Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Prevalence of Acute on Chronic Liver Failure in Autoimmune Hepatitis, Treatment Response and Mortality Burden Assessment: A Region-Predominant Systematic Review and Meta-Analysis.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high.

Connecting the Dots: Hydration, Micronutrients, and Immunity.

Dehydration, often unnoticed, can occur in adults due to heat-related illnesses, viral infections, and upper respiratory tract infections, leading to deficits in fluids, electrolytes, and energy (FEE), even without diarrhea. This fluid deficit, in turn, impairs immunity at cellular and molecular levels. Physiologically, the immune system rapidly reacts to threats by adjusting its structural permeability, allowing water and small solutes to be passed, facilitated by proteins like aquaporins (AQPs). These AQPs are also essential for immune cell communication and adjustments of the cytoskeleton for functions like chemotaxis and phagocytosis. Apart from hydration, maintaining an optimal intake of essential micronutrients, including vitamins C and E, copper, zinc, and selenium, is also critical for supporting immune function and acting as antioxidants. Transient alterations in immune function caused by acute stressors or nondiarrheal conditions heighten vulnerability to coexisting illnesses, particularly cold and upper respiratory tract infections, while also elevating the likelihood of recurrent health issues. Supplementing fluids with known FEE content according to quality standards and enhanced taste is recommended during acute illness and until complete recovery. Thus, dehydration, caused by various acute conditions, can impair immunity and delay recovery. Prioritizing hydration and nutrition in healthcare and general settings is imperative, even when diarrhea is absent.

Association of Physicians of India Expert Recommendations on Oral Fluid, Electrolytes, and Energy Management during Transition Care and Discharge for Hospitalized Patients with Nondiarrheal Illnesses.

Acute nondiarrheal illnesses (NDIs) involve overt or subclinical dehydration, requiring rehydration and electrolyte repletion. Dehydration is frequently under-recognized and under-managed, both in outpatient departments (OPDs) and inpatient departments (IPDs). Postadmission dehydration is associated with longer hospital stays and higher inhospital mortality rates. Recognizing and understanding dehydration in hospitalized patients is necessary due to the adverse outcomes associated with this condition. In this article, we aimed to develop practical consensus recommendations on the role of oral fluid, electrolyte, and energy (FEE) management in hospitalized patients with FEE deficits in NDI. The modified Delphi consensus methodology was utilized to reach a consensus. A scientific committee comprising eight experts from India formed the panel. Relevant clinical questions within three major domains were formulated for presentation and discussion: (1) burden and factors contributing to dehydration in hospitalized patients; (2) assessment of fluid and electrolyte losses and increased energy requirements in hospitalized patients; and (3) management of FEE deficits in hospitalized patients [at admission, during intravenous (IV) therapy, IV to oral de-escalation, and discharge]. The consensus level was classified into agreement (mean score ≥4), no consensus (mean score <4), and exclusion (mean score <4 after the third round of discussion). The questions that lacked agreement were discussed during the virtual meeting. The experts agreed that the most common factors contributing to dehydration in patients with NDI hospitalized in IPDs include decreased oral fluid intake, increased fluid loss due to the illness, insensible fluid loss, and a lack of awareness among doctors about dehydration, which can result in poor fluid intake. Time constraints, discontinuity of care, lack of awareness of the principles of fluid balance, lack of formal procedures for enforcing hydration schemes, and lack of adequate training are most often barriers to the assessment of hydration status in hospital settings. Experts used hydration biomarkers, such as changes in body weight, serum, or plasma osmolality; fluid intake; and fluid balance charts; along with urine output, frequency, quantity, and color, to determine hydration status in hospital settings. Experts agreed that appropriate FEE supplementation in the form of ready-to-drink (RTD) fluids can restore FEE deficits and shorten the length of hospital stays in hospitalized patients at admission, during de-escalation from IV to oral therapy, and at discharge. RTD electrolyte solutions with known concentrations of electrolytes and energy are good choices to avoid taste fatigue and replenish FEE in hospitalized patients during transition care and at discharge.

Assessment of Hydration Status Using Conventional Method and Salivary Osmolarity as a Point-of-care Tool.

