Solubility Enhancement and Inhalation Delivery of Cyclodextrin-Based Inclusion Complex of Delamanid for Pulmonary Tuberculosis Treatment.

Tuberculosis (TB) is a contiguous airborne disease caused by Mycobacterium tuberculosis (M.tb), primarily affecting the human lungs. The progression of drug-susceptible TB to drug-resistant strains, MDR-TB and XDR-TB, has become a global challenge toward eradicating TB. Conventional TB treatment involves frequent dosing and prolonged treatment regimens predominantly by an oral or invasive route, leading to treatment-related systemic adverse effects and patient's noncompliance. Pulmonary delivery is an attractive option as we could reduce dose, limit systemic side-effects, and achieve rapid onset of action. Delamanid (DLD), an antituberculosis drug, has poor aqueous solubility, and in this study, we aim to improve its solubility using cyclodextrin complexation. We screened different cyclodextrins and found that HP-ß-CD resulted in a 54-fold increase in solubility compared to a 27-fold and 13-fold increase by SBE-ß-CD and HP-É£-CD, respectively. The stability constant (265 ± 15 M-1) and complexation efficiency (8.5 × 10-4) suggest the formation of a stable inclusion complex of DLD and HP-ß-CD in a 2:1 ratio. Solid-state characterization studies (DSC, PXRD, and NMR) further confirmed successful complexation of DLD in HP-ß-CD. The nebulized DLD-CD complex solution showed a mass median aerodynamic diameter of 4.42 ± 0.62 µm and fine particle fraction of 82.28 ± 2.79%, suggesting deposition in the respiratory airways. In bacterial studies, minimum inhibitory concentration of DLD-CD complex was significantly reduced (four-fold) compared to free DLD in M.tb (H37Ra strain). Furthermore, accelerated stability studies confirmed that the inclusion complex was stable for 4 weeks with 90%w/w drug content. In conclusion, we increased the aqueous solubility of DLD through cyclodextrin complexation and improved its efficacy in vitro.

Functional Tricuspid Regurgitation in Patients With Chronic Mitral Regurgitation: An Evidence-Based Narrative Review.

Chronic mitral regurgitation leads to a series of downstream pathologic changes, including pulmonary hypertension, right ventricular dilation, tricuspid leaflet tethering, and tricuspid annular dilation, which can result in functional tricuspid regurgitation (FTR). The five-year survival rate for patients with severe FTR is reported to be as low as 34%. While FTR was often left uncorrected during left-heart valvular surgery, under the assumption that correction of the left-sided lesion would reverse the right-heart changes that cause FTR, recent data largely have supported concomitant tricuspid valve repair at the time of mitral surgery. In this review, the authors discuss the potentially irreversible nature of the changes leading to FTR, the likelihood of progression of FTR after mitral surgery, and the evidence for and against concomitant tricuspid valve repair at the time of mitral valve intervention. Lastly, this narrative review also examines advances in transcatheter therapies for the tricuspid valve and the evidence behind concomitant transcatheter tricuspid repair at the time of transcatheter mitral repair.

Complications of Transesophageal Echocardiography: A Review of Injuries, Risk Factors, and Management.

Transesophageal echocardiography (TEE) use has become widespread in cardiac surgical operating rooms over the last 2 decades. Surgical and medical decision-making often are guided by the findings of the TEE examination, rendering TEE an invaluable tool both inside and outside the operating room. TEE has become ubiquitous in some parts because it is considered safe and relatively noninvasive. However, it is imperative for clinicians to understand that TEE can cause severe and possibly life-threatening complications, and the risks of TEE must be balanced against its benefits as a diagnostic tool. Upper gastrointestinal (UGI) injuries are the most commonly described complications of TEE; however, the relative infrequency of injuries and lack of uniform reporting make it difficult to definitively identify potential risk factors. Some large retrospective trials suggested that patient factors (age, body mass index, anatomic abnormalities), comorbid conditions (previous stroke), and procedural variables (procedure time, cardiopulmonary bypass time, etc.) are associated with TEE-related injuries. In this narrative review of complications from TEE, the authors focus on the incidence of UGI injuries, the spectrum of injuries associated with TEE, risk factors that may contribute to UGI injuries, as well as diagnosis and management options. Lastly, the discussion focuses on the prevention of injuries as TEE use continues to become more prevalent.

