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.

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.

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.

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.

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.

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.

Publication Fate of Abstracts Presented at Four British Surgical Meetings: An 11-Year Follow-Up.

BACKGROUND: The gold standard for research is publication within a peer-reviewed journal. There is a discrepancy between the number of abstracts presented at scientific meetings and the number published as full articles. We identified publication rates for the 2012 meetings of four British surgical societies. These were the Association of Surgeons of Great Britain & Ireland (ASGBI), the Vascular Society of Great Britain and Ireland, the British Transplantation Society (BTS), and the Association of Coloproctology of Great Britain and Ireland (ACPGBI). We also compared publication rates with these societies' 2001 meetings and identified univariate factors associated with publication. MATERIALS AND METHODS: PubMed was searched to identify publications stemming from meeting abstracts. We extracted abstract characteristics to identify factors associated with publication and also characteristics of subsequent publications to enable comparison. RESULTS: Publication rates were 24.1% (ASGBI), 24.6% (BTS), 21.7% (ACPGBI), and 39.4% (Vascular Society of Great Britain and Ireland). Rates for ASGBI, BTS, and ACPGBI meetings were significantly lower compared to 2001 meetings (P = 0.001-0.026). Mean time to publication was 12.1-22.0 mo. Mean 5-y impact factor differed significantly between meetings (P = 0.001), with the BTS meeting having the highest mean 5-y impact factor (4.658). Factors associated with publication included being an oral presentation (ASGBI P = 0.001), multi-institution study (ASGBI P = 0.003), or randomized-controlled trial (BTS P = 0.049). CONCLUSIONS: Reduced publication rates may represent increased acceptance of low-quality abstracts at meetings or a more competitive journal submission process. Further data are required to strengthen conclusions. Nonetheless, authors and meeting organizers should push for higher quality abstracts to promote future peer-reviewed journal publication.

Pre-designed consent forms for total hip replacement, total knee replacement, and caesarean section: A national observational study of current English practice.

BACKGROUND: Pre-designed procedure-specific consent forms (PCFs) have potential advantages over handwritten forms for improving the consent process and disclosing material risks, as necessitated by the 2015 'Montgomery' ruling. We aimed to assess the use and quality of English NHS Trust PCFs for total hip replacement (THR), total knee replacement (TKR), and caesarean section (CS). METHODS: All 233 English NHS Trusts were sent a Freedom of Information request seeking PCFs for these operations. Listed risks, and whether their incidence was quoted, were compared against those listed in published PCFs from the British Orthopaedic Association (BOA) and the Royal College of Obstetricians and Gynaecologists (RCOG). RESULTS: 203/233 (87.1%) Trusts responded, contributing 17 THR PCFs, 15 TKR PCFs, and 33 CS PCFs. Overall, the type of risks listed for each operation was highly variable. 5.9% of THR PCFs contained all 18 BOA-quoted risks. No TKR PCF contained all 19 BOA-quoted risks. 24.2% of CS PCFs contained all 17 RCOG-quoted risks. For each operation, few PCFs listed incidences for quoted-risks. CONCLUSIONS: Very few Trusts use PCFs for these common operations. When PCFs are used, the reporting of risks and their likelihood is variable and insufficient. BOA- and RCOG-approved PCFs are high quality and influential on Trust-PCF design but still omit important risks. We fear PCFs analysed here do not sufficiently improve the consent process compared to handwritten forms. PCFs have potential to improve the quality of consent, however they need greater uptake and to be of greater quality.

Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk.

PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.

Emergence of promising novel DPP-4 inhibitory heterocycles as anti-diabetic agents: A review.

Diabetes has turned out to be an epidemic in the recent years all over the world, and today it has become a burden on the healthcare system. Over the years, with technological advancements, different classes of antidiabetic medications have emerged, like sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, but these are often loaded with serious aftermaths like hypoglycemia, weight gain, cardiovascular and renal issues. Dipeptidyl peptidase-4 (DPP-4) inhibition is an exciting and new approach in the treatment of type-2 diabetes. DPP-4 inhibitors or "gliptins" are weight neutral, pose lesser risk of hypoglycemia, and provide a long-term post-meal glycemic control. In this review, an attempt has been made to investigate novel potential compounds that can be added to the existing list of anti-diabetic drugs.

Evaluation of bioactive compounds and antioxidant potential of hydroethanolic extract of Moringa oleifera Lam. from Rajasthan, India.

Moringa oleifera Lam., the miracle tree, is widely used as a traditional medicine. The analyses of phytochemicals and antioxidant potential of hydroethanolic extract of various plant parts of M. oleifera revealed that leaves possessed the highest content of total phenolics (9.58 mg/g), ß-carotene (14.10 mg/g) and lycopene (2.60 mg/g). Flowers and bark showed the highest content of total flavonoids (3.5 mg/g) and anthocyanin (52.80 mg/g), respectively. Leaves also showed maximum antioxidant potential using nitric oxide scavenging assay (IC50 - 120 µg/ml) and deoxyribose degradation assay (IC50-178 µg/ml). Highest DPPH radical scavenging activity was observed in flowers (IC50-405 µg/ml). The GC-MS study revealed the presence of 29, 36 and 24 compounds in bark, leaf and flower, respectively. The major constituent identified were epiglobulol (41.68% in bark), phytol (23.54% in leaf) and ß-sitosterol (15.35% in flower).The phytochemicals identified possess several therapeutic activity, including antioxidant potential, which was confirmed through earlier reports. Moreover, the presence of 1,1,3-triethoxubutane in all the plant parts analyzed, projects it as an important source of waste water treatment as hydrophobic modifiers.

