Use of Potentially Inappropriate Medications among Older Adults with Dementia or Cognitive Impairment Attending Memory Clinics: A Protocol for a Systematic Review and Meta-Analysis.

Introduction: Older adults with dementia who are on multiple medications are more vulnerable to the use of potentially inappropriate medications (PIMs), which can significantly increase the risk of adverse events and drug-related problems. PIMs use is prevalent and varies among older adults with dementia or cognitive impairment (CI) attending memory clinics. However, the prevalence of PIMs, polypharmacy, and hyper-polypharmacy among older adults with dementia or CI who are attending memory clinics is not well understood. We will conduct a systematic review and meta-analyses to examine the overall estimate of the prevalence of the PIMs, polypharmacy, and hyper-polypharmacy use among older adults attending memory clinics, with dementia or CI. The secondary objective of this study will be to compile a list of commonly implicated PIMs and to investigate factors that may be associated with using PIMs in this population. Methods: Ovid MEDLINE, Ovid Embase, Scopus, Cochrane library, EBSCOhost CINAHL, and Ovid International Pharmaceutical Abstracts (IPA) will be systematically searched by a researcher (R.S.) with the help of a librarian (C.C.). All databases will be searched from inception to May 05, 2023. Cross-sectional, cohort, randomized clinical trials, quasi-experimental, and case-control studies will be included if they assess PIM's use among older adults with dementia and/or CI. A step-by-step guide by Pai et al. [Natl Med J India. 2004;17(2):86-95] will be followed when conducting this systematic review (S.R.). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist will be followed for reporting this SR. Conclusion: The findings from this SR/MA will identify the pooled prevalence of PIMs, providing a more precise estimate of the true prevalence of the PIMs, polypharmacy, hyper-polypharmacy in older adults with dementia or CI who are attending memory clinics at primary, secondary, or tertiary healthcare settings by considering the results of multiple studies.

The Role of Phytonutrient Kaempferol in the Prevention of Gastrointestinal Cancers: Recent Trends and Future Perspectives.

In recent years, kaempferol, a natural flavonoid present in various fruits and vegetables, has received significant attention in gastrointestinal cancer research due to its varied therapeutic effects. Kaempferol has been proven to alter several molecular mechanisms and pathways, such as the PI3/Akt, mTOR, and Erk/MAPK pathway involved in cancer progression, showing its inhibitory effects on cell proliferation, survival, angiogenesis, metastasis, and migration. Kaempferol is processed in the liver and small intestine, but limited bioavailability has been a major concern in the clinical implications of kaempferol. Nano formulations have been proven to enhance kaempferol's efficacy in cancer prevention. The synergy of nanotechnology and kaempferol has shown promising results in in vitro studies, highlighting the importance for more in vivo research and clinical trials to determine safety and efficacy. This review aims to focus on the role of kaempferol in various types of gastrointestinal cancer and how the combination of kaempferol with nanotechnology helps in improving therapeutic efficacy in cancer treatment.

An Unusual Case of Symptomatic Isolated Lingual Cysticercosis: Clinical Suspicion Helped Prevent Disseminated Disease.

Intraorally, cysticercosis is regarded as uncommon and a diagnostic challenge. Here, we report a diagnostic conundrum of an unusual case of innocuous appearing lesion on the tongue presenting as moderately tender swelling finally diagnosed as lingual cysticercosis, based on USG (Ultrasound), CT (Computed Tomography) findings and characteristic histopathologic features.

Clear cell oral squamous cell carcinoma as a diagnostic conundrum: report of 2 rare cases.

The occurrence of clear cell histologic sub-type of oral squamous cell carcinoma in the oral cavity is a distinct and exceedingly rare entity exhibiting aggressive behavior. To date, only 10 cases have been published in the literature. We describe 2 extremely rare cases, both presenting with swelling and ulcerated nodule-like proliferative growth in the mandible. Microscopically, sheets and lobules of neoplastic squamous epithelial cells showing clear cell differentiation were appreciated in both patients. Periodic acid-Schiff and mucicarmine revealed negative staining. Immunohistochemical (IHC) analysis for antibody for renal cell tumor marker CD 10 was immune-negative. The malignant clear cells in both cases showed intense positive reactions with IHC markers pan-cytokeratin and epithelial membrane antigen, confirming the diagnosis as a clear cell variant of oral squamous cell carcinoma (CCOSCC). The first patient was unwilling for treatment and eventually died within 2 months of the diagnosis. In the second patient, right hemi-mandibulectomy with level 1A and 1B lymph nodes was performed. Adjuvant chemotherapy with low-dose methotrexate was initiated. Follow-up after 2 months of surgery was uneventful. Current rare reports emphasize the significance of prompt and extensive diagnostic work-up of clear cell neoplasms, as the CCOSCC may be fatal.

