Aromatase inhibitor-induced arthralgia ameliorated by Mediterranean diet and active lifestyle guided by continuous glucose monitoring: a case report and review of the literature.

Aromatase inhibitors (AIs) are a cornerstone adjuvant treatment of many hormone receptor-positive breast cancers, and nearly half of women taking aromatase inhibitors suffer from AI-induced arthralgia (AIA), also known as AI-associated musculoskeletal syndrome (AIMSS), for which there are limited evidence-based treatments. Pharmacologic management and complementary methods including supplements, exercise, physical therapy, yoga, acupuncture, and massage have all shown mixed results. Comprehensive diet and lifestyle strategies are understudied in AIA/AIMSS despite their disease-modifying effects across many chronic conditions. Here we report a case of a woman with stage 2 estrogen and progesterone receptor-positive invasive ductal carcinoma on adjuvant anastrozole whose AI-induced arthralgia was durably controlled through a Mediterranean plant-forward diet and daily physical activity guided by continuous glucose monitoring. We posit that diet and a lifestyle inclusive of daily physical activity constitute a low-cost, low-risk, and potentially high-reward strategy for controlling common AI-induced musculoskeletal symptoms and that more investigation in this arena, including well-designed randomized trials, is warranted.

Treatment of diabetic complications: do flavonoids holds the keys?

Diabetes mellitus (DM) is an endocrinological disorder in which blood sugar levels get elevated and if unmanaged, it leads to several critical complications. Existing therapies or drugs are not able to attain absolute control of DM. Moreover, associated side/adverse effects associated with pharmacotherapy further worsen the Quality of life of patients. Present review is focused on therapeutical potential of flavonoids in management of diabetes and diabetic complications. Plenteous literature has established significant potential of flavonoids in the treatment of diabetes and diabetic complications. A number of flavonoids are found to be effective in treatment of not only diabetes but progression of diabetic complication was also found to be attenuated with the use of flavonoids. Moreover, SAR studies of some flavonoids also indicated the that efficacy of flavonoids is increased with a change in functional group of flavonoids in the treatment of diabetes and diabetic complications. A number of clinical trials are into action to investigate the therapeutic potential of flavonoids as first-line drugs or as adjuvants for treatment of diabetes and diabetic complications.. Owing to their diverse mechanism of action, efficacy and safety, flavonoids may be conscripted as potential candidate for treatment of diabetic complications.

Motivated to time: Effects of reinforcer devaluation and opportunity cost on interval timing.

Prior research suggests that interval timing performance is sensitive to reinforcer devaluation effects and to the rate of competing sources of reinforcement. The present study sought to replicate and account for these findings in rats. A self-paced concurrent fixed-interval (FI) random-ratio (RR) schedule of reinforcement was implemented in which the FI requirement varied across training conditions (12, 24, 48 s). The RR requirement-which imposed an opportunity cost to responding on the FI component-was adjusted so that it took about twice the FI requirement, on average, to complete it. Probe reinforcer devaluation (prefeeding) sessions were conducted at the end of each condition. To assess the effect of contextual reinforcement on timing performance, the RR requirement was removed before the end of the experiment. Consistent with prior findings, performance on the FI component tracked schedule requirement and displayed scalar invariance; the removal of the RR component yielded more premature FI responses. For some rats, prefeeding reduced the number of trials initiated without affecting timing performance; for other rats, prefeeding delayed responding on the FI component but had a weaker effect on trial initiation. These results support the notion that timing and motivational processes are separable, suggesting novel explanations for ostensible motivational effects on timing performance.

Histidinal-Based Potent Antimalarial Agents.

Herein we report the synthesis and evaluation of peptide-histidinal conjugated drug scaffolds, which have the potential to target the hemoglobin-degrading proteases falcipain-2/3 from the human malaria parasite. Scaffolds with various substitutions were tested for antimalarial activity, and compounds 8 g, 8 h, and 15 exhibited EC50 values of ∼0.018 µM, ∼0.069 µM, and ∼0.02 µM, respectively. Structure-based docking studies on falcipain-2/3 proteases (PDB:2GHU and PDB:3BWK) revealed that compounds 8 g, 8 h, and 15 interact strongly with binding sites of falcipain-2/3 in a substrate-like manner. In silico ADME studies revealed that the molecules of interest showed no or minimal violations of drug-likeness parameters. Further, phenotypic assays revealed that compound 8 g and its biotinylated version inhibit hemoglobin degradation in the parasite food vacuole. The identification of falcipain-2/3 targeting potent inhibitors of the malaria parasite can serve as a starting point for the development of lead compounds as future antimalarial drug candidates.

