Assessing Immunity to Hepatitis A and Hepatitis B Among Individuals in Custody Living With HIV.

Screening upon entry into prison for hepatitis A virus (HAV) and hepatitis B virus (HBV) provides an ideal public health opportunity to offer vaccination to individuals who are nonimmune. We conducted a retrospective review of HAV and HBV immunity among adults living with HIV in the Illinois Department of Corrections between January 1, 2019, and December 31, 2019. The primary objective was to assess rates of HAV and/or HBV immunity in individuals with HIV. In total, 436 people were included in the study. Of 425 patients who had data for HAV vaccination, 335 were immune. Of 421 patients who had data for HBV vaccination, 272 were immune. Of the 149 patients who were nonimmune to HBV, 22 had active HBV and 6 had an equivocal HBV surface antibody and negative HBV surface antigen. In total, 212 (52%) were immune to both HAV and HBV, and 31 (8%) had no immunity to either HAV or HBV. These data demonstrate an important opportunity to discuss and provide vaccination while in custody.

A diabetes registrar assisted workflow intervention in general practice for systematic initiation of cardiorenal medications for patients with type 2 diabetes and albuminuria in Aotearoa New Zealand.

AIMS: To evaluate whether a weekly diabetes registrar clinic and case discussions conducted over 12 weeks in primary care improves guideline management of type 2 diabetes (T2D). METHODS: A registrar-led diabetes clinic was incorporated into two primary care practices in Tamaki Makaurau Auckland for 3 months. Patients with T2D and albuminuria appearing on practice dashboards as not prescribed angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB), or sodium-glucose cotransporter-2 inhibitor/glucagon-like peptide-1 receptor agonist (SGLT2i/GLP1RA) were booked into these clinics. Opportunistic education sessions were provided by the diabetes registrar and prescribers were surveyed to understand the challenges in management of T2D. RESULTS: Of 125 patients booked, 80 attended the registrar clinic. Of these, 68% were clinically suitable for SGLT2i/GLP1RA and 8% for ACEi/ARB. SGLT2i/GLP1RA were initiated in 92% and ACEi/ARB in 89% of eligible patients. Two patients had contraindications for SGLT2i/GLP1RA, and one patient declined both. Additional cardiorenal medications were initiated in 16% of patients. Survey responses of 12 prescribers indicated acute illness takes priority over diabetes management, and lack of time and knowledge are main barriers to optimising diabetes care. CONCLUSIONS: A visiting diabetes registrar intervention was successful in initiating guideline medications for T2D in primary care. It remains to be evaluated whether this leads to practice-wide improvements in prescribing gaps in the short or longer term.

Transcending the challenge of evolving resistance mechanisms in Pseudomonas aeruginosa through ß-lactam-enhancer-mechanism-based cefepime/zidebactam.

Multi-drug resistant (MDR) Pseudomonas aeruginosa harbor a complex array of ß-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a ß-lactam/ß-lactam-enhancer, cefepime/zidebactam, and novel ß-lactam/ß-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of P. aeruginosa (n = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-ß-lactamases, serine ß-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and cefepime/taniborbactam demonstrated MIC90s of >128 mg/L, while cefepime/zidebactam MIC90 was 16 mg/L. In a neutropenic-murine lung infection model, a cefepime/zidebactam human epithelial-lining fluid-simulated regimen achieved or exceeded a translational end point of 1-log10 kill for the isolates with elevated cefepime/zidebactam MICs (16-32 mg/L), harboring VIM-2 or KPC-2 and alterations in PBP2 and PBP3. In the same model, to assess the impact of zidebactam on the pharmacodynamic (PD) requirement of cefepime, dose-fractionation studies were undertaken employing cefepime-susceptible P. aeruginosa isolates. Administered alone, cefepime required 47%-68% fT >MIC for stasis to ~1 log10 kill effect, while cefepime in the presence of zidebactam required just 8%-16% for >2 log10 kill effect, thus, providing the pharmacokinetic/PD basis for in vivo efficacy of cefepime/zidebactam against isolates with MICs up to 32 mg/L. Unlike ß-lactam/ß-lactamase inhibitors, ß-lactam enhancer mechanism-based cefepime/zidebactam shows a potential to transcend the challenge of ever-evolving resistance mechanisms by targeting multiple PBPs and overcoming diverse ß-lactamases including carbapenemases in P. aeruginosa.IMPORTANCECompared to other genera of Gram-negative pathogens, Pseudomonas is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed ß-lactam and ß-lactamase inhibitor combinations. This study shows that the novel ß-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of P. aeruginosa. This study highlights that the ß-lactam enhancer mechanism is a promising alternative to the conventional ß-lactam/ß-lactamase inhibitor approach in combating ever-evolving MDR P. aeruginosa.

