Multistage antiplasmodial activity of hydroxyethylamine compounds,in vitro and in vivo evaluations

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite''s multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain of P. falciparum blood-stage culture with 50% inhibitory concentrations (IC₅₀) in the low micromolar range. The compounds'' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC₅₀ values > 170 μM. The in vivo efficacy was studied in mice infected with P. berghei NK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound 1 with an IC₅₀ value of 1.89 μM. Mice infected with P. berghei sporozoites treated with compound 1 at 50 mg kg⁻¹ dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematic in silico studies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species.     

Unmet Needs of Women Living with Parkinson's Disease: Gaps and Controversies

Personalized medicine considering sex, gender, and cultural context has become the vanguard of delivery of care. However, women's issues in Parkinson disease (PD), especially from a psychosocial standpoint, have been an overlooked field. The key research areas include women-inclusive drug and device studies and genetic and hormonal considerations. Moreover, women with PD need to be educated and empowered on how to communicate their symptoms and needs, get engaged in research, get organized as a community, and support one another. Women with PD need tools to help track and convey their unique motor and nonmotor symptoms and psychological and social support needs. The management of PD needs to be customized to include the unique stages of women's lives, including menstrual cycles, pregnancy, perimenopause, menopause, and postmenopause. Specific guidelines for the use of hormonal treatments and customized dopamine replacement dosing need to be developed. Women need guidance on culturally sensitive wellness and self-care strategies that are customized for them. Basic core competencies in knowledge for all clinicians treating women with PD need to be established, including how to accurately diagnose, proactively identify, and treat the symptoms of PD in women and to ensure timely referral for specialty care, advanced therapies, and research studies. Caregivers and families need guidance on holistically supporting women with PD. The voices of women living with PD must be amplified to catalyze real change in this neglected field. This paper provides an overview of the current knowledge, gaps, and possible strategies to deal with the unmet needs of women living with PD with a focus on the clinical and psychosocial aspects. © 2022 International Parkinson and Movement Disorder Society     

Off-pump or on-pump coronary artery bypass grafting—a dilemma in elderly

Background

Off-pump coronary artery bypass graft surgery (OPCAB) has been performed for many years, but its use is increasing in frequency, and it remains an open question whether OPCAB is associated with better outcomes than on-pump coronary artery bypass graft (CABG) surgery especially in patients with age >65 years.

Methods

We randomly assigned patients 65 years of age or older who were scheduled for elective first-time CABG to undergo the procedure either without cardiopulmonary bypass (off-pump CABG) or with it (on-pump CABG). The primary end point was a composite of death, stroke, myocardial infarction, repeat revascularization, or new renal-replacement therapy at 30 days and at 12 months after surgery.

Results

A total of 581 patients underwent randomization. At 30 days after surgery, there was no significant difference between patients who underwent off-pump surgery and those who underwent on-pump surgery in terms of the composite outcome (9.8 vs. 10.1 %; odds ratio, 0.98; 95 % confidence interval [CI], 0.57 to 1.68; P?=?0.95) or four of the components (death, stroke, myocardial infarction, or new renal-replacement therapy). Repeat revascularization occurred more frequently after off-pump CABG than after on-pump CABG (1.5 vs. 0.3 %; odds ratio, 3.93; 95 % CI, 0.43 to 35.39; P?=?0.22). At 12 months, there was no significant between-group difference in the composite end point (13.1 vs. 13.3 %; hazard ratio, 0.98; 95 % CI, 0.60 to 1.58; P?=?0.94) or in any of the individual components.

Conclusions

In patients 65 years of age or older, there was no significant difference between on-pump and off-pump CABG with regard to the composite outcome of death, stroke, myocardial infarction, repeat revascularization, or new renal-replacement therapy within 30 days and within 12 months after surgery.

     

Diagnosis and grading of non-Hodgkin's lymphomas on fine needle aspiration cytology

Fine needle aspiration cytology (FNAC) enjoys popularity among clinicians worldwide, as a first line of investigation in all patients with lymphadenopathy and is preferred over biopsy because of its minimally invasive nature and cost-effectiveness. Although non-Hodgkin's lymphomas (NHL) are conventionally diagnosed and graded on biopsy specimens, it may be useful to be able to not only diagnose but also grade these cases on FNAC smears. The WHO and REAL classifications forming the basis of treatment in some centres rely on clinical features, immunocytochemistry and cytogenetics, which are beyond reach of most centres in the developing countries. This study therefore is aimed at diagnosing and grading NHLs on morphological parameters. The cytologic grading accuracy is compared with the histologic grades assigned according to the International Working Formulation (IWF) system which relies solely on morphological features, most important of which is cell size. Ninety five cases were retrieved over a 3 year period (May 2000 to April 2003). These were (i) cases where a cytological diagnosis of NHL or suspicious of NHL was made and corresponding histological sections available and (ii) cases where a diagnosis of NHL was made in histology and corresponding FNAC smears were available irrespective of the cytological diagnosis. The diagnostic accuracy of FNAC for NHLs was determined using histology as the gold standard. Cases were also graded on FNAC smears using a three tier grading system based upon cell size into low, intermediate and high grades. Cytologically assigned grades were correlated with the corresponding histological grades (IWF) to determine grading accuracy. An accurate diagnosis of NHL was thus possible in 67/95 (70.5%) cases. Overall accurate grading was seen in 65/95 (68%) cases using cytological criteria. Accurate cytologic grading was possible in 14/15 (93.33%) low grade, 11/18 (61.11%) intermediate and 40/62 (64.5%) high grade non Hodgkin's lymphomas. Kappa statistics revealed a very good agreement between cytological and histological grades for low grade NHL. The kappa scores for intermediate and high grade NHLs indicated moderate agreement. Using the two-tier system grading the kappa value for high grade lymphomas improved to 0.72, indicating good concordance. This study highlights the utility of FNAC as a morphological tool for diagnosing and grading NHLs in a significant number of cases. This modality may assist clinicians in management of cases of NHLs, especially in centres working within the constraints of limited availability or non availability of ancillary techniques.     