Emerging strategies: PARP inhibitors in combination with immune checkpoint blockade in BRCA1 and BRCA2 mutation-associated and triple-negative breast cancer.

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor monotherapy in germline BRCA1 and BRCA2 mutation-associated metastatic breast cancer is a well-tolerated and an effective therapeutic strategy, however, the durability of response can be limited. Checkpoint inhibitors targeting the PD-1/PD-L1 axis as monotherapy in metastatic triple-negative breast cancer (mTNBC) have a limited role due to low response rates, but are capable of long, durable responses. Combination PARP inhibition with checkpoint blockade is an emerging area of investigation with potential synergy to produce robust responses with durability. Mechanistically, PARP inhibition activates the stimulator of interferon gene (STING) pathway to promote dendritic cell and T lymphocyte recruitment, increases tumor neoantigens, and upregulates PD-L1 expression to increase the immunogenicity of the tumor and thereby potentially enhance responses to immunotherapy. Several clinical trials have reported early results on PARP inhibitor and PD-1/PD-L1 checkpoint inhibitor combinations. All studies have shown safety and tolerability of this combination regimen. In advanced breast cancer associated with a germline BRCA1 or BRCA2 mutation, response rates have been high and similar to what is observed with PARP inhibitor monotherapy. Additional follow-up is needed to see if combination with a checkpoint inhibitor can lead to a clinically meaningful extension of durability of response in patients with germline mutations in BRCA1 and BRCA2. In unselected mTNBC in the 1st-3rd line setting, response rates of combined PARP inhibitor and PD-1/PD-L1 inhibitors have ranged from 18-21%, with higher rates of response among those with alterations in homologous recombination DNA repair pathway genes. Multiple ongoing studies will report additional data on combinations of PARP inhibitors and checkpoint blockade in the future and this combination strategy remains an active area of investigation.

Assessing complex odor discrimination in mice using a novel instrumental patterning task.

Negative patterning tasks are a key tool to unveil the mechanisms by which stimulus representations are acquired-a central concern in Robert Rescorla's research. In these tasks, target stimuli are reinforced when presented individually (A+/B+) but not when presented in compound (AB-). The discrimination of single stimuli from their compound presentation is a challenge for theories of associative learning, because it cannot be explained by the simple accrual of associative strength. The present study examined the conditions under which mice learn this part-whole discrimination in olfactory stimuli using a novel instrumental methodology. In two experiments, reinforcement was contingent on distinct responses depending on whether a set of odor mixtures were presented in isolation or as a compound. Using C57BL/6 mice, Experiment 1 showed a mutual interference between learning a response to individual odors and learning a different response to those odors presented in compound. Using wild-type APP/PS1 mice (a control strain for a murine model of Alzheimer's disease), Experiment 2 replicated this interference and showed that it is stimulus-specific. These experiments show that the instrumental patterning task may not only complement Pavlovian negative patterning tasks but may also motivate its own questions on the representation of complex stimuli. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Incident comorbidities after tamoxifen or aromatase inhibitor therapy in a racially and ethnically diverse cohort of women with breast cancer.

PURPOSE: As survival with early-stage, hormone receptor (HR)-positive breast has improved, it is essential to understand the long-term risks of incident comorbidities with different adjuvant endocrine therapy (ET) options. METHODS: Women treated with tamoxifen and/or an aromatase inhibitor (AI) for stages 1-3, HR-positive/HER2-negative breast cancer from 2000 to 2016 in either of two healthcare systems in the San Francisco Bay Area were included. We considered the following comorbidities: cerebrovascular accidents, congestive heart failure, dementia, depression/anxiety, diabetes mellitus, hyperlipidemia, myocardial infarction, non-alcoholic steatohepatitis, osteoporosis/fracture, peripheral vascular disease, and venous thromboembolism. Cause-specific Cox proportional hazards models were fit to time-to-new-diagnosis for each comorbidity, accounting for death as a competing risk. Hazard ratios (HR) and 95% confidence intervals (CI) for tamoxifen versus AI were reported. RESULTS: Among 2,902 analyzed patients, the median age at diagnosis was 58.3 years; 67.6% were non-Hispanic white, 22.3% Asian, 7.5% Hispanic, and 1.7% non-Hispanic Black. Half (54.7%) used AIs only, 27.6% used tamoxifen only and 17.7% used both tamoxifen and AIs sequentially. Tamoxifen was associated with a lower risk of osteoporosis than AI (multivariable HR 0.45, 95% CI 0.32-0.62). No other incident comorbidity risk varied between users of tamoxifen versus AIs. CONCLUSION: In a diverse, multi-institutional, contemporary breast cancer cohort, the only incident comorbidity that differed between ET options was osteoporosis, a known side effect of AIs. These results may inform clinical decision-making about ET, and reassure patients who have bothersome symptoms on AIs that they are unlikely to develop worse comorbidities if they switch to tamoxifen.