Recent nanotheranostic approaches in cancer research.

Humanity is suffering from cancer which has become a root cause of untimely deaths of individuals around the globe in the recent past. Nanotheranostics integrates therapeutics and diagnostics to monitor treatment response and enhance drug efficacy and safety. We hereby propose to discuss all recent cancer imaging and diagnostic tools, the mechanism of targeting tumor cells, and current nanotheranostic platforms available for cancer. This review discusses various nanotheranostic agents and novel molecular imaging tools like MRI, CT, PET, SPEC, and PAT used for cancer diagnostics. Emphasis is given to gold nanoparticles, silica, liposomes, dendrimers, and metal-based agents. We also highlight the mechanism of targeting the tumor cells, and the limitations of different nanotheranostic agents in the field of research for cancer treatment. Due to the complexity in this area, multifunctional and hybrid nanoparticles functionalized with targeted moieties or anti-cancer drugs show the best feature for theranostics that enables them to work on carrying and delivering active materials to the desired area of the requirement for early detection and diagnosis. Non-invasive imaging techniques have a specificity of receptor binding and internalization processes of the nanosystems within the cancer cells. Nanotheranostics may provide the appropriate medicine at the appropriate dose to the appropriate patient at the appropriate time.

Alternative oxidase promotes high iron tolerance in Candida albicans.

IMPORTANCE: The yeast C. albicans exhibits metabolic flexibility for adaptability to host niches with varying availability of nutrients including essential metals like iron. For example, blood is iron deplete, while the oral cavity and the intestinal lumen are considered iron replete. We show here that C. albicans can tolerate very high levels of environmental iron, despite an increase in high iron-induced reactive oxygen species (ROS) that it mitigates with the help of a unique oxidase, known as alternative oxidase (AOX). High iron induces AOX1/2 that limits mitochondrial accumulation of ROS. Genetic elimination of AOX1/2 resulted in diminished virulence during oropharyngeal candidiasis in high iron mice. Since human mitochondria lack AOX protein, it represents a unique target for treatment of fungal infections.

Medication Reviews and Clinical Outcomes in Persons with Dementia: A Scoping Review.

Persons diagnosed with dementia are often faced with challenges related to polypharmacy and inappropriate medication use and could benefit from regular medication reviews. However, the benefit of such reviews has not been examined in this population. Therefore, the current scoping review was designed to identify the gaps in the current knowledge regarding the impact of medication reviews on the clinical outcomes in older adults with dementia. Relevant studies were identified by searching three databases (Ovid MEDLINE, Ovid EMBASE, and Scopus) from inception to January 2022 with a combination of keywords and medical subject headings. After the removal of duplicates and ineligible articles, 22 publications of the initial 8346 were included in this review. A total of 57 outcomes were identified, including those pertaining to the evaluation of medication use (n = 17), drug-related interventions (n = 11), drug-related problems (n = 10), dementia-related behavioral symptoms (n = 8), cost-effectiveness (n = 2), drug-related hospital admissions (n = 1), as well as outcomes classified as other (n = 7). Gaps identified through this scoping review included the paucity of studies measuring the impact of medication reviews on the medication management capacity and medication adherence, quality of life, and mortality.

Regulation of microglial responses after pediatric traumatic brain injury: exploring the role of SHIP-1.

