Combined hepatocellular cholangiocarcinoma in hepatectomy specimens: A clinicopathologic analysis.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon form of primary liver carcinoma. It is heterogenous in terms of morphology, immunohistochemistry, radiology, and clinical features; making it a challenging entity for diagnosis. Aims: The purpose of the present study was to evaluate clinicopathological characteristics of patients with cHCC-CCA. Settings and Design: Retrospective observational study. Materials and Methods: The patients diagnosed with cHCC-CC were identified from hepatic surgical specimens and were evaluated. Statistical Analysis: Survival was estimated as per Kaplan-Meier method. Results: Out of six patients, five had undergone resection while one had liver transplant. Five were male and one was female and the mean age was 52 years. Tumor markers revealed raised serum alfa-fetoprotein and CA19.9 in four and three patients, respectively. Five of the liver specimens were cirrhotic. Diagnosis was predominantly based on tumor morphology. All cases were of Allen and Lisa type B and cHCC-CCA as per WHO (2019) classification. Stem cell features <5% were noted in two cases. Immunohistochemistry for programmed death 1/programmed death ligand 1 (PD1/PDL1) was negative in both the hepatocellular and cholangiocellular components in all six cases. Mismatch repair (MMR) protein expression was retained in two and deficient in four cases. The median follow-up after surgery was 21.3 months (range, 5-46.2 months). Five patients had intrahepatic and/or extrahepatic recurrence on follow-up after surgery. The median recurrence-free survival was estimated at 13.1 months (95% CI 5.67-20.6). Three patients had received salvage treatment. The median overall survival was estimated at 20 months (95% CI 0-45.3). Conclusions: The present study highlights the role of morphology in the diagnosis of cHCC-CCA. The choice of locoregional and/or systemic therapy after surgery may be individualized based on the clinicopathological characteristics.

Use of Singlet Oxygen in the Generation of a Mononuclear Nonheme Iron(IV)-Oxo Complex.

Nonheme iron(III)-superoxo intermediates are generated in the activation of dioxygen (O2) by nonheme iron(II) complexes and then converted to iron(IV)-oxo species by reacting with hydrogen donor substrates with relatively weak C-H bonds. If singlet oxygen (1O2) with ca. 1 eV higher energy than the ground state triplet oxygen (3O2) is employed, iron(IV)-oxo complexes can be synthesized using hydrogen donor substrates with much stronger C-H bonds. However, 1O2 has never been used in generating iron(IV)-oxo complexes. Herein, we report that a nonheme iron(IV)-oxo species, [FeIV(O)(TMC)]2+ (TMC = tetramethylcyclam), is generated using 1O2, which is produced with boron subphthalocyanine chloride (SubPc) as a photosensitizer, and hydrogen donor substrates with relatively strong C-H bonds, such as toluene (BDE = 89.5 kcal mol-1), via electron transfer from [FeII(TMC)]2+ to 1O2, which is energetically more favorable by 0.98 eV, as compared with electron transfer from [FeII(TMC)]2+ to 3O2. Electron transfer from [FeII(TMC)]2+ to 1O2 produces an iron(III)-superoxo complex, [FeIII(O2)(TMC)]2+, followed by abstracting a hydrogen atom from toluene by [FeIII(O2)(TMC)]2+ to form an iron(III)-hydroperoxo complex, [FeIII(OOH)(TMC)]2+, that is further converted to the [FeIV(O)(TMC)]2+ species. Thus, the present study reports the first example of generating a mononuclear nonheme iron(IV)-oxo complex with the use of singlet oxygen, instead of triplet oxygen, and a hydrogen atom donor with relatively strong C-H bonds. Detailed mechanistic aspects, such as the detection of 1O2 emission, the quenching by [FeII(TMC)]2+, and the quantum yields, have also been discussed to provide valuable mechanistic insights into understanding nonheme iron-oxo chemistry.

Computational Design for Identification of Human Anti-MUC1 Heteroclitic Peptides in the Treatment of HER2-Positive Breast Cancer through Neural Network Training and Monomeric based Design.