A Prospective Study to Determine if Management of Cases of Gestational Diabetes Mellitus (GDM) can be Modified.

Background: To study maternal-fetal outcomes in patients of GDM diagnosed by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria but subsequently using a twenty-four-hour seven-value sugar profile to evaluate patients before instituting management. Methods: This prospective observational study was conducted at a tertiary hospital in New Delhi, India, over a period of one year. During this period, women diagnosed as GDM between 24 and 28 weeks of gestation using IADPSG criteria underwent seven-value sugar profile in twenty-four hours before initiating any therapy. Those with normal profile were kept on observation only, whereas others were managed by Medical Nutrition Therapy (MNT) with or without pharmacotherapy as required to maintain euglycemia. Maternal and fetal outcomes were documented and analysed to detect differences between the groups. Results: Out of 2279 pregnant women, 201 (8.8%) were diagnosed as GDM. The twenty-four-hour seven-value sugar profile was normal in 78 (38.8%) patients, who were managed only by close observation. Treatment was given to other patients; 93 (46.2%) patients were managed with MNT only, whereas pharmacotherapy by way of metformin was added to 22 (10.9%) patients and 8 (3.9%) patients required insulin. Differences in maternal-fetal outcomes between the treated and untreated groups were not found to be statistically significant. Conclusions: The policy of evaluating patients with twenty-four-hour seven-value sugar profile after an abnormal Oral Glucose Tolerance Test eliminated over one-third women from receiving treatment and interventions for GDM without compromising maternal-fetal outcomes.

Neoadjuvant Therapy in Breast Cancer: Histologic Changes and Clinical Implications.

Cytotoxic or endocrine therapy before surgery (neoadjuvant) for breast cancer has become standard of care, affording the opportunity to assess and quantify response in the subsequent resection specimen. Correlation with radiology, cassette mapping, and histologic review with a semi-quantitative reporting system such as residual cancer burden (RCB) provides important prognostic data that may guide further therapy. The tumor bed should be identified histologically, often as a collagenized zone devoid of normal breast epithelium, with increased vasculature. Identification of residual treated carcinoma may require careful high power examination, as residual tumor cells may be small and dyscohesive; features are widely variable and include hyperchromatic small, large, or multiple nuclei with clear, foamy, or eosinophilic cytoplasm. Calculation of RCB requires residual carcinoma span in 2 dimensions, estimated carcinoma cellularity (% area), number of involved lymph nodes, and span of largest nodal carcinoma. These RCB parameters may differ from AJCC staging measurements, which depend on only contiguous carcinoma in breast and lymph nodes.

A Comprehensive Review on Current Perspectives of Flavonoids as Antimicrobial Agent.

Flavonoids are the secondary plant metabolites with diversities of pharmacological activities like antioxidant, anticancer, anti-inflammatory, hepatoprotective, free radical scavenging activity and antiviral activities. Flavonoids have also been proved as a major contributor to an antimicrobial phytochemical. Being the major substituent of antibiotics, today flavonoids have attained great attention as there is an increase in the persistence of untreatable microbial infections due to microbial resistance. This review demonstrates the screening, isolation of extracts and derivatization of various flavonoids and their evaluation for antimicrobial potency. Recent advancements of various derivatives of flavonoids having antimicrobial activity have also been discussed in this review. This review helps researchers to get vast knowledge about flavonoids and also gives an idea for the current scenario of flavonoids and their applications as an antimicrobial agent.

A systematic review of outcomes of remote consultation in ENT.