Introduction: Severe traumatic brain injury (TBI) is the world's leading cause of permanent neurological disability in children. TBI-induced neurological deficits may be driven by neuroinflammation post-injury. Abnormal activity of SH2 domain-containing inositol 5' phosphatase-1 (SHIP-1) has been associated with dysregulated immunological responses, but the role of SHIP-1 in the brain remains unclear. The current study investigated the immunoregulatory role of SHIP-1 in a mouse model of moderate-severe pediatric TBI. Methods: SHIP-1+/- and SHIP-1-/- mice underwent experimental TBI or sham surgery at post-natal day 21. Brain gene expression was examined across a time course, and immunofluorescence staining was evaluated to determine cellular immune responses, alongside peripheral serum cytokine levels by immunoassays. Brain tissue volume loss was measured using volumetric analysis, and behavior changes both acutely and chronically post-injury. Results: Acutely, inflammatory gene expression was elevated in the injured cortex alongside increased IBA-1 expression and altered microglial morphology; but to a similar extent in SHIP-1-/- mice and littermate SHIP-1+/- control mice. Similarly, the infiltration and activation of CD68-positive macrophages, and reactivity of GFAP-positive astrocytes, was increased after TBI but comparable between genotypes. TBI increased anxiety-like behavior acutely, whereas SHIP-1 deficiency alone reduced general locomotor activity. Chronically, at 12-weeks post-TBI, SHIP-1-/- mice exhibited reduced body weight and increased circulating cytokines. Pro-inflammatory gene expression in the injured hippocampus was also elevated in SHIP-1-/- mice; however, GFAP immunoreactivity at the injury site in TBI mice was lower. TBI induced a comparable loss of cortical and hippocampal tissue in both genotypes, while SHIP-1-/- mice showed reduced general activity and impaired working memory, independent of TBI. Conclusion: Together, evidence does not support SHIP-1 as an essential regulator of brain microglial morphology, brain immune responses, or the extent of tissue damage after moderate-severe pediatric TBI in mice. However, our data suggest that reduced SHIP-1 activity induces a greater inflammatory response in the hippocampus chronically post-TBI, warranting further investigation.

High iron-mediated increased oral fungal burden, oral-to-gut transmission, and changes to pathogenicity of Candida albicans in oropharyngeal candidiasis.

BACKGROUND: Iron affects the diversity of the oral microbial landscape. Laboratory-strain CAI4 of Candida albicans that causes oropharyngeal candidiasis (OPC) exhibits iron-induced changes to the cell wall, impacting phagocytosis (by macrophages) and susceptibility of fungal cells to cell wall-perturbing antifungals, in vitro. AIM: To understand the effect of iron on the CAI4-strain, wild type (WT) SC5314-strain, and oral isolates of C. albicans. METHODS: An immunosuppressed murine model of OPC was used to assess the effect of iron on oral-to-gut infection and antifungal susceptibility of the CAI4-strain. In vitro antifungal susceptibility, cell wall analysis, and phagocytic assays were performed under low and high iron, for the SC5314-strain and oral isolates. RESULTS: High iron enhanced oral and gut fungal levels for the CAI4-strain in mice; CAI4 cells from low iron mice were more susceptible to antifungals. The SC5314-strain and oral isolates showed enhanced antifungal-resistance towards most antifungals tested, under high iron. Iron-mediated cell wall changes and phagocytic response in the SC5315-strain were similar to CAI4; oral isolates showed a variable response. CONCLUSION: Host iron can potentially alter infection severity and dissemination, efficacy of antifungal treatment, and host immune response during OPC. Clinical isolates showed most of these effects of iron, despite exhibiting a varied cell wall composition-change response to iron.

Antifungal properties of (2S, 4R)-Ketoconazole sulfonamide analogs.

Invasive candidiasis remains a significant health concern, as it is associated with a high mortality risk. In addition, the risk of infection is significantly elevated in immunocompromised patients such as those with HIV, cancer, or those taking imcmunosuppressive drugs as a result of organ transplantation. The majority of these cases are caused by C. albicans, and C. glabrata is the second most common cause. These infections are typically treated using approved antifungal agents, but the rise of drug-resistant fungi is a serious concern. As part of our on-going effort to identify novel antifungal agents, we have studied the in vitro antifungal properties of a series of sulfonamide analogs of (2S, 4R)-Ketoconazole. Herein we report on the in vitro activity against the key fungal pathogens C. albicans, and C. glabrata.

Pediatric traumatic brain injury and a subsequent transient immune challenge independently influenced chronic outcomes in male mice.