Classification of Heart Failure Events by Severity: Insights From the VICTORIA Trial.

BACKGROUND: Hospitalization due to heart failure (HFH) is a major source of morbidity, consumes significant economic resources and is a key endpoint in HF clinical trials. HFH events vary in severity and implications, but they are typically considered equivalent when analyzing clinical trial outcomes. OBJECTIVES: We aimed to evaluate the frequency and severity of HF events, assess treatment effects and describe differences in outcomes by type of HF event in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). METHODS: VICTORIA compared vericiguat with placebo in patients with HF with reduced ejection fraction (< 45%) and a recent worsening HF event. All HFHs were prospectively adjudicated by an independent clinical events committee (CEC) whose members were blinded to treatment assignment. We evaluated the frequency and clinical impact of HF events by severity, categorized by highest intensity of HF treatment (urgent outpatient visit or hospitalization treated with oral diuretics, intravenous diuretics, intravenous vasodilators, intravenous inotropes, or mechanical support) and treatment effect by event categories. RESULTS: In VICTORIA, 2948 HF events occurred in 5050 enrolled patients. Overall total CEC HF events for vericiguat vs placebo were 43.9 vs 49.1 events/100 patient-years (P = 0.01). Hospitalization for intravenous diuretics was the most common type of HFH event (54%). HF event types differed markedly in their clinical implications for both in-hospital and post-discharge events. We observed no difference in the distribution of HF events between randomized treatment groups (P = 0.78). CONCLUSION: HF events in large global trials vary significantly in severity and clinical implications, which may have implications for more nuanced trial design and interpretation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02861534).

Development of a Novel Surfactant-Based Viscoelastic Fluid System as an Alternative Nonpolymeric Fracturing Fluid and Comparative Analysis with Traditional Guar Gum Gel Fluid.

Surfactant-based viscoelastic (SBVE) fluids have recently gained interest from many oil industry researchers due to their polymer-like viscoelastic behaviour and ability to mitigate problems of polymeric fluids by replacing them during various operations. This study investigates an alternative SBVE fluid system for hydraulic fracturing with comparable rheological characteristics to conventional polymeric guar gum fluid. In this study, low and high surfactant concentration SBVE fluid and nanofluid systems were synthesized, optimized, and compared. Cetyltrimethylammonium bromide and counterion inorganic sodium nitrate salt, with and without 1 wt% ZnO nano-dispersion additives, were used; these are entangled wormlike micellar solutions of cationic surfactant. The fluids were divided into the categories of type 1, type 2, type 3, and type 4, and were optimized by comparing the rheological characteristics of different concentration fluids in each category at 25 °C. The authors have reported recently that ZnO NPs can improve the rheological characteristics of fluids with a low surfactant concentration of 0.1 M cetyltrimethylammonium bromide by proposing fluids and nanofluids of type 1 and type 2. In addition, conventional polymeric guar gum gel fluid is prepared in this study and analyzed for its rheological characteristics. The rheology of all SBVE fluids and the guar gum fluid was analyzed using a rotational rheometer at varying shear rate conditions from 0.1 to 500 s-1 under 25 °C, 35 °C, 45 °C, 55 °C, 65 °C, and 75 °C temperature conditions. The comparative analysis section compares the rheology of the optimal SBVE fluids and nanofluids in each category to the rheology of polymeric guar gum fluid for the entire range of shear rates and temperature conditions. The type 3 optimum fluid with high surfactant concentration of 0.2 M cetyltrimethylammonium bromide and 1.2 M sodium nitrate was the best of all the optimum fluids and nanofluids. This fluid shows comparative rheology to guar gum fluid even at elevated shear rate and temperature conditions. The comparison of average viscosity values under a different group of shear rate conditions suggests that the overall optimum SBVE fluid prepared in this study is a potential nonpolymeric viscoelastic fluid candidate for hydraulic fracturing operation that could replace polymeric guar gum fluids.

Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: The VICTORIA echocardiographic substudy.