AIMS: Generation of the human anti-MUC1 peptide through neural network training and monomeric design method. Analyzing 9-mer peptide potential computationally for treatment of HER2-positive breast cancer. BACKGROUND: With the advancements of cancer genome atlas project (TCGA), cancer dependancy project (DepMap) and human protein atlas (HPA), large-scale datasets are generated for oncology studies. However, after development of redefined breast cancer drug targets, there are key issues in successful breast cancer treatments that needed to be pursued which paved the pathway for new approaches or strategies. In that respect, our research data aimed to represent a new aspect of breast cancer drug development studies. OBJECTIVE: Extract human MUC1 sequences from various databases. Perform neural networking method for novel peptides sequences. Analyze the potentiality of generated heteroclitic peptide sequences for suitable vaccine candidate for breast cancer treatment. METHODS: Input scaffolds of protein database (PDB) files for human MUC1 were retrieved and loaded into Evo design server with monomeric based design option. Further, neural network training approaches were followed and other computational tools were used for alignment-independent prediction of protective antigens and subunit vaccines potency of designed heteroclitic peptides. RESULTS: Study findings revealed two human anti-MUC1 heteroclitic peptides of 9mers (WAVWTYVSV, FMSFYIMNL), which showed the lowest energy cluster and sequence identity, normalized relative error rate of secondary structure, solvent accessibility, backbone torsion angles for neural networking and RMSD values in evolutionary profiling, and online MHCPred IC50 interaction values. VaxiGen v2.0 server revealed subunit vaccine potency values of in-silico designed two heteroclitic peptides were 0.1551 (WAVWTYVSV) and 0.3508 (FMSFYIMNL) with a threshold value of 0.5 followed by AllerTOP v2.0 for their allergenicity nature in immunogenic reactions. CONCLUSION: Computationally designed heteroclitic peptide WAVWTYVSV indicated promising values which can be utilised as drug delivery or tumour marker candidate in the treatment of human breast cancer by eliciting lyse of tumor cells.

Internet gaming and related psychotic disorder: An emerging phenomenon.

Internet addiction has recently been suggested as a possible diagnostic entity in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and incorporated in the International Classification of Diseases 11th Revision (ICD-11) as a gaming disorder, predominantly, online or offline. Mostly, psychotic phenomena have been described by either alcohol or opioid withdrawal, but there is a paucity of literature on Internet-related psychosis. We report two cases from Northern India of sudden onset of psychosis due to Internet addiction. The contents of hallucinations and delusions reflected themes of Internet gaming. Psychosis as a specifier for Internet gaming disorder (IGD) is not defined in DSM-5, whereas it should be considered as one of the presentations of Internet addiction.

The attitude of medical undergraduate students from North India toward transgender and change thereafter by educational intervention.

Background: There is a widespread gap among medical professionals about transgender, and it needs to be addressed through proper educational intervention to inculcate positive attitudes toward transgender people. Aim: This study aimed to assess the attitude of medical undergraduate students toward transgender and change thereafter by educational intervention. Materials and Methods: A total of 169 final-year undergraduate students (aged 22-25 years; 50.3% males; all having heterosexual orientation) were assessed for their attitudes toward transgender people using the Genderism and Transphobia Scale (GTS) and Attitude toward Transgender Individuals Scale (ATTIS). Subsequently, an educational intervention was conducted. The attitude scores were again evaluated immediately and after one month of post-intervention. A paired t-test, independent-samples t-test, and analysis of variance (ANOVA) were used to compare the data. Results: Mean ATTIS and GTS scores before intervention were 67.02 ± 9.20 and 80.84 ± 26.07, respectively. After the educational intervention, these scores were 79.27 ± 7.18 and 63.20 ± 12.11, respectively, thus showing a significant change in both scores. The change in GTS score was significantly higher in males than in females (P < 0.001) and in urban than in rural residents (P = 0.017). No significant association of demographic factors was observed concerning the change in ATTIS scores. On evaluating the recall value, no significant decline in GTS or ATTIS scores was observed following a one month of interval. Conclusion: There is a need to positively reinforce these changes brought about by educational intervention in the attitude of undergraduate medical students toward transgender people. Such cognitive gains are achievable in developing a humanistic society.