Traumatic brain injury (TBI) is a major contributor to death and disability worldwide. Children are at particularly high risk of both sustaining a TBI and experiencing serious long-term consequences, such as cognitive deficits, mental health problems and post-traumatic epilepsy. Severe TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization post-TBI. Yet the potential chronic impact of such acute infections following pediatric TBI remains unclear. In this study, we hypothesized that a peripheral immune challenge, such as lipopolysaccharide (LPS)-mimicking a hospital-acquired infection-would worsen inflammatory, neurobehavioral, and seizure outcomes after experimental pediatric TBI. To test this, three-week old male C57Bl/6J mice received a moderate controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS (or 0.9% saline vehicle) at 4 days TBI. Mice were randomized to four groups; sham-saline, sham-LPS, TBI-saline or TBI-LPS (n = 15/group). Reduced general activity and increased anxiety-like behavior were observed within 24 h in LPS-treated mice, indicating a transient sickness response. LPS-treated mice also exhibited a reduction in body weights, which persisted chronically. From 2 months post-injury, mice underwent a battery of tests for sensorimotor, cognitive, and psychosocial behaviors. TBI resulted in hyperactivity and spatial memory deficits, independent of LPS; whereas LPS resulted in subtle deficits in spatial memory retention. At 5 months post-injury, video-electroencephalographic recordings were obtained to evaluate both spontaneous seizure activity as well as the evoked seizure response to pentylenetetrazol (PTZ). TBI increased susceptibility to PTZ-evoked seizures; whereas LPS appeared to increase the incidence of spontaneous seizures. Post-mortem analyses found that TBI, but not LPS, resulted in robust glial reactivity and loss of cortical volume. A TBI × LPS interaction in hippocampal volume suggested that TBI-LPS mice had a subtle increase in ipsilateral hippocampus tissue loss; however, this was not reflected in neuronal cell counts. Both TBI and LPS independently had modest effects on chronic hippocampal gene expression. Together, contrary to our hypothesis, we observed minimal synergy between TBI and LPS. Instead, pediatric TBI and a subsequent transient immune challenge independently influenced chronic outcomes. These findings have implications for future preclinical modeling as well as acute post-injury patient management.

Chronic Kidney Disease (CKD) - A Brand Ambassador/Alarming Bell for Potentially Inappropriate Medication in Elderly Inpatients.

BACKGROUND: Since the past decade, prevalence of Potentially Inappropriate Medication (PIM) among elderly inpatients has increased drastically. However, limited data is available on PIM indicators and PIMs use among the elderly in patients suffering from Chronic Kidney Disease (CKD). OBJECTIVE: The objective of this study is to determine the prevalence of PIMs in elderly hospitalized patients with CKD. METHODS: A cross-sectional study was carried out on 102 patients in a tertiary care hospital. PIMs were identified using Beers criteria 2019. Chi-square test was used to identify the association between variables and PIMs use. RESULTS: PIMs, as assessed according to AGS updated Beers criteria 2019 was found to be in more than 68.6% of patients of median age 65 years and 3 diagnoses and 7 days median length of stay. Most of the patients (47.1%) had ≥4 diagnosis. The most common comorbidities in patient were diabetes mellitus (n=54) and hypertension (n=55). Most of the subjects (66.7%) were on polypharmacy (5-9 medications/day) and 25.5% were on a higher level of polypharmacy (>10 medicines/day). Approximately 90% of the patients were having very low CrCl < 21ml/min (calculated with the help of Cockcroft- Gault formula). A significant association between PIM use and an increased number of diagnoses, polypharmacy or high-level polypharmacy, was observed. CONCLUSION: The prevalence of PIMs in elderly inpatients suffering from CKD is quite high. The study clearly indicates negligence/ lack of awareness amongst physicians leading to increase in PIM use. Authors propose that the CKD patients should attract special attention of physician and should be treated as brand ambassadors/alarming bell for PIM use.

Prevalence of Polypharmacy, Hyperpolypharmacy and Potentially Inappropriate Medication Use in Older Adults in India: A Systematic Review and Meta-Analysis.