AIM: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. METHODS AND RESULTS: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co-primary endpoints were changes in LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high-quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2 ; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI -3.8 ± 15.4 vs. -7.1 ± 20.5 ml/m2 ; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient-years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). CONCLUSIONS: In this pre-specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high-risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF.

A Novel ZnO Nanoparticles Enhanced Surfactant Based Viscoelastic Fluid Systems for Fracturing under High Temperature and High Shear Rate Conditions: Synthesis, Rheometric Analysis, and Fluid Model Derivation.

Surfactant-based viscoelastic (SBVE) fluids are innovative nonpolymeric non-newtonian fluid compositions that have recently gained much attention from the oil industry. SBVE can replace traditional polymeric fracturing fluid composition by mitigating problems arising during and after hydraulic fracturing operations are performed. In this study, SBVE fluid systems which are entangled with worm-like micellar solutions of cationic surfactant: cetrimonium bromide or CTAB and counterion inorganic sodium nitrate salt are synthesized. The salt reagent concentration is optimized by comparing the rheological characteristics of different concentration fluids at 25 °C. The study aims to mitigate the primary issue concerning these SBVE fluids: significant drop in viscosity at high temperature and high shear rate (HTHS) conditions. Hence, the authors synthesized a modified viscoelastic fluid system using ZnO nanoparticle (NPs) additives with a hypothesis of getting fluids with improved rheology. The rheology of optimum fluids of both categories: with (0.6 M NaNO3 concentration fluid) and without (0.8 M NaNO3 concentration fluid) ZnO NPs additives were compared for a range of shear rates from 1 to 500 Sec-1 at different temperatures from 25 °C to 75 °C to visualize modifications in viscosity values after the addition of NPs additives. The rheology in terms of viscosity was higher for the fluid with 1% dispersed ZnO NPs additives at all temperatures for the entire range of shear rate values. Additionally, rheological correlation function models were derived for the synthesized fluids using statistical analysis methods. Subsequently, Herschel-Bulkley models were developed for optimum fluids depending on rheological correlation models. In the last section of the study, the pressure-drop estimation method is described using given group equations for laminar flow in a pipe depending on Herschel-Bulkley-model parameters have been identified for optimum fluids are consistency, flow index and yield stress values.

Medication use by US patients with pulmonary hypertension associated with chronic obstructive pulmonary disease: a retrospective study of administrative data.

BACKGROUND: Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). While clinical guidelines recommend specific drug therapies for pulmonary arterial hypertension (PAH), these drug therapies are not recommended for PH due to lung disease. METHODS: This was a retrospective cohort study using the Optum® Clinformatics® Data Mart from January 2009-September 2019. An algorithm was designed to identify adults with ≥ 2 ICD-9-CM or ICD-10-CM diagnosis codes for PH and with ≥ 2 diagnosis codes for COPD. Sensitivity analyses were conducted among subgroups of patients with evidence of a right heart catheterization (RHC) or pulmonary function test (PFT). Patient characteristics, medications used, and durations of use of PAH and COPD medications were analyzed. RESULTS: A total of 25,975 patients met the study inclusion criteria. Their mean age was 73.5 (SD 10.0) years and 63.8% were female. Medications targeting PAH were prescribed to 643 (2.5%) patients, most frequently a phosphodiesterase-5 inhibitor (2.1%) or an endothelin receptor antagonist (0.75%). Medications for COPD were prescribed to 17,765 (68.4%) patients, most frequently an inhaled corticosteroid (57.4%) or short-acting beta agonist (50.4%). The median durations of use ranged from 4.9 to 12.8 months for PAH medications, and from 0.4 to 5.9 months for COPD medications. Of the subgroup of patients with RHC (N = 2325), 257 (11.1%) were prescribed a PAH medication and 1670 (71.8%) used a COPD medication. Of the subgroup with a PFT (N = 2995), 58 (1.9%) were prescribed a PAH medication and 2100 (70.1%) a COPD medication. CONCLUSIONS: Patients with PH associated with COPD were identified in a US administrative claims database. Very few of these patients received any of the medications recommended for PAH, and only about two thirds received medications for COPD.

WCK 4034: A promising oxazolidinone for treating gram positive infections.