Diagnosis of Pancreatic Cancer Using miRNA30e Biosensor.

This work describes miRNA-based electrochemical biosensor for detection of miRNA30e, a pancreatic cancer biomarker. The screen-printed gold electrode was functionalized using cysteine hydrochloride followed by immobilization of synthesized colloidal gold nanorods (10-12 nm diameter and 25-65 nm length). The gold nanorods modified electrode surface was amino functionalized for covalent attachment of single-stranded DNA probe against miRNA30e (miR30e). This platform was utilized for electrochemical measurements and response analysis of target miRNA30e. Electrochemical impedance spectroscopic measurements showed very poor sensitivity (13.51 Ω/µg/mL/cm2) using charge transfer resistance calibration plots. Cyclic voltammetry and differential pulse voltammetry-based miR30e quantification showed decreasing current response with increasing concentration of miR30e with detection range of 0.1 fg/mL-0.1 µg/mL (14.9 aM-14.9 nM). The sensitivity of DPV sensing (104.4 µA/µg/mL/cm2) was found to be 1.3 times higher than that of CV-based quantification (79.6 µA/µg/mL/cm2). miRNA-based biosensors have the potential of replacing current invasive, time consuming and technically difficult diagnostic procedures. Furthermore, the lower limit of detection of 14.9 aM miRNA30e makes it a promising tool for detection of cancer at early stages and hence increasing survival rate.

Therapeutic Approaches for Combating Aspergillus Associated Infection.

Now-a-days fungal infection emerges as a significant problem to healthcare management systems due to high frequency of associated morbidity, mortality toxicity, drug-drug interactions, and resistance of the antifungal agents. Aspergillus is the most common mold that cause infection in immunocompromised hosts. It's a hyaline mold that is cosmopolitan and ubiquitous in nature. Aspergillus infects around 10 million population each year with a mortality rate of 30-90%. Clinically available antifungal formulations are restricted to four classes (i.e., polyene, triazole, echinocandin, and allylamine), and each of them have their own limitations associated with the activity spectrum, the emergence of resistance, and toxicity. Consequently, novel antifungal agents with modified and altered chemical structures are required to combat these invasive fungal infections. To overcome these limitations, there is an urgent need for new antifungal agents that can act as potent drugs in near future. Currently, some compounds have shown effective antifungal activity. In this review article, we have discussed all potential antifungal therapies that contain old antifungal drugs, combination therapies, and recent novel antifungal formulations, with a focus on the Aspergillus associated infections.

Therapeutic approaches for combating Pseudomonas aeruginosa infections.

Pseudomonas aeruginosa is an opportunistic pathogen responsible for acute hospital-acquired infections. This review described various therapeutic approaches to treat infections caused by P. aeruginosa, including conventional therapy, novel antibiotic treatments and treatments other than antibiotics. Most of the developments are still in research that will provide novel treatment options in future.

Antimycotic Drugs and their Mechanisms of Resistance to Candida Species.

Fungal infections have shown an upsurge in recent decades, which is mainly because of the increasing number of immunocompromised patients and the occurrence of invasive candidiasis has been found to be 7-15 fold greater than that of invasive aspergillosis. The genus Candida comprises more than 150 distinct species, however, only a few of them are found to be pathogenic to humans. Mortality rates of Candida species are found to be around 45% and the reasons for this intensified mortality are inefficient diagnostic techniques and unfitting initial treatment strategies. There are only a few antifungal drug classes that are employed for the remedy of invasive fungal infections. which include azoles, polyenes, echinocandins, and pyrimidine analogs. During the last 2-3 decades, the usage of antifungal drugs has increased several folds due to which the reports of escalating antifungal drug resistance have also been recorded. The resistance is mostly to the triazole- based compounds. Due to the occurrence of antifungal drug resistance, the success rates of treatment have been reduced as well as major changes have been observed in the frequency of fungal infections. In this review, we have summarized the major molecular mechanisms for the development of antifungal drug resistance.

