Comparative analysis of the antibacterial efficacy and bioactive components of Thuja occidentalis obtained from four different geographical sites.

The purpose of this study was to determine whether or not there were significant differences in the antibacterial potential of Thuja occidentalis collected from four distinct geographical sites, namely Chamba (Himachal Pradesh, India), Jalandhar (Punjab, India), Aurangabad (Bihar, India) and Kakching (Manipur, India). The plant extracts were prepared in three different solvents: ethanol, methanol, and acetone. The antibacterial potential of the plant extracts was tested against five different bacterial species using well diffusion test. The minimum inhibitory and bactericidal concentrations of the plant sample exhibiting maximum zone of inhibition against different bacterial strains were calculated. Further, the total phenols, flavonoids, and antioxidant efficacy (using DPPH assay) were also analysed biochemically. The activity of different antioxidant enzymes including SOD, CAT and APX were also recorded as these enzymes protect the cells from free radical damage. GC-MS analysis was also performed on all plant extracts to identify the bioactive components. The results showed that the T. occidentalis collected from the Kakching, Manipur, East side of India showed the highest zone of inhibition against all the bacterial strains, followed by Chamba, Jalandhar, and lastly Aurangabad. To analyse the impact of phytochemicals on the antibacterial efficacy, a correlation was drawn between the biochemical parameters and zone of inhibition using Karl Pearson's method. Most bacterial species demonstrated a positive correlation between antibacterial effectiveness (zone of inhibition) and biochemical markers. The GC-MS study revealed positive correlation between zone of inhibition and peak area percentages of α-Pinene, ß-caryophyllene, Germacrene-D, and Humulene in all bacterial species indicating that these chemicals may play a key role in the bactericidal potential of T. occidentalis. Based on the results of this investigation, it is evident that the antibacterial effectiveness of T. occidentalis varies with its geographical location which may be attributed to the differences in the phytochemical makeup.

Tick-Borne Rhabdomyolysis: A Rare Case of Rhabdomyolysis and Acute Kidney Injury Due to Anaplasmosis.

Anaplasmosis is a tick-borne illness commonly seen in the northeastern states of the United States. The most common presenting signs are fever, malaise, and body aches accompanied by leukopenia, thrombocytopenia, and transaminitis. Rhabdomyolysis and acute kidney injury are rare presentations that can lead to significant morbidity.  We present the case of a patient who presented with non-specific symptoms of malaise, fatigue, and body aches and was found to have rhabdomyolysis and acute kidney injury on laboratory workup. A presumptive diagnosis of anaplasmosis was made, and the patient was started on treatment for the same. The patient recovered successfully. Our case highlights the rare presentation of anaplasmosis with rhabdomyolysis and acute kidney injury. Physician awareness is needed for early diagnosis and preventing morbidity.

Portrayal of Suicide in Bollywood Movies Over Last Two Decades: A Content Analysis.

Aim: To analyse Bollywood movies depicting suicides, released in last two decades, on content and scientific accuracy. Methodology: Online movie databases, blogs were accessed along with Google search to compile a list of movies portraying suicide (thought, plan, or act) in at least one character. Each movie was screened twice for details of character, symptoms, diagnosis, treatment, and scientific accuracy of depiction. Results: Twenty-two movies were analyzed. Most characters were middle-aged, unmarried, well educated, employed and affluent. Most common motives were emotional pain and guilt/shame. Most suicides were impulsive, method of choice was fall from height and resulted in death. Conclusion: Cinematic depiction of suicide may promote misconceptions among viewers. Alignment of cinematization with scientific knowledge is needed.

A Rare Case of Pulmonary Cavitary Disease Caused by Mycobacterium xenopi.

Mycobacterium xenopi is a slow-growing, acid-fast, non-tuberculous mycobacterium (NTM). It is often considered to be a saprophyte or an environmental contaminant. Mycobacterium xenopi has low pathogenicity and is usually seen in patients with pre-existing chronic lung diseases and immunocompromised patients. We present a case of Mycobacterium xenopi causing a cavitary lesion in a patient with chronic obstructive pulmonary disease (COPD) that was discovered incidentally during the low-dose CT scan done for lung cancer screening in a patient with COPD. The initial workup was negative for NTM. An Interventional-guided (IR) core needle biopsy was done given the high suspicion for NTM and revealed a positive culture for Mycobacterium xenopi.  Our case highlights the importance of considering NTM in the differential diagnosis of at-risk patients and pursuing invasive testing if there is a high clinical suspicion.