Strain-driven mound formation of substrate under epitaxial nanoparticles.

We observe the growth of crystalline SiC nanoparticles on Si(001) at 900 °C using in situ electron microscopy. Following nucleation and growth of the SiC, there is a massive migration of Si, forming a crystalline Si mound underneath each nanoparticle that lifts it 4-5 nm above the initial growth surface. The volume of the Si mounds is roughly five to seven times the volume of the SiC nanoparticles. We propose that relaxation of strain drives the mound formation. This new mechanism for relieving interfacial strain, which involves a dramatic restructuring of the substrate, is in striking contrast to the familiar scenario in which only the deposited material restructures to relieve strain.

A Quality Improvement Study to Identify Deterrents and Improve Voice Patient Compliance with Follow-Up.

OBJECTIVE: Evaluation and treatment for voice disorders may optimally involve multiple treatment modalities. However, even in multispecialty clinics, patients may be less likely to comply with follow-up compared to patients seen for other otolaryngologic complaints. We investigated the factors contributing to noncompliance and then implemented quality improvement metrics aimed at improving our clinical noncompliance rates. METHODS: Noncompliant patients were identified as those who had been seen in our multispecialty voice care clinic and instructed to follow-up but had not returned within 6months. Patients were telephoned for a brief survey. Surveys were completed in two rounds, pre- and post-quality improvement efforts. RESULTS: On the initial round of surveys, the most frequently cited reason for discontinuing care was financial (38.5%), some (30.8%) did not like the clinic location, and some felt follow-up would not be helpful (46.2%). The clinic location was subsequently moved outside of the downtown metropolitan area, and multidisciplinary care team approaches were implemented within this same, larger office space. A second round of surveys was then administered, wherein significantly fewer patients endorsed financial concerns as a reason for care discontinuation of care (Chi2 =8.689, P = 0.003). While fewer patients (22.6%) disliked the clinic location, this difference was not significant. A significantly greater number of patients endorsed feeling better as their reason for not following up (Chi2 =5.551, P = 0.018). CONCLUSIONS: This study reports quality improvement efforts aimed at identifying and addressing factors that contribute to voice care noncompliance. Ease of clinic access and affordability appear to be substantial factors. Optimizing clinic location, emphasizing the importance of continuity of care, and offering comprehensive approaches may improve patient adherence to voice care recommendations. LEVEL OF EVIDENCE: 2b.

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.

Natural wax recovery from Musa acuminata biomass using organic solvents.

The main aim of this study is to experimentally investigate the yield of extraction and the presence of wax in the extracted yield from Musaacuminata (banana) biomass based on various functional groups that are present in natural wax. Extraction of natural wax from Musaacuminata (banana) biomass has been done by using the Soxhlet apparatus method in the presence of both polar (ethyl acetate and ethanol) and non-polar (toluene and hexane) solvents. The extracted yield has been found as 3.58% from hexane, 5.16% from toluene, 7.03% from ethyl acetate, and 10.26% from ethanol. The wax was also found in the extracted yield only in the case of nonpolar solvents (toluene and hexane). The novelty of this work is that Musaacuminata (banana) waste biomass has been utilized to recover the natural wax using nonpolar solvents and also compared with that of polar solvents to check the scope of wax extraction using polar solvents. Also, statistical analysis has been performed of the extracted yield using both solvents. Thin Layer Chromatography (TLC) and Fourier Transform Infrared Spectroscopy (FTIR) methods have been used to determine the various hydrocarbon chains present in the extracted yield which is similar to that of natural wax.

Transformations in prefrontal ensemble activity underlying rapid threat avoidance learning.

The capacity to learn cues that predict aversive outcomes, and understand how to avoid those outcomes, is critical for adaptive behavior. Naturalistic avoidance often means accessing a safe location, but whether a location is safe depends on the nature of the impending threat. These relationships must be rapidly learned if animals are to survive. The prelimbic subregion (PL) of the medial prefrontal cortex (mPFC) integrates learned associations to influence these threat avoidance strategies. Prior work has focused on the role of PL activity in avoidance behaviors that are fully established, leaving the prefrontal mechanisms that drive rapid avoidance learning poorly understood. To determine when and how these learning-related changes emerge, we recorded PL neural activity using miniscope calcium imaging as mice rapidly learned to avoid a threatening cue by accessing a safe location. Over the course of learning, we observed enhanced modulation of PL activity representing intersections of a threatening cue with safe or risky locations and movements between them. We observed rapid changes in PL population dynamics that preceded changes observable in the encoding of individual neurons. Successful avoidance could be predicted from cue-related population dynamics during early learning. Population dynamics during specific epochs of the conditioned tone period correlated with the modeled learning rates of individual animals. In contrast, changes in single-neuron encoding occurred later, once an avoidance strategy had stabilized. Together, our findings reveal the sequence of PL changes that characterize rapid threat avoidance learning.