Background: Older people often receive multiple medications for chronic conditions, which often result in polypharmacy (concomitant use of 5‒9 medicines) and hyperpolypharmacy (concomitant use of ≥10 medicines). A limited number of studies have been performed to evaluate the prevalence of polypharmacy, hyperpolypharmacy, and potentially inappropriate medication (PIM) use in older people of developing countries. The present study aimed to investigate regional variations in the prevalence of polypharmacy, hyperpolypharmacy, and PIM use in older people (60 + years) in India. Methods: Studies were identified using Medline/PubMed, Scopus, and Google Scholar databases published from inception (2002) to September 31, 2020. Out of the total 1890 articles, 27 were included in the study. Results: Overall, the pooled prevalence of polypharmacy was 49% (95% confidence interval: 42-56; p < 0.01), hyperpolypharmacy was 31% (21-40; p < 0.01), and PIM use was 28% (24-32; p < 0.01) among older Indian adults. Polypharmacy was more prevalent in North-east India (65%, 50-79), whereas hyperpolypharmacy was prevalent in south India (33%, 17-48). Region-wize estimates for the pooled prevalence of PIM use in India were as follows: 23% (21-25) in East, 33% in West (24-42), 17.8% in North (11-23), and 32% (26-38) in South India. The prevalence of PIM use in adults aged ≥70°years was 35% (28-42), in those taking more medications (≥5.5/day) was 27% (22-31), and in adults using a high number of PIMs (≥3) was 29% (22-36). Subgroup analysis showed that cross-sectional studies had a higher pooled prevalence of polypharmacy 55% (44-65) than cohorts 45% (37-54). Hyperpolypharmacy in inpatient care settings was 37% (26-47), whereas PIM use was higher in private hospitals 31% (24-38) than government hospitals 25% (19-31). Conclusion: Polypharmacy and hyperpolypharmacy are widely prevalent in India. About 28% of older Indian adults are affected by PIM use. Thus, appropriate steps are needed to promote rational geriatric prescribing in India. Systematic Review Registration: https://clinicaltrials.gov, identifier [CRD42019141037].

Knockout of MRA_1916 in Mycobacterium tuberculosis H37Ra affects its growth, biofilm formation, survival in macrophages and in mice.

Mycobacterium tuberculosis H37Ra (Mtb-Ra) ORF MRA_1916 is annotated as a D-amino acid oxidase (DAO). These enzymes perform conversion of d-amino acids to corresponding imino acids followed by conversion into α-keto-acids. In the present study Mtb-Ra recombinants with DAO knockout (KO) and knockout complemented with DAO over-expressing plasmid (KOC) were constructed. The growth studies showed loss of growth of KO in medium containing glycerol as a primary carbon source. Substituting glycerol with acetate or with FBS addition, restored the growth. Growth was also restored in complemented strain (KOC). KO showed increased permeability to hydrophilic dye EtBr and reduced biofilm formation. Also, its survival in macrophages was low. Phagosome maturation studies suggested enhanced colocalization of KO, compared to WT, with lysosomal marker cathepsin D. Also, an increased intensity of Rab5 and iNOS was observed in macrophages infected with KO, compared to WT and KOC. The in vivo survival studies showed no increase in CFU of KO. This is the first study to show functional relevance of DAO encoded by MRA_1916 for Mtb-Ra growth on glycerol, its permeability and biofilm formation. Also, this study clearly demonstrates that DAO deletion leads to Mtb-Ra failing to grow in macrophages and in mice.

A systemic immune challenge to model hospital-acquired infections independently regulates immune responses after pediatric traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of disability in young children, yet the factors contributing to poor outcomes in this population are not well understood. TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization, and such infections may modify TBI pathobiology and recovery. In this study, we hypothesized that a peripheral immune challenge such as lipopolysaccharide (LPS)-mimicking a hospital-acquired infection-would worsen outcomes after experimental pediatric TBI, by perpetuating the inflammatory immune response. METHODS: Three-week-old male mice received either a moderate controlled cortical impact or sham surgery, followed by a single LPS dose (1 mg/kg i.p.) or vehicle (0.9% saline) at 4 days post-surgery, then analysis at 5 or 8 days post-injury (i.e., 1 or 4 days post-LPS). RESULTS: LPS-treated mice exhibited a time-dependent reduction in general activity and social investigation, and increased anxiety, alongside substantial body weight loss, indicating transient sickness behaviors. Spleen-to-body weight ratios were also increased in LPS-treated mice, indicative of persistent activation of adaptive immunity at 4 days post-LPS. TBI + LPS mice showed an impaired trajectory of weight gain post-LPS, reflecting a synergistic effect of TBI and the LPS-induced immune challenge. Flow cytometry analysis demonstrated innate immune cell activation in blood, brain, and spleen post-LPS; however, this was not potentiated by TBI. Cytokine protein levels in serum, and gene expression levels in the brain, were altered in response to LPS but not TBI across the time course. Immunofluorescence analysis of brain sections revealed increased glia reactivity due to injury, but no additive effect of LPS was observed. CONCLUSIONS: Together, we found that a transient, infection-like systemic challenge had widespread effects on the brain and immune system, but these were not synergistic with prior TBI in pediatric mice. These findings provide novel insight into the potential influence of a secondary immune challenge to the injured pediatric brain, with future studies needed to elucidate the chronic effects of this two-hit insult.