Dehydration is a well-known problem worldwide, and its assessment can be challenging due to confusing physical signs. The most effective way to assess hydration status is through the costly stable isotope methodology, but this approach has practical limitations. More commonly accepted and utilized indicators of hydration status are hematological and urinary parameters. However, hematological markers require invasive methods, and urinary markers have varying degrees of success in tracking hydration changes. While alterations in body weight can serve as a means of promptly evaluating hydration status, various factors such as food consumption, fluid intake, fecal losses, and urine production can impact these changes. Researchers have turned their attention to saliva as a potential marker and point-of-care (POC) testing to address the limitations of existing biomarkers. Saliva is appealing due to its easy collection process and similarities to extracellular fluid in terms of water and ion concentrations. Recent studies have shown that saliva flow rate, osmolarity/osmolality, and total protein concentration can effectively monitor changes in body mass during acute dehydration. Misdiagnosing dehydration can have severe clinical consequences, leading to morbidity and even mortality. This narrative review focuses on recognizing the significance of hydration assessment, monitoring, and the potential of salivary osmolarity (SOSM) as an assessment tool. Healthcare professionals can improve their practices and interventions to optimize hydration and promote overall wellness using such tools.

Use of electrical stimulation for accelerated orthodontics in humans: a systematic review and meta-analysis.

AIM: The main objective of this systematic review is to comprehensively evaluate all the relevant studies to evaluate the effectiveness of electrical stimulation to accelerate orthodontic tooth movement in human patients. METHODS: Using a suitable search strategy, various databases like PubMed, CENTRAL, Scopus and Google Scholar were surveyed for relevant randomized controlled trials (RCTs); after which a hand search of related orthodontic journals was completed. The risk of bias of studies was checked using Cochrane's ROB-2 tool. The quality of evidence of the included studies was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Rate of orthodontic tooth movement was compared and thus efficiency of electrical stimulation to accelerate tooth movement was assessed. Meta-analysis was done on 2 studies out of the 4; rate of orthodontic tooth movement was compared at two time periods after start of treatment (3rd month and 5th month) with standardized mean difference (SMD) as summary estimate, with p < 0.05 denoting statistical significance. Publication bias was checked using a funnel plot. RESULTS: Via exploration of the online databases and hand searching, 1080 studies were found after removing duplicates. After full text assessment, 13 studies in total were selected that used electrical stimulation, out of which 4 studies were included in the qualitative analysis as they met the inclusion criteria. The meta-analysis was done for 3rd month and 5th month with SMD as 0.69(-1.26-0.12) and 1.64(-3.44-0.16), respectively. The strength of evidence in the meta-analysis is moderate. There was no publication bias as shown by funnel plot. DISCUSSION: The studies included showed increased risk of selection and performance bias. Also due to the limited number of studies available, there was difficulty in reaching definitive conclusions. The meta-analysis showed a significant difference among the control and experimental group for the 3rd month. CONCLUSION: Even though a positive correlation is found between electrical stimulation and acceleration of orthodontic tooth movement, it is advised to conduct further studies, particularly with human participants, to establish a more conclusive outcome. REGISTRATION: This review has received no funding. The protocol for the study was registered in the Prospective Registration of Systematic Review (PROSPERO)(CRD42023495077).

Role of Biliary Stent in Recurrence of Biliary Stones and Complications After Stone Clearance in Patients Awaiting Cholecystectomy: A Randomized Trial.

INTRODUCTION: The role of prophylactic biliary stenting after clearance of choledocholithiasis in patients awaiting cholecystectomy for concomitant cholelithiasis is controversial. We planned a randomized controlled trial to study the effect of prophylactic biliary stenting after achieving biliary clearance in reducing recurrence of choledocholithiasis and biliary complications in patients awaiting cholecystectomy. METHODS: Patients with concomitant cholelithiasis and choledocholithiasis were included, and those who had evidence of clearance of choledocholithaisis (documented on occlusion cholangiogram during endoscopic retrograde cholangiography [ERC]) were randomized to prophylactic biliary stenting or no stenting. Choledocholithaisis recurrence rate (primary outcome), biliary complications and need for repeat/emergency ERC (secondary outcomes) were compared till 3 months after clearance. RESULTS: Between September 2021 and July 2022, 70 patients were randomized into group A, stenting (n = 35), and group B, no stenting (n = 35). Sixty-six patients were included in the final analysis. Baseline characteristics were comparable between the 2 groups. Ten (15.2%) patients had recurrence of choledocholithiasis, and it was comparable between the 2 groups (7/34 [20.6%] and 3/34 [9.4%], P = 0.306). Five patients (2 cholecystitis and 3 post-ERC pancreatitis) from the stent group while none from the no stent group developed complications, and this difference was statistically significant ( P = 0.024). None of the patients in both the groups needed emergency ERC during the follow-up. DISCUSSION: This randomized trial shows a higher complication rate with prophylactic stenting, while there is no benefit in preventing choledocholithiasis recurrence in patients waiting for cholecystectomy after biliary clearance (CTRI registration number: CTRI/2021/09/036538).