AIMS: Remote or tele-consultation has become an emerging modality of consultation in many specialities, including ENT. Advantages include increasing accessibility, potential to reduce costs and, during the COVID-19 pandemic, reduced risk of infection transmission. Here, we systematically collate and synthesise the evidence base on outcomes from remote consultation in adult and paediatric ENT services. METHODS: We performed a review in accordance with PRISMA guidelines. We searched Medline and Embase for relevant articles. Outcomes include specific patient pathway efficiency measures (including number of healthcare visits, lead time, touch time and handoff), patient/clinician satisfaction, cost analysis and safety implications. RESULTS: From 6325 articles screened, 53 met inclusion criteria. Publications included studies on remote consultation for initial, preoperative and follow-up assessment (including postoperative). In most instances, remote consultation reduced costs and time from referral to assessment and was associated with high patient satisfaction. However, a face-to-face follow-up appointment was required in 13%-72% of initial consultations, suggesting that remote consultation is only appropriate in selected cases. CONCLUSION: Remote consultation is appropriate and preferable for ENT consultation in specific conditions and circumstances. Future research should look to better define those conditions and circumstances, and report using recognised quality standards and outcome measures.

Teaching Cheminformatics through a Collaborative Intercollegiate Online Chemistry Course (OLCC).

While cheminformatics skills necessary for dealing with an ever-increasing amount of chemical information are considered important for students pursuing STEM careers in the age of big data, many schools do not offer a cheminformatics course or alternative training opportunities. This paper presents the Cheminformatics Online Chemistry Course (OLCC), which is organized and run by the Committee on Computers in Chemical Education (CCCE) of the American Chemical Society (ACS)'s Division of Chemical Education (CHED). The Cheminformatics OLCC is a highly collaborative teaching project involving instructors at multiple schools who teamed up with external chemical information experts recruited across sectors, including government and industry. From 2015 to 2019, three Cheminformatics OLCCs were offered. In each program, the instructors at participating schools would meet face-to-face with the students of a class, while external content experts engaged through online discussions across campuses with both the instructors and students. All the material created in the course has been made available at the open education repositories of LibreTexts and CCCE Web sites for other institutions to adapt to their future needs.

Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition.

Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.

On the Appropriate Measure to Estimate Hyperbolic Discounting Rate (K) using the Method of Least Squares.

The estimation of the rate at which value declines with delay requires identifying the correct discounting model, applying the appropriate parameter estimation method, and choosing the dependent measure from which parameters are estimated. The simplest adequate discounting model is the hyperbolic model; the simplest method to estimate its sole free parameter, K, is the method of least squares. Estimates of K based on relative subjective values (RSV), although typical, are not necessarily more reliable than those obtained through other measures. We consider an alternative measure termed immediacy premium (IP): the ratio of value lost over value preserved due to outcome delay. According to hyperbolic discounting, IP is a linear function of delay. As a result, estimates of K obtained from IP circumvent the divergence between individual and aggregate estimates obtained with the RSV method. Moreover, published data suggests that estimates of K based on RSV and IP differ systematically in humans and in pigeons. Regardless of the dependent measure adopted, estimates of K obtained from nonhuman animals, but not from humans, yield residuals that conform with error-distribution assumptions of the method of least squares. Although residuals obtained using the IP method in human data diverged more from normality than those obtained using the RSV method, the sequential dependence over delays of the former was weaker than that of the latter. We therefore recommend adopting both RSV and IP when estimating hyperbolic K using the method of least squares, resorting to more elaborate estimation methods when inferences drawn from these estimates are inconsistent.

Two-dimensional transthoracic echocardiographic finding of left atrial compression resulting from blunt trauma to the thoracic spine.

We present an adult female in whom two-dimensional transthoracic echocardiography demonstrated encroachment of the thoracic spine on the left atrium (LA) resulting in a very small, compressed LA cavity by a prominent thoracic spine shadow. Computed tomography (CT) scan of the chest showed compression of the LA produced by localized anterior deformation of the thoracic spine which had resulted from blunt injury to her spine following a fall from a swing several years previously.

Laparoscopic Inguinal Hernia Repair: Transabdominal Preperitoneal or Totally Extraperitoneal? Results of a 14-year Prospective Study.