Blunt Trauma to the Heart: A Review of Pathophysiology and Current Management.

Blunt cardiac injury (BCI), defined as an injury to the heart from blunt force trauma, ranges from minor to life-threatening. The majority of BCIs are due to motor vehicle accidents; however, injuries caused by falls, blasts, and sports-related injuries also can be sources of BCI. A significant proportion of patients with BCI do not survive long enough to receive medical care, succumbing to their injuries at the scene of the accident. Additionally, patients with blunt trauma often have coexisting injuries (brain, spine, orthopedic) that can obscure the clinical picture; therefore, a high degree of suspicion often is required to diagnose BCI. Traditionally, hemodynamically stable injuries suspicious for BCI have been evaluated with electrocardiograms and chest radiographs, whereas hemodynamically unstable BCIs have received operative intervention. More recently, computed tomography and echocardiography increasingly have been utilized to identify injuries more rapidly in hemodynamically unstable patients. Transesophageal echocardiography can play an important role in the diagnosis and management of several BCIs that require operative repair. Close communication with the surgical team and access to blood products for potentially massive transfusion also play key roles in maintaining hemodynamic stability. With proper surgical and anesthetic care, survival in cases involving urgent cardiac repair can reach 66%-to-75%. This narrative review focuses on the types of cardiac injuries that are caused by blunt chest trauma, the modalities and techniques currently used to diagnose BCI, and the perioperative management of injuries that require surgical correction.

"I want to live, but " the desire to live and its physical, psychological, spiritual, and social factors among advanced cancer patients: evidence from the APPROACH study in India.

BACKGROUND: The limited access to palliative care resources along with the social stigma around cancer largely explains the poor quality of life (QoL) of Indian advanced cancer patients. As advanced cancer patients with poor QoL often harbour a desire for hastened death (DHD), it is imperative to understand factors affecting DHD, or the desire to live (DTL) among advanced cancer patients in India. We aim to examine the relationship between DTL and physical, psychological, spiritual, and social factors measuring patients' QoL alongside their awareness of their late cancer stage. METHODS: We surveyed 200 patients from a tertiary cancer hospital in India to collect their DTL, awareness of cancer stage, demographic characteristics, and standardized measures for patients' QoL. We used a linear probability regression model to quantify the association between these factors and patients' DTL among the final sample of 192 patients with no missing information for the variables of interest. RESULTS: Among the various domains affecting cancer patients' QoL, we found that the pain severity score (ranging from 0 to 10) and psychological distress score (ranging from 0 to 42) are negatively associated with the DTL. One point increase in each score reduced the DTL by 2.2% (p < 0.05) and 0.7% (p < 0.05), respectively. Our results also showed that patients whose perceived socio-economic status (SES) is poor have a 16% (p < 0.05) lower probability of DTL, compared to those with higher SES (lower middle class, upper middle class, and wealthy). Controlling for caste, religion, gender, age, marital status and years of education, we found psychological distress is statistically higher among patients belonging to this bottom SES. CONCLUSIONS: We found that pain severity, psychological distress and perceived low SES are negatively associated with the desire to live in advanced cancer patients. Future research should focus on developing interventions to improve physical pain and psychological distress, particularly for patients who are socially and economically disadvantaged.

Mitral Regurgitation in Patients With Coexisting Chronic Aortic Regurgitation: An Evidence-Based Narrative Review.

Chronic aortic regurgitation (AR) frequently leads to significant downstream changes to the left ventricle and pulmonary vasculature; these structural and physiologic changes result in lower- than expected patient survival. Progressive, uncorrected AR can lead to left ventricle dilation and subsequent mitral valve leaflet tethering, as well as mitral annular dilation, resulting in secondary mitral regurgitation (MR) in up to 45% of patients. Surgical aortic valve replacement (AVR) improves secondary MR in most patients, but survival is significantly lower in those patients who do not show improvement in MR after AVR. Thus, there is considerable debate on whether the mitral valve should be intervened upon at the time of the AVR. In this review, the authors address the long-term outlook for patients with chronic AR and concurrent MR. The authors also review the available evidence on concomitant mitral valve surgery in patients undergoing AVR for AR. Lastly, this narrative review examines the recent advances in transcatheter mitral valve repair and replacement, and explores the potential role of transcatheter mitral therapies in patients with secondary MR due to AR.