Increased resistance to gram positive infections have highlighted the limitations of currently available drug treatments including penicillins, macrolides and glycopeptides. As an alternative to address these challenges; Linezolid, the first antibiotic from oxazolidinone class, have shown the promising activities against such infections, although associated toxicological issues limiting the use of linezolid for prolonged treatments. In order to circumvent disadvantages allied with the marketed drugs, we herein reporting the synthesis of WCK 4034, an oxazolidinone antibiotic through our structure activity relationship (SAR) program. Through this exercise, WCK 4034, has shown competitive MIC values against Methicillin Sensitive S. aureus (MSSA, Sta-001), Methicillin Resistant S. aureus (MRSA, Sta-032), S. pneumoniae ATCC 49619 and H. influenza ATCC 35054 species as like linezolid. Although with an additional advantage; WCK 4034 has been found superior during dog PK studies as compare to Linezolid. With the preliminary studies in our hand, we herein assuming these improved pharmacokinetic values would be helpful. Moreover, WCK 4034 has successfully completed pre-clinical studies and ready to enter the clinical space, and paved the way for in house development of other oxazolidinone NCEs.

Evaluation of Immunologic and Virologic Function in Reincarcerated Patients Living With HIV or AIDS.

Despite receipt of antiretroviral therapy (ART) while incarcerated, formerly incarcerated individuals living with HIV may experience numerous barriers to follow-up HIV care and continuation of ART once released from prison. The goal of this retrospective electronic medical chart review was to determine virologic and immunologic function of individuals living with HIV who were reincarcerated within the Illinois Department of Corrections. Of 200 patients reincarcerated during the study period, 167 met inclusion criteria. The rate of participants who were on ART and virologically suppressed decreased from 73% at time of release to 49.7% at time of reincarceration (p < .01). Of the 57 individuals who did not engage in follow-up, 39% were virologically suppressed at time of reincarceration. Despite virologic suppression while incarcerated, increased linkage, engagement, and retention in medical care upon release from prison is essential in maintaining virologic suppression.

WCK 1152, WCK 1153: Discovery and structure activity relationship for the treatment of resistant pneumococcal and staphylococcal respiratory infections.

Novel antibacterial agents needed constantly to counter the ever emergent resistance development to commercially available drugs; one of the effective synthetic antibacterial classes is fluoroquinolone (FQ). This study includes structure activity relationship based design and synthesis of novel fluoroquinolone molecules active against resistant pathogens bearing mutations of DNA gyrase and/or topoisomerase IV which also express efflux pumps. Here, series of compounds were prepared by treating 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid as a core with various 4-substituted-3,3-dialkyl piperidines as side chains, through conventional synthetic approaches. Subsequently, antibacterial activities of these fluoroquinolones were examined against Streptococcus pneumoniae, SPN 5844 (Moxi resistant DNA gyrase and topo IV mutant) and SPN 706 (FQ efflux positive). The current manuscript covers >50 examples of fluoroquinolone NCEs, amongst 20 NCEs have shown MIC in the range of (0.4 to >6.25 µg/ml) for SPN 5844 and (0.1-12.5 µg/ml) for SPN 706 strains. During the course of this study; WCK 919, comprising two chiral isomers; WCK 1152 and WCK 1153 were emerged as lead among the different series synthesized. Advance studies suggested either WCK 1152 or WCK 1153 are the worthy candidates for further clinical developments for respiratory infections caused by resistant pneumococci and staphylococci. However, on the basis of in house preclinical work, WCK 1152 had been selected for phase-1 domestic clinical trials.

Ensuring robustness in the quality of antibiotic susceptibility test discs for four novel antibiotics.

Antibiotic susceptibility test (AST) discs are used as an in-vitro diagnostic tool to select the appropriate antibiotic to treat an infection. Generally, the concentration of the drug loaded on to the AST discs is measured by studying its activity against quality control organisms. This methodology has several limitations-it is time consuming, requires trained manpower, has a wider acceptance criteria of zone of inhibitions-causing ambiguity in judging smaller variations in drug concentration. To overcome these issues, we have developed and validated high-performance liquid chromatographic (HPLC) methods for the determination of strength of AST discs for in-house researched antibiotics, namely Levonadifloxacin/WCK 771, Nafithromycin/WCK 4873, Cefepime-Tazobactam/WCK 4282, and Cefepime-Zidebactam/WCK 5222. The drugs were extracted from the AST discs using an appropriate solvent. The developed methods are simple, accurate, precise, reproducible, rugged, and robust. They are efficient in terms of time, and can be easily conducted in a quality control laboratory during release as well as stability evaluation of AST disc. Application of HPLC methods for the determination of strength of AST discs ensures flawless quality and, consequently, a better selection of drugs to treat bacterial infections in clinics.