Generic ibrutinib a potential cost-effective strategy for the first-line treatment of chronic lymphocytic leukaemia.

Though the chronic lymphocytic leukaemia (CLL) management options in India are still limited compared to the novel drug options in resource-rich settings, the availability of less costly generics and the government health insurance scheme has enabled many patients to access the newer drugs in India. The current study compared the cost-effectiveness and cost-utility of existing initial management options for the progression-free survival (PFS) time horizon from the patient's perspective. A two-health-state, PFS and progressive disease, Markov model was assumed for three regimens (generics): ibrutinib monotherapy, bendamustine-rituximab (B-R), and rituximab-chlorambucil (RClb) used as the frontline treatment of CLL patients in India. All costs, utilization of services, and consequences data during the PFS period were collected from interviewing patients during follow-up visits. The transition probability (TP) and average PFS information were obtained from landmark published studies. EQ-5D-5L questionnaires were utilized to assess the quality of life (QoL). Quality-adjusted life years (QALY) were measured during the PFS period. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) were studied. Upon analysis, the entire monetary expense during the PFS time was ₹1581964 with ibrutinib, ₹171434 with B-R, and ₹91997 with RClb treatment arm. Pooled PFS and QALY gain was 10.33 and 8.28 years for ibrutinib, 4.08 and 3.53 years for the B-R regimen, and 1.33 and 1.23 years in RClb arms, respectively. Ibrutinib's ICER and ICUR were ₹214587.32 per PFS year gain and ₹282384.86 per QALY gain when assessed against the B-R regimen. Ibrutinib also performed better in ICER and ICUR against the RClb arm with ₹157014.29 per PFS year gain and ₹200413.6 per QALY gain. In conclusion, generic ibrutinib is a cost-effective initial line of management compared to other commonly used treatment regimes in resource-limited settings.

Tandem 1,6-Addition/Annulations of Alkynyl p-Quinone Methides with Bis-nucleophiles: Entry to Functionalized Furans, Isoxazoles, Pyrazoles, and Pyridines.

The reaction of alkynyl p-quinone methide (pQM) with keto-methylenes through a base-mediated tandem 1,6-addition/annulation sequence, [2 + 3] annulation, affording the furans is reported for the first time. A variety of functionalized furans, including fused derivatives, were obtained in good to excellent yields under mild reaction conditions. The efficacy of alkynyl pQMs is highlighted by extending their use to access isoxazoles, pyrazoles via [3 + 2] annulation, and pyridines through [3 + 3] annulation in the presence of different bis-nucleophiles.

ipso-Cyclization of unactivated biaryl ynones leading to thio-functionalized spirocyclic enones.

Ceric ammonium nitrate (CAN)-promoted oxidative ipso-cyclization of unactivated biaryl ynones with S-centered radicals (SCN/SCF3) to access spiro[5,5]trienones has been established. This approach displayed excellent regioselectivity towards spirocyclization and tolerated a variety of functional groups. Dearomatization of hitherto unknown aryl/heteroaryl groups is also disclosed. DMSO is employed as a low-toxicity, inexpensive solvent as well as a source of oxygen.

Domino alkyne insertion/aldol reaction/aromatization of 2-alkynyl indole-3-carbaldehyde with 1,3-diketones: entry to 2-indolyl phenols.

A novel one-pot base-promoted insertion of indolyl 2-alkynes into a C-C single bond of 1,3-diketones, followed by intramolecular aldol reaction and dehydrative aromatization is described. This reaction cascade leads to the construction of 2-indolyl phenols involving the formation of the C1-C2 and C3-C4 bonds of phenols resulting from the formal insertion process with a good substrate scope. Further, these bifunctional compounds were used in a novel arylative annulation in the presence of Grignard reagents to provide chromeno-indole frameworks.