Transcriptome profiling and pathway analysis in squamous cell carcinoma of buccal mucosa.

BACKGROUND: High recurrence and poor overall survival in buccal mucosa squamous cell carcinoma (BMSCC) are not well addressed due to lack of efficient prognostic biomarkers and targeted therapies. To uncover gene candidates for the same, transcriptome profiling has been examined in BMSCC, which is not explored yet. METHODS: We compared 9 BMSCC and 2 normal oral FFPE tissues using Agilent SurePrint G3 Human gene expression v3 microarray chips. The obtained RNA signatures were interrogated in the cancer genome atlas (TCGA) dataset for alteration values and survival data. RESULTS: We found total 237 protein coding RNAs and 85 long non-coding RNAs (lncRNAs) which displayed significant differential expression with criteria of at-least 2 fold change and Benjamini Hochberg FDR < .05. In protein coding RNAs, RUNX3 and EMX2 showed utmost degree of up-regulation and down-regulation, respectively. Likewise, among lncRNAs, ARGFXP2 and lnc-SYCP3-2 displayed highest degree of up-regulation and down-regulation, respectively. Besides, an analysis of the RNA list in TCGA dataset spotted deregulation of 21 genes in both, our cohort and TCGA cohort. Among which, MRTO4 and EIF3J genes, and LINC00310, a lncRNA showed greatest expression alterations. Strikingly, at RNA expression level, up-regulation of two genes, EIF3J and SDCBP, was significantly associated with disease free survival and poor overall survival, respectively. CONCLUSION: Our data documented significant findings to enhance understanding of the disease biology. The proposed RNA candidates (RUNX3, EMX2, MRTO4, EIF3J, SDCBP and LINC00310) may serve as putative therapeutic targets and potential biomarkers for BMSCC diagnosis and prognosis.

"Aberrant sialylation plays a significant role in oral squamous cell carcinoma progression".

OBJECTIVE: Aberrant glycosylation, mainly sialylation and fucosylation, is recently considered as a major hallmark of cancer. Aberrant sialylation has long been associated with various neoplastic diseases. However, role of aberrant sialylation in oral cancer is still in its infancy. The present study aimed to examine mRNA expressions of α-2, 3, α-2, 6 sialyltransferase (ST) families and sialidase in 160 human oral cancer tissues. METHODS: mRNA expression of ST3GAL1, ST3GAL2, ST3GAL3, ST3GAL4, ST3GAL6, ST6GAL1, and neuraminidase 3 (NEU3) was analyzed by RT-qPCR in 80 paired malignant and adjacent normal tissues from oral cancer patients. RESULTS: The results indicated significant (P ≤ .05) down-regulation of various STs (ST3GAL1, ST3GAL2, ST3GAL3, ST3GAL4, ST3GAL6, and ST6GAL1) and sialidases (NEU3) in malignant tissues as compared to adjacent normal tissues. Higher mRNA levels of ST3GAL2 and ST3GAL3 were significantly associated with advanced stage of the disease, lymph node involvement, and perineural invasion, which denote their role in progression and metastasis of oral cancer. Present study also revealed altered sialylation patterns according to anatomical site of the disease and tobacco habit. CONCLUSION: The study demonstrated significant role of elevated mRNA levels of ST3GAL2 and ST3GAL3 in disease progression and metastasis of oral carcinoma.

Contemporary Challenges for Fellowship Training in Adult Cardiothoracic Anesthesiology: Perspectives From Program Directors Around the United States.

The fellowship in adult cardiothoracic anesthesiology has matured as an accredited program. This special article addresses current challenges in this educational milieu. The first challenge relates to serving as a program director in the contemporary era. The second challenge deals with the accreditation process, including the site visit. The third challenge discusses the integration of structural heart disease and interventional echocardiography into daily practice. The fourth challenge deals with the issues that face fellowship education in the near future. Taken together, these perspectives provide a review of the contemporary challenges facing fellowship education in adult cardiothoracic anesthesiology.