Preclinical safety evaluation of levonadifloxacin, a novel anti-methicillin-resistant Staphyloccocus aureus benzoquinolizine fluoroquinolone by intravenous and oral administration.

Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class-specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ-associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat-dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (l-arginine salt of levonadifloxacin) and WCK 2349 (l-alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771- or WCK 2349-treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat-dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism.

BACKGROUND: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels. OBJECTIVE: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism. MATERIAL AND METHODS: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration. RESULTS: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events. DISCUSSION AND CONCLUSIONS: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

Esophageal Perforation After Anterior Cervical Surgery: A Case Report and Literature Review.

SUMMARY AND BACKGROUND: Esophageal perforation (EP) after anterior cervical surgery is a rare but potentially life-threatening condition. EP caused by malpositioned implants in cervical spine injury with multiple comorbidities is challenging to treat simultaneously. STUDY: This was a case report study. PURPOSE OF STUDY: The aim of this study was to present successful treatment of EP in a subluxated C5-C6 level with implant failure, infection, septicemia, and comorbidities. The aim was to emphasize the need for a multispecialty approach while treating serious complications. CASE: A 72-year-old woman presented to the ER with a history of operated cervical spine a week ago and having breathlessness, fever, wound infection, and tracheostomy in situ. After primary investigations, the patient was initially treated in the intensive care unit, where bleeding from the tracheostomy site was noticed. Upon endoscopy, EP was diagnosed due to implant failure. She was operated for revision cervical spine surgery (drainage of pus with anterior and posterior cervical fixation) and percutaneous endoscopic gastrostomy tube insertion (esophageal diversion). On exploration of EP, a decision was made to perform conservative treatment as initial tag sutures did not hold due to infection. Postoperatively, the patient developed rectal bleed 3 times, which was ultimately treated with cecal bleed embolization. The infected cervical wound was managed with an open dressing. The patient was managed with intermittent assisted ventilation through tracheostomy postoperatively. Barium swallow at 10 weeks confirmed healing of EP and oral feed was started. Tracheostomy closure was performed once the wound had healed, and the patient was discharged with improved neurology at 12 weeks. CONCLUSIONS: Perioperative problems after cervical surgery such as breathing difficulty, wound discharge, and worsening of neurology may lead to suspicion of underlying EP due to implant failure. Upper gastrointestinal endoscopy needs to be considered for a prompt diagnosis. Revision spine surgery with treatment of perforation simultaneously and maintenance of enteral nutrition through a percutaneous endoscopic gastrostomy tube with a multispecialty approach is recommended for this potentially life-threatening condition.

Recurrent Syncope and Ventricular Arrhythmias Induced by Coronary Artery Spasm.

We present a case of recurrent coronary artery spasm induced ventricular arrhythmias. A 73-year-old female developed a syncopal episode requiring brief cardiopulmonary resuscitation (CPR) with later spontaneous resolution and bradycardia. During admission, the patient had a recurrent syncopal episode while in supine position. Upon reviewing cardiac monitor, it was noted that the syncope coincided with a series of recorded arrhythmias. Invasive cardiac angiogram revealed a non-obstructive lesion at the right coronary artery with no other abnormalities suggesting spastic activity as the source of the arrhythmia. Subsequently, the patient successfully underwent an Implantable Cardioverter- Defibrillator (ICD) placement and stenting in the right coronary. Patient symptoms resolved and no further arrhythmias were detected in the ICD recording.

Region-Specific Associations between Environmental Factors and Escherichia coli in Freshwater Beaches in Toronto and Niagara Region, Canada.

Poor freshwater beach quality, measured by Escherichia coli (E. coli) levels, poses a risk of recreational water illness. This study linked environmental data to E. coli geometric means collected at 18 beaches in Toronto (2008-2019) and the Niagara Region (2011-2019) to examine the environmental predictors of E. coli. We developed region-specific models using mixed effects models to examine E. coli as a continuous variable and recommended thresholds of E. coli concentration (100 CFU/100 mL and 200 CFU/100 mL). Substantial clustering of E. coli values at the beach level was observed in Toronto, while minimal clustering was seen in Niagara, suggesting an important beach-specific effect in Toronto beaches. Air temperature and turbidity (measured directly or visually observed) were positively associated with E. coli in all models in both regions. In Toronto, waterfowl counts, rainfall, stream discharge and water temperature were positively associated with E. coli levels, while solar irradiance and water level were negatively associated. In Niagara, wave height and water level had a positive association with E. coli, while rainfall was negatively associated. The differences in regional models suggest the importance of a region-specific approach to addressing beach water quality. The results can guide beach monitoring and management practices, including predictive modelling.