Human monkeypox: epidemiology, transmission, pathogenesis, immunology, diagnosis and therapeutics.

"Zoonoses" describe diseases that may be acquired by humans from animals. Due to the constant contact between humans and other animals, many infectious diseases are disseminated. This may happen via direct contact, such as bites or scratches, or by indirect contact, such as when eating bush meat or using contaminated animal parts. Monkeypox disease is one such zoonotic infection which is now emerging as a disease of global concern, and the World Health Organization has already labelled it a public health emergency. The virus is related to other orthopox viruses and may be further classified into two genetically separate clades, the West African and the Central African. The latter is far more pathogenic than the former. Utilizing virotransducer and virostealth proteins, the virus is able to control the host's T-cell-mediated responses and impede the release of cytokines and chemokines.Monkeypox may be treated with tecovirimat, cidofovir, or brincidofovir, and prevention with the vaccination JYNNEOS is recommended. The disease's fast global expansion warrants concern despite the fact that it is less fatal than that caused by the variola virus. Before the sickness reaches catastrophic proportions, we must draw on our prior experiences and act prudently. This article serves as an introduction to the monkeypox virus and its associated pathology, treatments, diagnostics, and preventative measures.

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance.

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

Discovery and molecular basis of subtype-selective cyclophilin inhibitors.

Although cyclophilins are attractive targets for probing biology and therapeutic intervention, no subtype-selective cyclophilin inhibitors have been described. We discovered novel cyclophilin inhibitors from the in vitro selection of a DNA-templated library of 256,000 drug-like macrocycles for cyclophilin D (CypD) affinity. Iterated macrocycle engineering guided by ten X-ray co-crystal structures yielded potent and selective inhibitors (half maximal inhibitory concentration (IC50) = 10 nM) that bind the active site of CypD and also make novel interactions with non-conserved residues in the S2 pocket, an adjacent exo-site. The resulting macrocycles inhibit CypD activity with 21- to >10,000-fold selectivity over other cyclophilins and inhibit mitochondrial permeability transition pore opening in isolated mitochondria. We further exploited S2 pocket interactions to develop the first cyclophilin E (CypE)-selective inhibitor, which forms a reversible covalent bond with a CypE S2 pocket lysine, and exhibits 30- to >4,000-fold selectivity over other cyclophilins. These findings reveal a strategy to generate isoform-selective small-molecule cyclophilin modulators, advancing their suitability as targets for biological investigation and therapeutic development.

Rapid surveillance of COVID-19 by timely detection of geographically robust, alive and emerging hotspots using Particle Swarm Optimizer.

A novel virus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a pandemic called Coronavirus disease 2019 (COVID-19). According to the World Health Organization, COVID-19 was first detected in Wuhan city in December 2019 and has affected 216 countries with 9473214 confirmed cases and 484249 deaths globally as on June 26th, 2020. Also, this outbreak continues to grow in many countries like the United States of America (U.S.), Brazil, India, and Russia. To ensure rapid surveillance and better decision-making by government authorities in different countries, it is vital to identify alive and emerging hotspots within a country promptly. State-of-the-art methods based on space-time scan statistics (like SaTScan) are not geographically robust. Also, due to the enumeration of many Spatio-temporal cylinders, the computation cost of Spatio-temporal SaTScan (ST-SaTScan) is very high. In the applications like COVID-19 where we need to detect the emerging hotspots daily as soon as the new count of cases gets updated, ST-SaTScan seems inefficient. Therefore, this paper proposes a Particle Swarm Optimizer-based scheme to timely detect geographically robust, alive, and emerging COVID-19 hotspots in a country. Timely detection can help government officials design better control strategies like increasing testing in hotspots, imposing stricter containment rules, or setting up temporary hospital beds. Performance of ST-SaTScan and proposed scheme have been analyzed for four worst-hit U.S. states for the incubation period of 14 days between June 11th, 2020, and June 24th, 2020. Results indicate that the proposed scheme detects hotspots of a higher likelihood ratio (a measure to indicate the significance of hotspot) than ST-SaTScan in significantly less time. We also applied the proposed scheme to detect the emerging COVID-19 hotspots in all states of the U.S. During the study period, the proposed scheme has detected 104 emerging COVID-19 hotspots.