Which Aspects of the CanMEDS Competencies are Most Valued in Radiologists? Perspectives of Trainees From Other Specialties.

PURPOSE: Radiologists work primarily in collaboration with other healthcare professionals. As such, these stakeholder perspectives are of value to the development and assessment of educational outcomes during the transition to competency-based medical education. Our aim in this study was to determine which aspects of the Royal College CanMEDS competencies for diagnostic radiology are considered most important by future referring physicians. METHODS: Institutional ethics approval was obtained. After pilot testing, an anonymous online survey was sent to all residents and clinical fellows at our university. Open-ended questions asked respondents to describe the aspects of radiologist service they felt were most important. Thematic analysis of the free-text responses was performed using a grounded theory approach. The resulting themes were mapped to the 2015 CanMEDS Key Competencies. RESULTS: 115 completed surveys were received from residents and fellows from essentially all specialties and years of training (out of 928 invited). Major themes were 1) timeliness and accessibility of service, 2) quality of reporting, and 3) acting as a valued team member. The competencies identified as important by resident physicians were largely consistent with the CanMEDS framework, although not all key competencies were covered in the responses. CONCLUSIONS: This study illustrates how CanMEDS roles and competencies may be exemplified in a concrete and specialty-specific manner from the perspective of key stakeholders. Our survey results provide further insight into specific objectives for teaching and assessing these competencies in radiology residency training, with the ultimate goal of improving patient care through strengthened communication and working relationships.

Chemotherapeutic Strategies for Combating Staphylococcus aureus Infections.

Staphylococcus aureus is a prominent human pathogen that causes nosocomial and community acquired infections. The accelerating emergence and prevalence of staphylococcal infections have grotesque health consequences which are mostly due to its anomalous capability to acquire drug resistance and scarcity of novel classes of antibacterials. Many combating therapies are centered on primary targets of S. aureus which are cell envelope, ribosomes and nucleic acids. This review describes various chemotherapeutic strategies for combating S. aureus infections including monotherapy, combination drug therapy, phage endolysin therapy, lysostaphins and antibacterial drones. Monotherapy has dwindled in due course of time, but combination therapy, endolysin therapy, lysostaphin and antibacterial drones are emerging alternatives which efficiently conquer the shortcomings of monotherapy. Combinations of more than one antibiotic agents or combination of adjuvant with antibiotics provide a synergistic approach to combat infections causing pathogenic strains. Phage endolysin therapy and lysostaphin are also presented as possible alternatives to conventional antibiotic therapies. Antibacterial Drones go a step further by specifically targeting the virulence genes in bacteria, giving them a certain advantage over existing antibacterial strategies. But the challenge remains on the better understanding of these strategies for executing and implementing them in the health sector. In this day and age, most of the S. aureus strains are resistant to an ample number of antibiotics, so there is an urgent need to overcome such multidrug-resistant strains for the welfare of our community.

Comparative safety and efficacy of tibolone and escitalopram in postmenopausal women.