Overexpression of VEGF165 is associated with poor prognosis of cervical cancer.

BACKGROUND: Cervical cancer is a major health hazard to Indian women. Human papillomavirus (HPV) infection is an established risk factor for cervical carcinogenesis. However, understanding the cervical cancer biology beyond HPV infection is very crucial to predict aggressive behavior, prognosis, treatment response and survival. In the present study, we explored the role of vascular endothelial growth factor A (VEGFA) isoforms, VEGFC and VEGFD in cervical cancer progression and its association with HPV 16 and 18 infections. MATERIAL AND METHODS: A total of 110 cervical cancer tissues and 50 normal cervical tissues were collected for the study. Reverse transcription-polymerase chain reaction was employed to analyze tissue VEGFA isoforms, VEGFC and VEGFD expression. RESULTS: VEGF165 was significantly higher, whereas VEGFC and VEGFD were significantly lower in malignant cervical carcinoma tissues as compared to normal cervix tissues. Expression levels of VEGF121 and VEGFC were significantly associated with type of tumor growth while VEGF165 was significantly associated with lymph node metastasis. VEGF165 transcript levels were significantly higher in patients with squamous cell carcinoma (SCC) and developed recurrence. Most strikingly, higher VEGF165 expression was significantly associated with worst disease-free survival (DFS) specifically in patients with SCC. CONCLUSION: Association of VEGF165 with lymph node metastasis, disease recurrence and worst DFS indicated that VEGF165 is an important prognostic factor in cervical carcinogenesis.

Trichosporon-Blood Stream Infection.

AIM: Trichosporon species are the major emerging opportunistic pathogen in immunocompromised patients. Its diverse refractoriness to conventional antifungal drugs and association with high mortality rate is worrisome. The present study aims to determine the risk factors, treatment outcome and antifungal susceptibility pattern of Trichosporon species in blood stream infections. MATERIAL AND METHODS: All patients with blood culture positive for Trichosporon species from January 2012 to August 2016 at PD Hinduja National Hospital and research centre were evaluated retrospectively. Species identification and antifungal susceptibility by broth microdilution method for various drugs was determined using Vitek2 compact automated system. RESULTS: 12 patients were found to have Trichosporon blood stream infection. 9 isolates that were speciated all were T. asahii. All patients had central venous catheter and received prior antibiotics. Overall mortality rate was 50%. CONCLUSION: Higher mortality was associated with central venous catheter and voriconazole should be used as drug of choice for treatment. Identification of Trichosporon species along with its sensitivity and proper treatment of patients is of utmost importance.

Role of aberrant glycosylation enzymes in oral cancer progression.

BACKGROUND: Carcinogenesis, a multistep process involves sequential changes during neoplastic transformation. The various hallmarks of cancer aid in cell survival, proliferation, and dissemination. Aberrant glycosylation, a recently defined hallmark of cancer, is influenced by glycosylation enzymes during carcinogenesis. Therefore, the present study measured α-2,3 and α-2,6 sialyltransferase (ST), sialidase, and α-L-fucosidase activity in patients with oral precancerous conditions (OPC) and oral cancer patients. SUBJECTS: The study enrolled 100 oral cancer patients, 50 patients with OPC, 100 healthy controls, and 46 posttreatment follow-ups of oral cancer patients. Blood and saliva were collected from all the participants. MATERIALS AND METHODS: Sialidase activity was measured by spectrofluorimetric method, α-2,3 and α-2,6 ST by ELISA using biotinylated lectins, and α-L-fucosidase by spectrophotometric method. RESULTS: The results depicted increased levels of sialidase, α-2,3 and α-2,6 ST, α-L-fucosidase in patients with OPC and oral cancer patients. Receiver operating characteristic curve indicated significant discriminatory efficacy in distinguishing controls and oral cancer patients for serum and salivary sialidase and α-L-fucosidase activity, and serum α-2,6 ST. Furthermore, serum and salivary α-L-fucosidase activity and serum sialidase activity significantly distinguished controls and patients with OPC. Serum and salivary sialidase, α-L-fucosidase, and serum α-2,3 ST activity were higher in patients with metastasis as compared to nonmetastatic patients. Higher values of serum α-L-fucosidase activity were significantly associated with low-overall survival. CONCLUSION: The increased levels of enzymes correlated with tumor initiation, progression, and metastasis in oral cancer patients. The alterations in glycosyltransferases/glycosidases thus support the view of glycosylation as a hallmark of cancer.