Optimal Planar Flow Network Designs for Tissue Engineered Constructs with Built-in Vasculature

Convective delivery of nutrients is important to enhance mass transport within tissue engineered (TE) products. Depending on the target tissue, an ideal TE product will have an integrated microvasculature that will eliminate mass transport limitations that can occur during product growth in vitro and integration in vivo. A synthetic approach to develop microvasculature involves development of network designs with efficient mass transfer characteristics. In this paper, utilizing a planar bifurcating network as a basis, we develop an approach to design optimal flow networks that have maximum mass transport efficiency for a given pressure drop. We formulated the optimization problem for a TE skin product, incorporating two types of duct flow, rectangular and square, and solved using a generalized reduced gradient algorithm. Under the conditions of this study, we found that rectangular ducts have superior mass transport characteristics than square ducts. Microvascular area per volume values obtained in this work are significantly greater than those reported in the literature. We discuss the effect of network variables such as porosity and generations on the optimal designs. This research forms the engineering basis for the rational development of TE products with built-in microvasculature and will pave the way to design complex flow networks with optimal mass transfer characteristics.     

Cavernous sinus haemangioma: systematic review and pooled analysis relating to a rare skull base pathology

Neurosurgical Review - Cavernous sinus haemangiomas (CSHs) are rare malformations of the microcirculation arising from the cavernous sinus. A systematic review and pooled data analysis of the...     

Best practices to optimize utilization of the National Living Donor Assistance Center for the financial assistance of living organ donors

Living organ donors face direct costs when donating an organ, including transportation, lodging, meals, and lost wages. For those most in need, the National Living Donor Assistance Center (NLDAC) provides reimbursement to defray travel and subsistence costs associated with living donor evaluation, surgery, and follow‐up. While this program currently supports 9% of all US living donors, there is tremendous variability in its utilization across US transplant centers, which may limit patient access to living donor transplantation. Based on feedback from the transplant community, NLDAC convened a Best Practices Workshop on August 2, 2018, in Arlington, VA, to identify strategies to optimize transplant program utilization of this valuable resource. Attendees included team members from transplant centers that are high NLDAC users; the NLDAC program team; and Advisory Group members. After a robust review of NLDAC data and engagement in group discussions, the workgroup identified concrete best practices for administrative and transplant center leadership involvement; for individuals filing NLDAC applications at transplant centers; and to improve patient education about potential financial barriers to living organ donation. Multiple opportunities were identified for intervention to increase transplant programs’ NLDAC utilization and reduce financial burdens inhibiting expansion of living donor transplantation in the United States.     

Primary vs delayed primary closure in patients undergoing lower limb amputation following trauma: A randomised control study

Lower limb crush injury is a major source of mortality and morbidity in trauma patients. Complications, especially surgical site infections (SSIs) are a major source of financial burden to the institute and to the patient as it delays rehabilitation. As such, every possible attempt should be made to reduce any complications. We, thus, aimed to compare the outcomes in early vs delayed closure of lower extremity stumps in cases of lower limb crush injury requiring amputation, so as to achieve best possible outcome. A randomised controlled study was conducted in the Division of Trauma Surgery & Critical Care at Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi from 1 September 2018 to 30 June 2019 and included patients undergoing lower limb amputation below hip joint. Patients were randomised in two groups, in one group amputation stump was closed primarily, while in the second group delayed primary closure of stump was performed. We compared rate of SSI, length of hospital stay, and number of surgeries in both the groups. Fifty‐six patients with 63 amputation stumps were recruited in the study. Mean age of patients in the study was 34 years, of which about 95% patients were males. The most common mechanism of injury was road traffic injury in 66% of patients. Mean injury severity score was 12.28 and four patients had diabetes preoperatively. Total 63 extremities were randomised with 30 cases in group I and 33 cases in group II as per computer‐generated random number. Above knee amputations was commonest (57.14%) followed by below knee amputations (33.3%). Two patients died in the current study. In group I, In‐hospital infection was detected in 7 cases (23.3%) and in group II 9 cases (27.3%) had SSI during hospital admission (P > .05). Mean hospital stay in group I was 10.32 ± 7.68 days and in group II was 11 ± 8.17 days (P > .05). Road traffic injuries and train‐associated injuries are a major cause of lower limb crush injuries, leading to limb loss. Delayed primary closure of such wounds requires extra number of surgical interventions than primary closure. There is no difference in extra number of surgical interventions required in both the groups. Thus, primary closure can be safely performed in patients undergoing lower limb amputations following trauma, provided that a good lavage and wound debridement is performed.