Background: Laparoscopic inguinal hernia repairs are most commonly either transabdominal preperitoneal (TAPP) or totally extraperitoneal (TEP) operations. The indications and comparative outcome data for both approaches are often conflicting and thus we sought to compare the two. Methods: 678 consecutive laparoscopic inguinal hernia repairs (190 TAPP and 488 TEP) were prospectively recorded onto a database from June 2004-December 2018. Age, gender, hernia characteristics, operative times, complication and 12-month recurrence rate data were compared. Results: 49.5% of TAPP repairs were recurrent hernias, and 95.5% of TEP repairs were bilateral hernias. TAPP patients were significantly older than TEP patients (60.65 versus 55.60, p 0.01). Unilateral TAPP repairs had a significantly shorter operative time than unilateral TEP repairs (50.94 versus 65.71 minutes, p=0.01). There was no significant difference in overall complication rate between TAPP and TEP repairs (6.84% versus 7.38%, p=0.87), and this was consistent across different hernia groups. TAPP repairs recurred at a significantly higher rate than TEP repairs (3.16% versus 0.61%, p=0.02) overall, but recurrence rates were not significantly different when broken down by hernia group. Conclusions: Applying the broad principle of utilizing the TAPP approach for recurrent hernias and the TEP approach for bilateral hernias, outcomes from both operations are similar.

Electron and X-ray Focused Beam-Induced Cross-Linking in Liquids: Toward Rapid Continuous 3D Nanoprinting and Interfacing using Soft Materials.

Multiphoton polymer cross-linking evolves as the core process behind high-resolution additive microfabrication with soft materials for implantable/wearable electronics, tissue engineering, microrobotics, biosensing, drug delivery, etc. Electrons and soft X-rays, in principle, can offer even higher resolution and printing rates. However, these powerful lithographic tools are difficult to apply to vacuum incompatible liquid precursor solutions used in continuous additive fabrication. In this work, using biocompatible hydrogel as a model soft material, we demonstrate high-resolution in-liquid polymer cross-linking using scanning electron and X-ray microscopes. The approach augments the existing solid-state electron/X-ray lithography and beam-induced deposition techniques with a wider class of possible chemical reactions, precursors, and functionalities. We discuss the focused beam cross-linking mechanism, the factors affecting the ultimate feature size, and layer-by-layer printing possibilities. The potential of this technology is demonstrated on a few practically important applications such as in-liquid encapsulation of nanoparticles for plasmonic sensing and interfacing of viable cells with hydrogel electrodes.

An unexpected diagnosis of paediatric subcutaneous sacrococcygeal extraspinal ependymoma: lessons learnt and review of the literature.

This case describes a 9-year-old male who presented to general surgical clinic with a 3-year history of persistent natal cleft swelling, previously unsuccessfully treated as a pilonidal abscess in the community with multiple courses of antibiotics. In clinic, a 50 × 30-mm soft tissue swelling was found in the natal cleft and a clinical diagnosis of a pilonidal cyst was made. A cream-coloured solid mass measuring 50 × 35 × 30 mm was subsequently excised under general anaesthetic, with specialist histology and immunostaining confirming an unexpected diagnosis of a subcutaneous extraspinal myxopapillary ependymoma, a tumour usually found in the neuraxis. Given the atypical anatomical site of the tumour, the case presented a unique management challenge. Ultimately, the patient underwent a re-operation after specialist multi-disciplinary discussion and is currently disease free at 18 months post-surgery. The authors wish to contribute their experiences of managing this rare extraspinal ependymoma to the few existing reports in the literature.

A computational formulation of the behavior systems account of the temporal organization of motivated behavior.

The behavior systems framework suggests that motivated behavior-e.g., seeking food and mates, avoiding predators-consists of sequences of actions organized within nested behavioral states. This framework has bridged behavioral ecology and experimental psychology, providing key insights into critical behavioral processes. In particular, the behavior systems framework entails a particular organization of behavior over time. The present paper examines whether such organization emerges from a generic Markov process, where the current behavioral state determines the probability distribution of subsequent behavioral states. This proposition is developed as a systematic examination of increasingly complex Markov models, seeking a computational formulation that balances adherence to the behavior systems approach, parsimony, and conformity to data. As a result of this exercise, a nonstationary partially hidden Markov model is selected as a computational formulation of the predatory subsystem. It is noted that the temporal distribution of discrete responses may further unveil the structure and parameters of the model but, without proper mathematical modeling, these discrete responses may be misleading. Opportunities for further elaboration of the proposed computational formulation are identified, including developments in its architecture, extensions to defensive and reproductive subsystems, and methodological refinements.