Clonazepam tops the list of potentially inappropriate psychotropic (PIP) medications in older adults with psychiatric illness: A cross-sectional study based on Beers criteria 2019 vs STOPP criteria 2015.

BACKGROUND: In older adults, polypharmacy and potentially inappropriate psychotropic (PIP) medication use are prominent prescription challenges. However, there is limited information available on the use of PIP medication in older adults having psychiatry illness. OBJECTIVE: To find out the most commonly prescribed PIP in tertiary care hospitals of developing countries with respect to Beers criteria 2019 and Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) and predictors of PIP. METHODS: A cross-sectional analysis of 456 patients of either sex with a median age of 65 years visiting the outpatient department of psychiatry was performed at the tertiary care hospital of North India with respect to Beers criteria 2019 and STOPP criteria 2015. Bivariate logistic regression was used to figure out the predictors of PIP medication. RESULTS: Results of the study reflects a staggering number of older adults, (more than 91 % and 73 %) out of total 456 patients were prescribed with at least one PIP medication as per Beers criteria and STOPP criteria, respectively. Long-acting benzodiazepine like clonazepam, chlordiazepoxide were identified as one of the most commonly prescribed PIP medications with respect to the both set of criteria. Further analysis revealed that polypharmacy (≥5 medications with odds Ratio (OR) 17.33, 95% Confidence Interval (CI) 1.42-210.66, P-0.025) as the sole important predictor for PIP medication. CONCLUSION: According to the Beers criterion and the STOPP criteria, the use of PIP medicine is very prevalent among older adults with psychiatric illness. The Beers criteria dramatically diagnose more PIP medication than STOPP criteria.

Potentially Inappropriate Medication Use in Older Hospitalized Patients with Type 2 Diabetes: A Cross-Sectional Study.

Background: Older patients with type 2 diabetes mellitus (T2DM) are at greater risk of receiving potentially inappropriate medications (PIM) during hospitalization which may result in adverse outcomes. Aim: To evaluate the extent of PIM use in the older population with T2DM during hospitalization in a tertiary care hospital in India. Methods: A cross-sectional study was carried out from August 2019 to January 2020 in a tertiary care teaching hospital among the older population (aged ≥ 65 years) hospitalized with T2DM. Medications prescribed during hospitalization were reviewed following Beers Criteria 2019 to identify the extent of polypharmacy and PIM use. Binary logistic regression was applied to determine the factors associated with PIM use. Results: The mean age of the 150 patients hospitalized with T2DM was 68.85 ± 5.51 years, most of whom were men (54.7%). The participants had at least four comorbidities and were receiving an average of nine medications per day; the median length of hospital stay was 8 days (interquartile range (IQR): 4-19 days). Overall, three quarters (74%) of the participants had at least one PIM prescribed during their hospitalization as per Beers Criteria. Significant factors associated with the use of PIM during hospitalization are patients taking a higher number of medications (odds ratio (OR): 7.85, 95% CI 1.49-41.10), lower creatinine clearance values (OR: 12.90, 95% CI 2.81-59.28) and female patients (OR: 2.29; 95% CI: 1.05-4.97). Conclusions: PIM use is frequently observed in older T2DM patients during hospitalization. Polypharmacy, reduced renal function and female gender are associated with higher PIM use. Engaging clinical pharmacists in evaluating medication appropriateness can improve the outcomes of older patients.

Logistic LASSO Regression for Dietary Intakes and Breast Cancer.