BACKGROUND: A high prevalence of psychiatric disorders, particularly depressive and anxiety disorders among women is observed through the postmenopausal stage. AIM: The aim of this study is to compare the safety and efficacy of tibolone (TIB) and escitalopram (ESCIT) in postmenopausal women (PMW). MATERIALS AND METHODS: It was an interventional, open-label, hospital-based, follow-up study conducted on 60 PMW with the diagnosis of depression as per the Diagnostic and Statistical Manual of Mental Disorder-5 criteria. Patients were divided into two groups of 30 each, i.e. Group I (TIB-2.5 mg/day) and Group II (ESCIT-10-20 mg/day). The primary outcome was assessed for change in climacteric symptom scores on Greene's Climacteric Scale (GCS), severity of depression and anxiety on Hamilton Rating Scale for Depression (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A), and sexual functioning on Arizona Sexual Experience Scale (ASEX). The secondary outcome of well-being was assessed on World Health Organization Quality of life (QOL)-BREF. All the observations were carried out from baseline and at 2, 4, 8, and 12 weeks. RESULTS: Both the groups showed significant improvement in climacteric and depressive symptoms. However, at the 8th and 12th weeks, mean ± standard deviation scores were significantly lower in Group I (GCS score - 24.80 ± 4.92, 20.30 ± 3.56; HAM-D score - 16.57 ± 5.83, 10.2 ± 5.67) compared to Group II (GCS score - 27.27 ± 5.83 and 23.33 ± 5.70, HAM-D score - 19.97 ± 7.98 and 16.17 ± 10.11). No significant difference between the groups was seen for anxiety on HAM-A scores. Only in Group I, there was significant improvement in ASEX scores. QoL in Group I had shown significant improvement in physical and psychological domain compared to Group II at different time interval, i.e. 4th and 8th week onward. In Group I, Alternative Dispute Resolution was reported to be 23.3%, whereas it was 56.7% in Group II. However, none were serious to warrant discontinuation. CONCLUSION: TIB was better than ESCIT in improving depression, climacteric symptoms, and physical and psychological domain of QoL with an additional benefit of restoring sexual functioning.

Organophosphate poisoning in a young child: a case report.

Unintentional ingestions are a common form of poisoning in children worldwide. Organophosphates are commonly used in households worldwide and are a common cause of childhood poisonings. This case report describes an unintentional ingestion of a child in East Africa. A thorough patient history and a high index of suspicion are needed in recognizing an organophosphate poisoning. Prompt patient stabilization and treatment improve outcomes. Neurologic sequela may occur and thus patient follow-up is recommended.

Diffuse Alveolar Hemorrhage With Avelumab Maintenance Therapy.

Immune checkpoint blockade is a rapidly expanding therapeutic modality in oncology. However, its adverse effects extend beyond the cytotoxicity of conventional chemotherapy. Pneumotoxicity associated with immune checkpoint therapy presents a diagnostic conundrum that has been further complicated by the COVID-19 pandemic. We report a case of a patient with metastatic urothelial carcinoma who developed diffuse alveolar hemorrhage (DAH) following treatment with avelumab.

Functional Connectivity Between the Posterior Default Mode Network and Parahippocampal Gyrus Is Disrupted in Older Adults with Subjective Cognitive Decline and Correlates with Subjective Memory Ability.

BACKGROUND: Subjective cognitive decline (SCD) is associated with increased risk of developing Alzheimer's disease (AD). However, the underlying mechanisms for this association remain unclear. Neuroimaging studies suggest the earliest AD-related changes are large-scale network disruptions, beginning in the posterior default mode (pDMN) network. OBJECTIVE: To examine the association between SCD and pDMN network connectivity with medial temporal lobe (MTL) regions using resting-state functional magnetic resonance imaging. METHODS: Forty-nine participants with either SCD (n = 23, 12 females; mean age: 70.7 (5.5)) or who were cognitively unimpaired (CU; n = 26, 16 females, mean age: 71.42 (7.3)) completed the Memory Functioning Questionnaire, a measure of subjective memory, and underwent resting state functional MRI at 3 Tesla. Functional connectivity between the posterior cingulate cortex (PCC), as the key pDMN node, and MTL regions were compared between SCD and CU groups. Further, the association between pDMN-MTL connectivity and the Frequency of Forgetting subscale of the Memory Functioning Questionnaire was examined. RESULTS: Connectivity between the PCC-MTL was observed in the CU group but was absent in SCD (t(47) = 2.69, p = 0.01). Across all participants, self-perception of frequency of forgetting, but not objective memory, was strongly correlated with connectivity between the PCC-left parahippocampal gyrus (r = 0.43, p = 0.002). CONCLUSION: These findings support the hypothesis that increased AD risk in SCD may be mediated by disrupted pDMN-parahippocampal connectivity. In addition, these findings suggest that frequency of forgetting may serve as a potential biomarker of SCD due to incipient AD.