Factors contributing to flares of ulcerative colitis in North India- a case-control study.

BACKGROUND: Ulcerative colitis is a relapsing and remitting disease that may be associated with flares. The causes of flares in the Indian setting are not well recognized. METHODS: The present prospective case-control study was conducted at a single center in North India. Cases were defined as patients admitted for flare of ulcerative colitis, while controls were patients in remission enrolled from the outpatient department. The basis of the diagnosis of flare was a simple clinical colitis activity index (SCCAI) of ≥ 5 and endoscopic activity, while remission was based on SCCAI < 4 and a normal fecal calprotectin. A questionnaire evaluating recent infections, stress, drug intake (antibiotics, pain medication), adherence to therapy, and use of complementary and alternative therapy (CAM) was administered. RESULTS: We included 84 patients (51 with flare and 33 in remission) with a median age of 38 years, of whom 47 (55.9%) were males. The two groups were similar for baseline parameters, including age (38, 23-50 and 38, 25.5-48.5 years), male gender (52.9% and 60.6%), extent of disease, extraintestinal manifestations (21.6% and 12.1%), use of 5-aminosalicylates (76.5% and 90.9%). The thiopurine use was lower in those having a flare (15.7% and 36.4%). Amongst the predictors of flare, the recent infections (39.2% and 30.3%), recent travel (31.4 and 27.3%), eating outside food (47.1% and 39.4%), consumption of milk products (88.2% and 75.8%), use of pain medication (43.1% and 33.3%) and recent stress (62.7% and 60.6%) were similar between cases and controls. The rates of antibiotic use (29.4% and 6.1%), lack of adherence (50.9% and 15.2%), and intake of CAM (70.6% and 33.3%) were higher in those with flare. Patients attributed a lack of adherence to the cost of therapy, presumed cure (due to lack of symptoms), and fear of adverse effects. CONCLUSION: Lack of adherence to inflammatory bowel disease therapies and recent CAM and antibiotic intake was higher in patients with flares of UC. The study makes ground for educational intervention(s) promoting knowledge and adherence to IBD therapies.

Comparison of stainless steel and titanium-molybdenum alloy closing loop archwires using numeric simulation model based on finite element method.

INTRODUCTION: The objective of this study was to determine and compare the moment-to-force (Mc/F) ratio and the type of tooth movement generated in the anterior and posterior segments in orthodontic space closure with stainless steel and titanium-molybdenum alloy loop archwires. METHODS: Three-dimensional model of the maxilla from which the first premolar was extracted, 18 × 25-mil slot stainless steel brackets, and 16 × 22-mil stainless steel and ß titanium-molybdenum alloy (TMA) closing loop archwires with anterior gable bend of 15° and posterior gable bend of 25° were constructed. The archwires were engaged in the brackets, and 1-mm activations were carried out, which were repeated 5 times. The anterior and posterior segment Mc/F ratio and the type of tooth movement generated by the 2 wires were compared. RESULTS: It was found that the Mc/F ratio for the anterior segment was approximately 5 mm, and for posterior teeth was approximately 10 mm for both stainless steel and TMA closing loop archwire. The anterior teeth exhibited controlled tipping, whereas the posterior teeth showed bodily tooth movement, which was in accordance with the Mc/F ratio that was obtained. CONCLUSIONS: The Mc/F ratio and the type of tooth movement exhibited by stainless steel and TMA closing loop archwires were similar in both anterior and posterior segments.

Rationalizing the Use of COVID-19 Questionable Efficacy Drugs in a Low Middle-income Country: A Hospital Tocilizumab Committee Experience.