A multitude of dietary factors from dietary fat to macro and micronutrients intakes have been associated with breast cancer, yet data are still equivocal. Therefore, utilizing data from the large, multi-year, cross-sectional National Health and Nutrition Examination Survey (NHANES), we applied a novel, modern statistical shrinkage technique, logistic least absolute shrinkage and selection operator (LASSO) regression, to examine the association between dietary intakes in women, ≥50 years, with self-reported breast cancer (n = 286) compared with women without self-reported breast cancer (1144) from the 1999-2010 NHANES cycle. Logistic LASSO regression was used to examine the relationship between twenty-nine variables, including dietary variables from food, as well as well-established/known breast cancer risk factors, and to subsequently identify the most relevant variables associated with self-reported breast cancer. We observed that as the penalty factor (λ) increased in the logistic LASSO regression, well-established breast cancer risk factors, including age (ß = 0.83) and parity (ß = -0.05) remained in the model. For dietary macro and micronutrient intakes, only vitamin B12 (ß = 0.07) was positively associated with self-reported breast cancer. Caffeine (ß = -0.01) and alcohol (ß = 0.03) use also continued to remain in the model. These data suggest that a diet high in vitamin B12, as well as alcohol use may be associated with self-reported breast cancer. Nonetheless, additional prospective studies should apply more recent statistical techniques to dietary data and cancer outcomes to replicate and confirm the present findings.

Down-regulation of malate synthase in Mycobacterium tuberculosis H37Ra leads to reduced stress tolerance, persistence and survival in macrophages.

Malate synthase is a condensing enzyme responsible for conversion of glyoxylate to malate in the presence of acetyl-CoA. This reaction helps in bypassing the TCA cycle reactions involving carbon loss and leads to diverting some of the carbon skeletons to gluconeogenic events while rest can continue to provide TCA cycle intermediates. Malate synthase (GlcB) is encoded by MRA_1848 of Mycobacterium tuberculosis H37Ra (Mtb-Ra). We developed a knockdown (KD) Mtb-Ra strain by down-regulating GlcB. The survival studies suggested increased susceptibility to oxidative and nitrosative stress as well as to rifampicin. The susceptibility profile was reversed in the presence of free radical scavengers. Also, KD showed reduced biofilm maturation, failed to enter persistent state, and showed reduced growth inside macrophages. The study of post-endocytosis events showed differences in late stage endosomal maturation behavior in macrophages infected with KD compared to WT. Increased iNOS, LAMP1 and cathepsin D expression was observed in macrophages infected with KD compared to WT.

Biochemical and functional characterization of MRA_1571 of Mycobacterium tuberculosis H37Ra and effect of its down-regulation on survival in macrophages.

Amino acid biosynthesis has emerged as a source of new drug targets as many bacterial strains auxotrophic for amino acids fail to proliferate under in vivo conditions. Branch chain amino acids (BCAAs) are important for Mycobacterium tuberculosis (Mtb) survival and strains deficient in their biosynthesis were attenuated for growth in mice. Threonine dehydratase (IlvA) is a pyridoxal-5-phosphate (PLP) dependent enzyme that catalyzes the first step in isoleucine biosynthesis. The MRA_1571 of Mycobacterium tuberculosis H37Ra (Mtb-Ra), annotated to be coding for IlvA, was cloned, expressed and purified. Purified protein was subsequently used for developing enzyme assay and to study its biochemical properties. Also, E. coli BL21 (DE3) IlvA knockout (E. coli-ΔilvA) was developed and genetically complemented with Mtb-Ra ilvA expression construct (pET32a-ilvA) to make complemented E. coli strain (E. coli-ΔilvA + pET32a-ilvA). The E. coli-ΔilvA showed growth failure in minimal medium but growth restoration was observed in E. coli-ΔilvA + pET32a-ilvA. E. coli-ΔilvA growth was also restored in the presence of isoleucine. The IlvA localization studies detected its distribution in cell wall and membrane fractions with relatively minor presence in cytosolic fraction. Maximum IlvA expression was observed at 72 h in wild-type (WT) Mtb-Ra infecting macrophages. Also, Mtb-Ra IlvA knockdown (KD) showed reduced survival in macrophages compared to WT and complemented strain (KDC).