Use of cauliflower mosaic virus DNA markers to assess the potential for pathogen transmission from physicians' white coats.

In an observational study, the sleeves and pockets of physicians' white coats often directly or indirectly contacted patients and environmental surfaces. DNA markers on the sleeves or pockets were frequently transferred to surfaces and patients. These findings suggest that contaminated white coats have the potential to contribute to pathogen transmission.

Smart About Meds (SAM): a pilot randomized controlled trial of a mobile application to improve medication adherence following hospital discharge.

OBJECTIVE: The objectives of this pilot study were (1) to assess the feasibility of a larger evaluation of Smart About Meds (SAM), a patient-centered medication management mobile application, and (2) to evaluate SAM's potential to improve outcomes of interest, including adherence to medication changes made at hospital discharge and the occurrence of adverse events. MATERIALS AND METHODS: We conducted a pilot randomized controlled trial among patients discharged from internal medicine units of an academic health center between June 2019 and March 2020. Block randomization was used to randomize patients to intervention (received access to SAM at discharge) or control (received usual care). Patients were followed for 30 days post-discharge, during which app use was recorded. Pharmacy claims data were used to measure adherence to medication changes made at discharge, and physician billing data were used to identify emergency department visits and hospital readmissions during follow-up. RESULTS: Forty-nine patients were eligible for inclusion in the study at hospital discharge (23 intervention, 26 control). In the 30 days of post-discharge, 15 (65.2%) intervention patients used the SAM app. During this period, intervention patients adhered to a larger proportion of medication changes (83.7%) than control patients (77.8%), including newly prescribed medications (72.7% vs 61.7%) and dose changes (90.9% vs 81.8%). A smaller proportion of intervention patients (8.7%) were readmitted to hospital during follow-up than control patients (15.4%). CONCLUSION: The high uptake of SAM among intervention patients supports the feasibility of a larger trial. Results also suggest that SAM has the potential to enhance adherence to medication changes and reduce the risk of downstream adverse events. This hypothesis needs to be tested in a larger trial. TRIAL REGISTRATION: Clinicaltrials.gov, registration number NCT04676165.

Smart about medications (SAM): a digital solution to enhance medication management following hospital discharge.

OBJECTIVE: To outline the development of a software solution to improve medication management after hospital discharge, including its design, data sources, intrinsic features, and to evaluate the usability and the perception of use by end-users. MATERIALS AND METHODS: Patients were directly involved in the development using a User Center Design (UCD) approach. We conducted usability interviews prior to hospital discharge, before a user started using the application. A technology acceptance questionnaire was administered to evaluate user self-perception after 2 weeks of use. RESULTS: The following features were developed; pill identification, patient-friendly drug information leaflet, side effect checker, and interaction checker, adherence monitoring and alerts, weekly medication schedule, daily pill reminders, messaging service, and patient medication reviews. The usability interviews show a 98.3% total success rate for all features, severity (on a scale of 1-4) 1.4 (SD 0.79). Regarding the self-perception of use (1-7 agreement scale) the 3 highest-rated domains were: (1) perceived ease of use 5.65 (SD 2.02), (2) output quality 5.44 (SD 1.65), and (3) perceived usefulness 5.29 (SD 2.11). DISCUSSION: Many medication management apps solutions have been created and most of them have not been properly evaluated. SAM (Smart About Medications) includes the user perspective, integration between a province drug database and the pharmacist workflow in real time. Its features are not limited to maintaining a medication list through manual entry. CONCLUSION: We can conclude after evaluation that the application is usable and has been self-perceived as easy to use by end-users. Future studies are required to assess the health benefits associated with its use.