A Mononuclear Non-Heme Manganese(III)-Aqua Complex in Oxygen Atom Transfer Reactions via Electron Transfer.

Metal-oxygen complexes, such as metal-oxo [M(O2-)], -hydroxo [M(OH-)], -peroxo [M(O22-)], -hydroperoxo [M(OOH-)], and -superoxo [M(O2•-)] species, are capable of conducting oxygen atom transfer (OAT) reactions with organic substrates, such as thioanisole (PhSMe) and triphenylphosphine (Ph3P). However, OAT of metal-aqua complexes, [M(OH2)]n+, has yet to be reported. We report herein OAT of a mononuclear non-heme Mn(III)-aqua complex, [(dpaq)MnIII(OH2)]2+ (1, dpaq = 2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamidate), to PhSMe and Ph3P derivatives for the first time; it is noted that no OAT occurs from the corresponding Mn(III)-hydroxo complex, [(dpaq)MnIII(OH)]+ (2), to the substrates. Mechanistic studies reveal that OAT reaction of 1 occurs via electron transfer from 4-methoxythioanisole to 1 to produce the 4-methoxythioanisole radical cation and [(dpaq)MnII(OH2)]+, followed by nucleophilic attack of H2O in [(dpaq)MnII(OH2)]+ to the 4-methoxythioanisole radical cation to produce an OH adduct radical, 2,4-(MeO)2C6H3S•(OH)Me, which disproportionates or undergoes electron transfer to 1 to yield methyl 4-methoxyphenyl sulfoxide. Formation of the thioanisole radical cation derivatives is detected by the stopped-flow transient absorption measurements in OAT from 1 to 2,4-dimethoxythioanisole and 3,4-dimethoxythioanisole, being compared with that in the photoinduced electron transfer oxidation of PhSMe derivatives, which are detected by laser-induced transient absorption measurements. Similarly, OAT from 1 to Ph3P occurs via electron transfer from Ph3P to 1, and the proton effect on the reaction rate has been discussed. The rate constants of electron transfer from electron donors, including PhSMe and Ph3P derivatives, to 1 are fitted well by the electron transfer driving force dependence of the rate constants predicted by the Marcus theory of outer-sphere electron transfer.

Antibiotic Adjuvants: A Promising Approach to Combat Multidrug Resistant Bacteria.

The escalating emergence and prevalence of infections caused by multi-drug resistant (MDR) pathogenic bacteria accentuate the crucial need to develop novel and effectual therapeutic strategies to control this threat. The recent past surprisingly indicates a staggering decline in effective strategies against MDR. Different approaches have been employed to minimize the effect of resistance, but the question still lingers over the astounding number of drugs already tried and tested. Furthermore, the detection of new drug targets and the action of new antibacterial agents against already existing drug targets also complicate the condition. Antibiotic adjuvants are considered as one such promising approach for overcoming bacterial resistance. Adjuvants can potentiate the action of generally adopted antibacterial drugs against MDR bacterial pathogens either by minimizing the impact and emergence of resistance or improving the action of antibacterial drugs. This review provides an overview of the mechanism of antibiotic resistance, the main types of adjuvants and their mode of action, achievements and progression.

Ceftriaxone-Induced Immune Hemolytic Anemia.

Ceftriaxone is a commonly used antibiotic in hospitals for the treatment of pneumonia, urinary tract infection, bacteremia, meningitis, skin, and soft tissue infection. It can be associated with common allergic reactions like skin rash, itching, and, rarely, angioedema. Ceftriaxone-induced immune hemolytic anemia (IHA) is a rare and potentially fatal complication if not identified and managed in time. We report a case of ceftriaxone-induced IHA in a young woman.