curcumin can serve as a possible treatment for SARS- CoV. OBJECTIVE: The objective of the study was to determine the relationship of CBC parameters with renal parameters and liver function tests and to develop the hypothesis that curcumin may be the best and non-invasive drug for coronavirus. Materials &Methods: The differences between the results of 91 confirmed cases of covid-19 (symptomatic and asymptomatic) and 100 controls were assessed by an independent t-test and Mann-Witney U Wilcoxon test. Microscopy, hematological tools, and techniques were used to assess the improvements/abnormalities in blood components and parameters. RESULTS: This is a case control study along with the feasibility of curcumin as covid treatment. The association between parameters was assessed by Pearson & Spearman correlation analysis. The level of significance was p<0.05. Changes were observed in urea (p=0.000), creatinine (p=0.02), total bilirubin (P=0.000), SGPT (ALT) (p=0.000), RBC (p=0.001), HGB (p=0.001), MCV (p=0.002), MCH (p=0.03), MPV, PDW, NE%, LY%, and MO% EO% (p=0.00), in comparison to normal controls. Differences in the correlation of electrolytes, RPM, and LFT tests along with CBC parameters in Pakistani and Chinese individuals provided a new idea for using various diagnostic and therapeutic tools in different ethnic groups. The covid-19 infected blood components and parameters showed rapid improvement/recovery, especially the total count of platelets and WBCs (lymphocytes and basophils), HGB, HCT, MCV, and MCH. CONCLUSION: Curcumin drugs can be used as an immediate remedy/treatment to cure COVID-19 patients.

A decision tree network with semi-supervised entropy learning strategy for spectroscopy aided detection of blood hemoglobin.

Non-invasive techniques for rapid blood testing are gaining traction in global healthcare as they optimize medical screening, diagnosis and clinical decisions. Fourier transform infrared (FT-IR) spectroscopy is one of the most common technologies that can be used for non-destructive aided medical detection. Typically, after acquiring the Fourier transform infrared spectrum, spectral data preprocessing and feature extraction and quantitative analysis of several indicators of blood samples can be accomplished, in combination with chemometric method studies. At present, blood hemoglobin (HGB) concentration is one of the most valuable information for the clinical diagnosis of patient's health status. FT-IR spectroscopy is employed as a green technique aided medical test of blood HGB. Then the acquired HGB concentration data is switched to the spectral feature data by the studies of advanced chemometric method, in help for hiding the sensitive medical information to protect the privacy of patients. The decision tree network architecture is proposed for feature extraction of FT-IR data in order to find the small set of wavenumbers that are able to quantify HGB. A semi-supervised learning strategy is designed for tuning the number of network neuron nodes, in the way of searching for the maximum entropy increment. Each neuron is optimized by the growing of a semi-supervised decision tree, to accurately identify the informative FT-IR wavenumbers. The features extracted by the semi-supervised learning decision tree network guarantees the FT-IR aided detection model has high efficiency and high prediction accuracy. A model of quantifying the HGB concentration shows that the proposed decision tree network with semi-supervised entropy learning strategy outperforms the usual methods of full spectrum partial least square model and the fully connected neural network model in prediction accuracy. The framework is expected to support the FT-IR spectral technology for aided detection of medical and clinical data.

Growth and development status of children with severe β-thalassemia and its correlation with serum HGB and SF levels in Bazhong area / 公共卫生与预防医学

Objective To analyze the growth and development status of children with severe β-thalassemia major (β-TM) in Bazhong area and its correlation with hemoglobin concentration (HGB) and serum ferritin (SF) level, and to provide a theoretical basis for the diagnosis and treatment of children with β-TM in Bazhong area. Methods A total of 292 children with β-TM admitted to Bazhong Central Hospital from January 2019 to December 2020 were selected. The Z-score method was used to evaluate the growth and development of the children. According to the growth and development of the children, they were divided into the normal group (normal growth and development, n=163) and delayed group (growth and development delay, n=129). Another 60 healthy children were selected as the control group. The levels of HGB, serum SF, free triiodothyronine (FT3), free tetraiodothyroxine (FT4), and thyroid stimulating hormone (TSH) were compared among the three groups of children, and clinical data such as age, sex and age of onset were collected from the case system. Univariate analysis and logistic regression were used to analyze the independent risk factors of growth and development delay in β-TM children. Pearson correlation was used to analyze the correlation between growth retardation and HGB and serum SF levels in β-TM children. Results The serum SF and TSH levels in the delayed group were significantly higher than those in the normal group and the control group, while the levels of HGB and serum FT4 were significantly lower than those in the normal group and control group (P2000 ng/mL were risk factors for growth retardation in β-TM children (P2000 ng/mL, the height, weight, and HGB and serum SF levels should be monitored regularly.