Use of viral DNA surrogate markers to study routes of transmission of healthcare-associated pathogens.

BACKGROUND: The hands of healthcare personnel are the most important source for transmission of healthcare-associated pathogens. The role of contaminated fomites such as portable equipment, stethoscopes, and clothing of personnel in pathogen transmission is unclear. OBJECTIVE: To study routes of transmission of cauliflower mosaic virus DNA markers from 31 source patients and from environmental surfaces in their rooms. DESIGN: A 3-month observational cohort study. SETTING: A Veterans' Affairs hospital. METHODS: After providing care for source patients, healthcare personnel were observed during interactions with subsequent patients. Putative routes of transmission were identified based on recovery of DNA markers from sites of contact with the patient or environment. To assess plausibility of fomite-mediated transmission, we assessed the frequency of transfer of methicillin-resistant Staphylococcus aureus (MRSA) from the skin of 25 colonized patients via gloved hands versus fomites. RESULTS: Of 145 interactions involving contact with patients and/or the environment, 41 (28.3%) resulted in transfer of 1 or both DNA markers to the patient and/or the environment. The DNA marker applied to patients' skin and clothing was transferred most frequently by stethoscopes, hands, and portable equipment, whereas the marker applied to environmental surfaces was transferred only by hands and clothing. The percentages of MRSA transfer from the skin of colonized patients via gloved hands, stethoscope diaphragms, and clothing were 52%, 40%, and 48%, respectively. CONCLUSIONS: Fomites such as stethoscopes, clothing, and portable equipment may be underappreciated sources of pathogen transmission. Simple interventions such as decontamination of fomites between patients could reduce the risk for transmission.

Evaluation of a Mobile Application to Enhance Medication Management Following Hospital Discharge: Study Protocol for a Pilot Randomized Controlled Trial.

Over 3 million hospitalizations and 17 million ER visits occur in Canada each year. A substantial proportion of these encounters are preventable and attributable to medication non- adherence. Non-adherence to medication changes during discharge increases the risk of adverse events post-discharge. A mobile application was developed to improve medication management of post-discharge patients. A pilot randomized controlled trial was conducted to assess the application's usability and efficacy in decreasing non-adherence to medication changes made at discharge.

Clothing and shoes of personnel as potential vectors for transfer of health care-associated pathogens to the community.

In an acute care hospital, we demonstrated that the clothing and shoes that physicians and nurses wear home from health care facilities can be contaminated with health care-associated pathogens, particularly methicillin-resistant Staphylococcus aureus. These findings suggest that the clothing and shoes of personnel have the potential to serve as vectors for the transfer of health care-associated pathogens to the community.

What Makes a Kinase Promiscuous for Inhibitors?

ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a large kinome profiling dataset, we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the other 398 kinases in the dataset. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 with the type I inhibitors dasatinib and VX-680. Surprisingly, we find that DDR1 binds these type I inhibitors in an inactive conformation typically reserved for type II inhibitors. Our computational and biochemical studies show that DDR1 is unusually stable in this inactive conformation, giving a mechanistic explanation for inhibitor promiscuity. This phenotypic clustering analysis provides a strategy to obtain functional insights not available by sequence comparison alone.

Contaminated clothing of methicillin-resistant Staphylococcus aureus (MRSA) carriers is a potential source of transmission.

We examined the burden of methicillin-resistant Staphylococcus aureus (MRSA) on the clothing of MRSA carriers in a hospital and long-term care facility and assessed the potential for clothing to be a source of transmission. Of 50 MRSA carriers studied, 37 (74%) had MRSA recovered from clothing. For a subset of carriers with clothing contamination, transfer of MRSA from clothing to gloved hands and to a wheelchair occurred in 8 of 13 (62%) and 5 of 10 (50%) carriers, respectively. These findings suggest that measures to reduce clothing contamination should be investigated as a potential means to reduce MRSA transmission in healthcare settings.

Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. PATIENTS AND METHODS: Chemotherapy naive mCRPC patients received docetaxel 75 mg/m2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. RESULTS: Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. CONCLUSION: The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen.

A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.

Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.