BACKGROUND: Only corticosteroids have confirmed mortality benefits in coronavirus disease of 2019 (COVID-19). Rational use of costlier drugs with questionable benefits poses a great concern to hospital pharmacies in low middle-income countriesAim: The present study aimed to assess the rational utilization of hospital supply tocilizumab and understand its clinical benefits in hospitalized COVID-19 pneumonia patientsMethods: The Hospital Tocilizumab Committee (HTC) decision support system framework was developed to make patients eligible or ineligible for tocilizumab procurement from the hospital pharmacy. A total of 33 consecutive patients receiving tocilizumab were analyzed retrospectively in the 3-month study period. The records of the inpatient stay of the patients were observed for pulse, blood pressure, respiratory rate (RR), oxygen saturation (SpO2), fraction of inspired oxygen (FiO2) laboratory work-up, hospital stay duration, and mortality benefit, if any. Patients were analyzed as "died," "survived," and "composite" subgroupsResults: The study observed death as a final outcome in 48% of patients. The study observed a significant effect of tocilizumab on C-reactive protein (CRP) (p = 0.02) and ferritin (p = 0.018) levels on a 10-day follow-up when all patients were analyzed together. Rising and declining trends of RR and FiO2 were observed among the "died" (RR, p = 0.02; FiO2, p = 0.03) and survived (RR, p = 0.03; FiO2, p = 0.05) subgroups. The second dose of tocilizumab was received by 88% of survivors as against 50% of patients who died (p = 0.04)Conclusion: Hospital Tocilizumab Committee (HTC) was successfully established to continue the assessment of the costlier drug with uncertain treatment benefits. A repeat dose of tocilizumab may provide a mortality benefit in Asian Indians.

Injury surveillance during elite women's national boxing championship in India.

Background: Injury surveillance is the cornerstone of any prevention program. However the same pertaining to women's boxing is meager. We hence intended to analyse the incidence, pattern and characteristics of injuries in female boxers during the 4th Elite Women's National Boxing Championship, 2019, in India. Methods: A total of 235 female Indian boxers participated in the tournament. Injuries from the competition injury database maintained in accordance with the injury code proposed by the Australian Sports Injury Data Dictionary were compiled to observe the pattern and analysed. The outcomes measured were incidence in terms of injury rate and injury risk and injury pattern in terms of site, nature, mechanism, severity and time of injury. Results: The injury rate was observed to be 43.98 injuries per 1000 athlete bouts of exposure (95% confidence interval [CI]: 33.71-54.07) and 293.21 injuries per 1000 athlete hours of competition (95% CI: 225.94-360.47). The most commonly injured site was head, face and neck regions. Most injuries were bruises/contusions followed by cuts and epistaxis. No concussions were reported. Conclusion: This study observed that women are less prone to injuries than their male counterparts, even though a logical comparison is difficult because of the lack of data and standardization in women's boxing.

Phosphorylation of Influenza A Virus NS1 at Serine 205 Mediates Its Viral Polymerase-Enhancing Function.

Influenza A virus (IAV) nonstructural protein 1 (NS1) is a protein with multiple functions that are regulated by phosphorylation. Phosphoproteomic screening of H1N1 virus-infected cells revealed that NS1 was phosphorylated at serine 205 in intermediate stages of the viral life cycle. Interestingly, S205 is one of six amino acid changes in NS1 of post-pandemic H1N1 viruses currently circulating in humans compared to the original swine-origin 2009 pandemic (H1N1pdm09) virus, suggesting a role in host adaptation. To identify NS1 functions regulated by S205 phosphorylation, we generated recombinant PR8 H1N1 NS1 mutants with S205G (nonphosphorylatable) or S205N (H1N1pdm09 signature), as well as H1N1pdm09 viruses harboring the reverse mutation NS1 N205S or N205D (phosphomimetic). Replication of PR8 NS1 mutants was attenuated relative to wild-type (WT) virus replication in a porcine cell line. However, PR8 NS1 S205N showed remarkably higher attenuation than PR8 NS1 S205G in a human cell line, highlighting a potential host-independent advantage of phosphorylatable S205, while an asparagine at this position led to a potential host-specific attenuation. Interestingly, PR8 NS1 S205G did not show polymerase activity-enhancing functions, in contrast to the WT, which can be attributed to diminished interaction with cellular restriction factor DDX21. Analysis of the respective kinase mediating S205 phosphorylation indicated an involvement of casein kinase 2 (CK2). CK2 inhibition significantly reduced the replication of WT viruses and decreased NS1-DDX21 interaction, as observed for NS1 S205G. In summary, NS1 S205 is required for efficient NS1-DDX21 binding, resulting in enhanced viral polymerase activity, which is likely to be regulated by transient phosphorylation.IMPORTANCE Influenza A viruses (IAVs) still pose a major threat to human health worldwide. As a zoonotic virus, IAV can spontaneously overcome species barriers and even reside in new hosts after efficient adaptation. Investigation of the functions of specific adaptational mutations can lead to a deeper understanding of viral replication in specific hosts and can probably help to find new targets for antiviral intervention. In the present study, we analyzed the role of NS1 S205, a phosphorylation site that was reacquired during the circulation of pandemic H1N1pdm09 "swine flu" in the human host. We found that phosphorylation of human H1N1 virus NS1 S205 is mediated by the cellular kinase CK2 and is needed for efficient interaction with human host restriction factor DDX21, mediating NS1-induced enhancement of viral polymerase activity. Therefore, targeting CK2 activity might be an efficient strategy for limiting the replication of IAVs circulating in the human population.