Acute and subchronic oral toxicity assessment of extract from Etlingera pavieana rhizomes.

In Southeast Asia, the rhizome of Etlingera pavieana is commonly consumed and parts of the rhizomes have been used as a medicine for the treatment of several disorders. Its pharmacological effects have previously been reported. However, its potential toxicity has not been described. This study aimed to evaluate in vivo toxicity of E. pavieana rhizome extract (EPE) in Sprague Dawley rats. Acute toxicity testing of EPE at a single dose of 2,000 mg/kg produced no toxic effects in female rats after 14 days of treatment. Subchronic toxicity testing showed that all doses of EPE (500, 1,000, and 2,000 mg/kg/day) produced no sign of toxicity during 90 days of treatment. All biochemical and hematological values were within normal ranges. There were no significant histopathological differences in the internal organs among the tested groups. Therefore, the no-observed-adverse-effect level of EPE was 2,000 mg/kg/day in both male and female rats, thereby confirming the safety of EPE for use in traditional medicines.

Quemadura por inhalación de humo e intoxicación por monóxido de carbono en paciente pediátrico

Introducción: El monóxido de carbono es uno de los mayores contaminantes de la atmósfera terrestre, su toxicidad es bien conocida por el ser humano. Las fuentes productoras responsables de aproximadamente 80 % de las emisiones de monóxido de carbono son los vehículos automotores que utilizan como combustible gasolina o diesel, los procesos industriales que utilizan compuestos del carbono y el fuego dentro de los hogares. Sus efectos tóxicos agudos incluida la muerte se han estudiados ampliamente, no así sus potenciales efectos adversos a largo plazo. Objetivo: Describir el comportamiento de la intoxicación aguda por monóxido de carbono en paciente pediátrico, su diagnóstico y tratamiento. Presentación del caso: paciente de 11 años de edad que sufre intoxicación aguda por monóxido de carbono. Ingresa en el Hospital Universitario procedente del primer nivel de atención médica como urgencia vital. Se estabiliza e identifican las alteraciones multisistémicas producidas por lesiones asociadas con la inhalación de humo y gases tóxicos en espacios cerrados. Se determina su correcto tratamiento. Conclusiones: La forma más pertinente de disminuir la morbilidad y la mortalidad en pacientes como el que se presenta, se basa en dos pilares: la correcta identificación y el acertado manejo para cada intoxicación. La aplicación de estos dos aspectos puede lograr un factor protector. Hay subregistro de la ocurrencia de los casos de intoxicación por monóxido de carbono que no son atendidos en los servicios de salud y de los que producen la muerte inmediata, por lo que es importante su diagnóstico y tratamiento oportuno.

Introduction: Carbon monoxide is one of the largest pollutants in the Earth's atmosphere, its toxicity is well known to humans. The producing sources responsible for approximately 80% of carbon monoxide emissions are motor vehicles that use gasoline or diesel as fuel, industrial processes that use carbon compounds and fire inside homes. Its acute toxic effects including death have been studied extensively, but its potential long-term adverse effects have not been studied. Objective: To describe the behavior of acute carbon monoxide poisoning in pediatric patients, their diagnosis and treatment. Case presentation: 11-year-old patient suffering from acute carbon monoxide poisoning. He is admitted to the University Hospital from the first level of medical care as a vital emergency. Multisystem alterations caused by lesions associated with the inhalation of smoke and toxic gases in enclosed spaces are stabilized and identified. Its correct treatment is determined. Conclusions: The most pertinent way to reduce morbidity and mortality in patients such as the one presented is based on two pillars: correct identification and correct management for each poisoning. The application of these two aspects can achieve a protective factor. There is underreporting of the occurrence of cases of carbon monoxide poisoning that are not treated in health services and those that cause immediate death, so their detection, diagnosis and timely treatment is important.

Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.

Triosephosphate isomerase deficiency (TPI Df) is a rare, aggressive genetic disease that typically affects young children and currently has no established treatment. TPI Df is characterized by hemolytic anemia, progressive neuromuscular degeneration, and a markedly reduced lifespan. The disease has predominately been studied using invertebrate and in vitro models, which lack key aspects of the human disease. While other groups have generated mammalian Tpi1 mutant strains, specifically with the mouse mus musculus, these do not recapitulate key characteristic phenotypes of the human disease. Reported here is the generation of a novel murine model of TPI Df. CRISPR-Cas9 was utilized to engineer the most common human disease-causing mutation, Tpi1 E105D , and Tpi1 null mice were also isolated as a frame-shifting deletion. Tpi1 E105D/null mice experience a markedly shortened lifespan, postural abnormalities consistent with extensive neuromuscular dysfunction, hemolytic anemia, pathological changes in spleen, and decreased body weight. There is a ∼95% reduction in TPI protein levels in Tpi1 E105D/null animals compared to wild-type littermates, consistent with decreased TPI protein stability, a known cause of TPI Df. This work illustrates the capability of Tpi1 E105D/null mice to serve as a mammalian model of human TPI Df. This work will allow for advancement in the study of TPI Df within a model with physiology similar to humans. The development of the model reported here will enable mechanistic studies of disease pathogenesis and, importantly, efficacy testing in a mammalian system for emerging TPI Df treatments.

Successful preoperative embolization of a cystic-solid variant of cerebellopontine angle hemangioblastoma.

Tumors of the cerebellopontine angle (CPA) represent an heterogeneous group which can arise extradural, intradural-extraaxial or intraaxial compartment. Hemangioblastomas of the cerebellopontine angle (CPA) are extremely rare. Computed tomography (CT) and magnetic resonance imaging (MRI) are often the gold-standard radiological imaging modalities used in characterizing the lesion's features, and its relationship with the surrounding structures. They are vascular lesions and may cause profuse bleeding intraoperatively, that is why angiography remains a crucial diagnostic and therapeutic tool, by reducing both the presurgical differential diagnosis, as well as the intraoperative bleeding by providing capability of embolization of this vascular tumor. We present the case of a 65 year old patient with a cystic-solid variety of HMB at the right CPA, which was successfully treated by a combination of an endovascular preoperative embolization and surgery without major complications or neurological deficits.

Defining the optimal threshold and prognostic utility of pre-treatment hemoglobin level as a biomarker for survival outcomes in head and neck cancer patients receiving chemoradiation.

OBJECTIVES: We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker. MATERIALS AND METHODS: A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes. RESULTS: A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p < 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p < 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p < 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82). CONCLUSION AND RELEVANCE: Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

Quantitative Ultrasound Assessment of Hepatic Steatosis.

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is widespread chronic disease of the live in humans with the prevalence of 30% of the United States population.1,2 The goal of the study is to validate the performance of quantitative ultrasound algorithms in the assessment of hepatic steatosis in patients with suspected NAFLD. Methods: This prospective study enrolled a total of 31 patients with clinical suspicion of NAFLD to receive liver fat measurements by quantitative ultrasound and reference MRI measurements (proton density fat-fraction, PDFF). The following ultrasound (US) parameters based on both raw ultrasound RF (Radio Frequency) data and 2D B-mode images of the liver were analyzed with subsequent correlation with MRI-PDFF: hepatorenal index, acoustic attenuation coefficient, Nakagami coefficient parameter, shear wave viscosity, shear wave dispersion and shear wave elasticity. Ultrasound parameters were also correlated with the presence of hypertension and diabetes. Results: The mean (± SD) age and body mass index of the patients were 49.03 (± 12.49) and 30.12 (± 6.15), respectively. Of the aforementioned ultrasound parameters, the hepatorenal index and acoustic attenuation coefficient showed a strong correlation with MRI-PDFF derivations of hepatic steatosis, with r-values of 0.829 and 0.765, respectively. None of the remaining US parameters showed strong correlations with PDFF. Significant differences in Nakagami parameters and acoustic attenuation coefficients were found in those patients with and without hypertension. Conclusions: Hepatorenal index and acoustic attenuation coefficient correlate well with MRI-PDFF-derived measurements of hepatic steatosis. Quantitative ultrasound is a promising tool for the diagnosis and assessment of patients with NAFLD.