Design and synthesis of an oral prodrug alalevonadifloxacin for the treatment of MRSA infection.

Levonadifloxacin is a parenteral anti-MRSA benzoquinolizine antibacterial drug recently launched as, EMROK in India to treat acute bacterial skin and skin structure infections (ABSSSI) in hospitalized patients. As a step down therapy an oral form of levonadifloxacin with comparable PK/PD was needed because the levonadifloxacin exhibits very poor oral absorption. To improve the drugability in terms of oral absorption a pro-drug approach was evaluated. Structurally levonadifloxacin provides two sites amenable for ester or amide formation, a carboxyl function of benzoquinolizine pharmacophore and hydroxyl group on piperidine side chain. Several aliphatic, aromatic and amino acid esters of C-2 carboxylic acid, C-4-hydroxyl piperidine and double esters at both C-2, C-4 positions were synthesized. The cleavage of prodrugs was studied in vitro as well as in animal models to access their suitability as prodrug function. Among C-2 carboxylic ester prodrugs, daloxate (WCK 2320) showed highest cleavage in serum as well as in liver enzyme; however its stability in aqueous solution was unfavorable. In contrast, most of the esters at the hydroxyl group like propionyl ester (WCK 2305) and amino acid esters such as l-alanine (WCK 2349), l-valine (WCK 2630) were cleaved readily releasing active drug. Thus, indicating C-4-hydroxyl piperidine was amenable site for enzymatic cleavage over esters of C-2 carboxylic acid. Additionally, amino acid esters provided an opportunity to make salt, facilitating improved aqueous solubility. Methanesulfonate salt of l-alanine ester of levonadifloxacin (WCK 2349) was successfully developed and launched as oral prodrug alalevonadifloxacin (EMROK-O).

Blood Pressure and Safety Events With Vericiguat in the VICTORIA Trial.

Background Although safety and tolerability of vericiguat were established in the VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial in patients with heart failure with reduced ejection fraction, some subgroups may be more susceptible to symptomatic hypotension, such as older patients, those with lower baseline systolic blood pressure (SBP), or those concurrently taking angiotensin receptor neprilysin inhibitors. We described the SBP trajectories over time and compared the occurrence of symptomatic hypotension or syncope by treatment arm in potentially vulnerable subgroups in VICTORIA. We also evaluated the relation between the efficacy of vericiguat and baseline SBP. Methods and Results Among patients receiving at least 1 dose of the study drug (n=5034), potentially vulnerable subgroups were those >75 years old (n=1395), those with baseline SBP 100-110 mm Hg (n=1344), and those taking angiotensin receptor neprilysin inhibitors (n=730). SBP trajectory was plotted as mean change from baseline over time. The treatment effect on time to symptomatic hypotension or syncope was evaluated overall and by subgroup, and the primary efficacy composite outcome (heart failure hospitalization or cardiovascular death) across baseline SBP was examined using Cox proportional hazards models. SBP trajectories showed a small initial decline in SBP with vericiguat in those >75 years old (versus younger patients), as well as those receiving angiotensin receptor neprilysin inhibitors (versus none), with SBP returning to baseline thereafter. Patients with SBP <110 mm Hg at baseline showed a trend to increasing SBP over time, which was similar in both treatment arms. Safety event rates were generally low and similar between treatment arms within each subgroup. In Cox proportional hazards analysis, there were similar numbers of safety events with vericiguat versus placebo (adjusted hazard ratio [HR], 1.18; 95% CI, 0.99-1.39; P=0.059). No difference existed between treatment arms in landmark analysis beginning after the titration phase (ie, post 4 weeks) (adjusted HR, 1.14; 95% CI, 0.93-1.38; P=0.20). The benefit of vericiguat compared with placebo on the primary composite efficacy outcome was similar across the spectrum of baseline SBP (P for interaction=0.32). Conclusions These data demonstrate the safety of vericiguat in a broad population of patients with worsening heart failure with reduced ejection fraction, even among those predisposed to hypotension. Vericiguat's efficacy persisted regardless of baseline SBP. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.