FeCl3-mediated selenylative benzannulation of aryl alkynones to 3-selenyl ß-naphthols.

An efficient selenylative cyclization of aryl-alkynones with diselenides in the presence of iron(III)chloride at room temperature to prepare 3-seleno-2-naphthols in good yields has been described. Furthermore, the resulting products were transformed into selenyl-naphthofuran and selenyl-1,2-naphthoquinone derivatives.

Total synthesis of remdesivir.

Remdesivir, the first drug approved by the FDA to treat COVID-19, is in high demand for patients infected with the SARS-CoV-2 virus. Herein, we report a facile approach minimizing the protecting group manipulations to afford remdesivir in good overall yield.

Effect of platelet-rich plasma on the rate of orthodontic tooth movement.

INTRODUCTION: This study aimed to evaluate the effect of platelet-rich plasma (PRP) on the rate of orthodontic tooth movement (OTM) during en-masse anterior retraction. METHODS: Twenty adult patients with Angles Class I bimaxillary protrusion or crowding requiring first premolar extraction for routine orthodontic treatment were divided into control and experimental groups. The control group did not receive PRP, whereas the experimental group received PRP in the alveolar mucosa of the maxillary 6 anterior teeth just before starting en-masse retraction. Measurements were recorded on digital models made from scanned plaster casts at the beginning of space closure and the end of 3 months. The overall rate of OTM between both groups was compared. The amount of anchorage loss and type of anterior retraction on lateral cephalogram was also compared between the groups. RESULTS: The overall rate of OTM was minimally increased but not statistically significant in the experimental vs control group (P = 0.838). Anterior retraction parameters in both groups showed incisors moving primarily by controlled tipping and partly by translation. An intergroup comparison of all cephalometric parameters for anchorage loss and anterior retraction showed statistically insignificant differences between both groups. CONCLUSIONS: PRP is ineffective in accelerating the rate of OTM during en-masse anterior retraction.

Impact of broad-spectrum antibiotic exposures and multidrug-resistant gram-negative bacteremia on hematopoietic cell transplantation outcomes.

INTRODUCTION: There is a close association between the use of broad-spectrum antibiotics, gut microbiome alteration, multidrug resistant (MDR) gram-negative bacilli (GNB) bacteremia, graft versus host disease (GVHD), and mortality post-allogeneic hematopoietic cell transplantation (allo-HCT). This study reports the impact of the high use of carbapenems and colistin and MDR bacteremia pre- and post-HCT on HCT outcomes. METHODS: This was a single-center, partial retrospective, and prospective study from 2016 to 2020. Both pre- and post-HCT antibiotic exposures and blood culture/sensitivity were recorded. MDR GNB was defined as either non-susceptibility to third-generation cephalosporin or carbapenems. In the absence of positive cultures, the treating physician escalated antibiotics from third-generation cephalosporins to carbapenem and/or colistin as per clinical discretion. De-escalation policy was not strictly enforced. RESULTS: MDR GNB bacteremia was seen in 29 of 76 (38%) of patients peri-HCT. The utilization rates for carbapenems and colistin was significantly higher in the cohort with MDR GNB bacteremia pre-HCT (70% vs. 32%, p = 0.002 and 31% vs. 6.4%, p = 0.007, respectively) and post-HCT (100% vs. 74.5%, p = 0.002, and 55.2% vs. 8.5%, p < 0.0001, respectively). The cohort with MDR GNB bacteremia had significantly more severe acute GVHD at day+100 (45% vs. 17.5%, p = 0.009). The median survival was 204 days compared to not reached in the cohort without any MDR GNB bacteremia (p = 0.005). CONCLUSION: This study shows pre- and post-HCT MDR GNB bacteremia is associated with an increased risk of severe acute GVHD and mortality. Patients with MDR GNB bacteremia had higher exposure to pre- and post-HCT carbapenems and colistin.