Case report of metastatic melanoma presenting as an unusual cause of gastrointestinal hemorrhage in an elderly gentleman.

Introduction: and Importance: Melanomas are capable of metastasizing to both regional and distant sites and are notably known to metastasize to the skin, lungs, brain, liver, bone, and gastrointestinal tract. Metastatic melanoma is infrequently diagnosed in vivo, and usually found only on post-mortem evaluation at autopsy. Case Presentation: Here we present the case of a 64-year-old male who originally presented with melena, fatigue, exertional dyspnea and one episode of near-syncope. He was found to have a hemoglobin of 5.4 gm/dL on initial presentation with largely unremarkable abdominal examination. CTAP demonstrated an area of circumferential small bowel wall thickening, concerning for malignancy. The patient underwent an EGD that was noted for mild gastric fundal erosions, which failed to explain his presenting symptoms. VCE was later performed following discharge to visualize the small bowel, which revealed two bleeding lesions within the small bowel. This was complicated by the device becoming lodged on the more proximal mass, and he was admitted again for push-enteroscopy and device retrieval. At the time of this admission, he continued to be symptomatic and was profoundly anemic with a hemoglobin of 4.7 gm/dL. Clinical Discussion: EGD with push enteroscopy was performed, revealing two small masses in the mid-distal duodenum and jejunum, which were tattooed and biopsied. He underwent robotic-assisted laparoscopic small bowel resection of the affected portions of the small bowel, without complications. Surgical samples were consistent with melanoma, and further dermatologic examination revealed a suspicious lesion located on the patient's posterior right shoulder was biopsied and also consistent with melanoma, confirming the suspicion for metastatic process from primary cutaneous lesion. Conclusions: We present this case as a rare diagnostic opportunity to observe metastatic melanoma of the small bowel, including a review of pertinent symptomatology and epidemiological data from previous literature. Our case serves as a reminder to consider metastatic melanoma as a rather uncommon cause of severe blood loss anemia, while also providing an overview of endoscopic modalities available for visualizing the small bowel in the management of suspected small bowel malignancy.

Two Cases of Methimazole-Induced Agranulocytosis With Their Risk Factors.

Background: Antithyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of thyrotoxicosis. Agranulocytosis is a rare but lethal adverse effect of antithyroid medications. We have reported 2 cases of MMI-induced agranulocytosis with similar risk factors that likely predisposed them to this adverse reaction. Case Report: Case 1 involved a 71-year-old woman, with a history of Graves disease, who presented with an altered mental status. She was recently discharged on 40 mg of MMI twice daily, and she continued this dose for 2 months. She was readmitted and found to have neutropenic fever in the setting of MMI-induced agranulocytosis. MMI was discontinued, and she was started on filgrastim. Her cell counts gradually improved, and she was subsequently discharged.Case 2 involved a 68-year-old woman, with a history of Graves disease, who presented with severe back pain, nausea, and vomiting. She was recently discharged on 10 mg of MMI twice daily, which was increased to 10 mg 3 times a day. She was readmitted to the hospital because of a septic shock in the setting of pneumonia, colitis, bacteremia, and MMI-induced agranulocytosis. A bone marrow biopsy showed a polyclonal infiltrate with up to 85% plasma cells. Despite treatment with antibiotics, filgrastim, and continuous renal replacement therapy, she ultimately passed away. Discussion: Although these cases had differing outcomes, they shared similar features and risk factors, including older age, female sex, and relatively higher doses of MMI. Conclusion: Close follow up and awareness of risk factors, such as age, female sex, and higher doses of MMI, may decrease the risk of MMI-induced agranulocytosis and fatal outcomes.