Acute kidney injury following implementation of an enhanced recovery after surgery (ERAS) protocol in colorectal surgery.

PURPOSE: Fluid management within Enhanced Recovery After Surgery (ERAS) protocols is designed to maintain a euvolemic state avoiding the negative sequelae of hypervolemia or hypovolemia. We sought to determine the effect of a recent ERAS protocol implementation on kidney function and on the incidence of postoperative acute kidney injury (AKI). METHODS: A total of 132 elective colorectal resections performed using our ERAS protocol were compared to a propensity-matched group prior to ERAS implementation. Fluid balance, urine output, creatinine, and blood urea nitrogen (BUN) were recorded for all patients, and the incidence of AKI was determined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: Implementation of our ERAS protocol decreased average postoperative length of hospital stay (5.5 vs 7.7 days, p < 0.0001) and time to return of bowel function (2.5 vs 4.1 days, p < 0.0001). The rate of postoperative AKI increased following implementation of the protocol (11.4 vs 2.3%, p < 0.0001). However, by the time of discharge, the average creatinine of ERAS patients who had experienced AKI had returned to their preoperative baseline values (p = 0.9037). Significant univariate predictors of AKI in ERAS patients were longer operative times (p < 0.01) and the diagnosis of diverticulitis (p < 0.01). Within our ERAS patients, AKI was associated with a prolonged postoperative length of hospital stay (p < 0.01). CONCLUSIONS: Despite the proven benefits of the Enhanced Recovery After Surgery (ERAS) protocols, care should be taken during protocol implementation to monitor for and to prevent acute kidney injury.

Asanguinous Del Nido Cardioplegia for an Aortic Valve Replacement Patient with Cold Agglutinins.

A patient with known cold agglutinins requiring an aortic valve replacement was referred for surgery. Asanguinous, Del Nido cardioplegia was used for myocardial protection. Warm induction followed by cold infusion prevented any agglutination and eliminated the need for subsequent cardioplegia doses. Following the cross-clamp period, the heart returned to normal sinus rhythm without need for defibrillation. Postoperative ejection fraction and systolic function were normal.

Pilot intervention for discrimination-related coping among HIV-positive Black sexual minority men.

OBJECTIVES: Discrimination is associated with worse health. Although interventions have been developed to improve coping with general stressors and chronic illness, no literature to date has reported the development and testing of an intervention specifically to address coping with discrimination. We examined the feasibility, acceptability, and preliminary effects of Still Climbin', a pilot intervention created to improve coping with discrimination experienced by HIV-positive Black sexual minority men, who face significant HIV-related disparities. METHOD: Still Climbin' was culturally tailored using community stakeholder input and formative qualitative research. Still Climbin' consists of 8 weekly group sessions and a graduation session, based on principles of cognitive behavior therapy. Sixty-four HIV-positive Black sexual minority men were recruited from community venues; 38 were randomized to the intervention and 26 to a wait-list control group. Participants completed assessments at baseline and 3- and 6-months postbaseline. Intervention participants completed postsession feedback forms. RESULTS: Repeated-measures regressions indicated significant intervention effects on improved coping in response to discrimination, including functional (problem-solving) coping [b (SE) = 0.39 (0.19), p = .04], humor [b (SE) = 0.48 (0.22), p = .03], and cognitive/emotional debriefing [b (SE) = 0.30 (0.14), p = .04], a culturally relevant form of coping that includes self-protective strategies (e.g., strategic avoidance of certain places or people). Intervention participants rated the sessions positively in response to closed- and open-ended questions. CONCLUSIONS: Still Climbin' was feasible and acceptable to participants, and showed promise for improving coping with discrimination, which ultimately can lead to better health outcomes and reduced disparities. (PsycINFO Database Record (c) 2018 APA, all rights reserved).