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Antibiotic resistance, especially in multidrug-resistant ESKAPE pathogens, remains a worldwide problem. Combination antimicrobial therapies may be an important strategy to overcome resistance and broaden the spectrum of existing antibiotics. However, this strategy is limited by the ability to efficiently screen large combinatorial chemical spaces. Here, we deployed a high-throughput combinatorial screening platform, DropArray, to evaluate the interactions of over 30,000 compounds with up to 22 antibiotics and 6 strains of Gram-negative ESKAPE pathogens, totaling to over 1.3 million unique strain-antibiotic-compound combinations. In this dataset, compounds more frequently exhibited synergy with known antibiotics than single-agent activity. We identified a compound, P2-56, and developed a more potent analog, P2-56-3, which potentiated rifampin (RIF) activity against and . Using phenotypic assays, we showed P2-56-3 disrupts the outer membrane of . To identify pathways involved in the mechanism of synergy between P2-56-3 and RIF, we performed genetic screens in . CRISPRi-induced partial depletion of lipooligosaccharide transport genes ( - , ) resulted in hypersensitivity to P2-56-3/RIF treatment, demonstrating the genetic dependency of P2-56-3 activity and RIF sensitization on genes in Consistent with outer membrane homeostasis being an important determinant of P2-56-3/RIF tolerance, knockout of maintenance of lipid asymmetry complex genes and overexpression of certain resistance-nodulation-division efflux pumps - a phenotype associated with multidrug-resistance - resulted in hypersensitivity to P2-56-3. These findings demonstrate the immense scale of phenotypic antibiotic combination screens using DropArray and the potential for such approaches to discover new small molecule synergies against multidrug-resistant ESKAPE strains.

Aug. 22--About 100 cows owned by the family of former U.S. Sen. Bob Graham roam on grassy fields in Miami Lakes, grazing and mooing and evoking the town's dairy farm past. The dairy left Miami Lakes 25 years ago. The Graham Companies continue to graze heifers in town and in unincorporated areas -- about 100 miles from the dairy's main herd -- for the tax break. No one is complaining. This is a town that loves cows, celebrating them in the official seal, in roads named Cow Pen and New Barn, and in a cultural arts program called, simply, \"We Love Cows.\" Several artists have been commissioned to paint life-size fiberglass cows for public display.

Florida gave up as much as $745 million in tax revenue last year on agricultural tax breaks, Broward and Miami-Dade counties about $60 million between them. Yet a state that depends on agriculture as its second-largest industry has lost roughly eight million acres of farmland since 1954, a drop of more than 40 percent. In Florida, landowners who pave over farmland don't have to pay back a dime. Back-tax proposals have been quashed by developers, one of the most powerful special interests in state government, and the farm lobby, which fears that any tweaking of the greenbelt law could undermine it altogether. -- Make landowners promise not to build for a certain number of years. California's law, considered a model, requires landowners to sign 10-year commitments; even more generous tax relief is awarded to those who make 20-year commitments. Violators must pay up to 25 percent of the land's market value -- $250,000 on a lot worth $1 million. Maryland collects a tax when agricultural land is sold, waived only if the new owner promises to keep farming for the next five years.

Background Human tear protein biomarkers are useful for detecting ocular and systemic diseases. Unfortunately, existing tear film sampling methods (Schirmer strip; SS and microcapillary tube; MCT) have significant drawbacks, such as pain, risk of injury, sampling difficulty, and proteomic disparities between methods. Here, we present an alternative tear protein sampling method using soft contact lenses (SCLs). Results We optimized the SCL protein sampling in vitro and performed in vivo studies in 6 subjects. Using Etafilcon A SCLs and 4M guanidine-HCl for protein removal, we sampled an average of 60 ± 31 µg of protein per eye. We also performed objective and subjective assessments of all sampling methods. Signs of irritation post-sampling were observed with SS but not with MCT and SCLs. Proteomic analysis by mass spectrometry (MS) revealed that all sampling methods resulted in the detection of abundant tear proteins. However, smaller subsets of unique and shared proteins were identified, particularly for SS and MCT. Additionally, there was no significant intrasubject variation between MCT and SCL sampling. Conclusions These experiments demonstrate that SCLs are an accessible tear-sampling method with the potential to surpass current methods in sampling basal tears. Graphical Abstract

Many patients with ER+ HER2− primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2–4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2− breast cancer during and in the aftermath of the COVID-19 crisis.

Abstract Background: Hip arthroscopy is a rapidly expanding practice in orthopaedic surgery that is most used to treat femoroacetabular impingement syndrome (FAIS) with associated labral tears. Studies of knee arthroscopy and total knee arthroplasty demonstrate the effectiveness of neuraxial anesthesia with an additional advantage of decreased postoperative pain scores. The first direct comparison of neuraxial and general anesthesia for hip arthroscopy studied the immediate postoperative period and identified improved pain control without major adverse effects in the neuraxial anesthesia group. Objective: To compare the short-term (3-months to 3 years) clinical and patient reported outcomes in patients who received neuraxial anesthesia versus general anesthesia for hip arthroscopy to treat FAIS. Methods: Patients undergoing isolated hip arthroscopy to address FAIS from October 2017 to July 2020 with available two year postoperative patient reported outcome data were retrospectively reviewed. Patient reported outcomes were obtained from an IRB approved hip preservation registry. Primary outcomes included surgical complications, revision surgery, and postoperative patient reported outcomes including the International Hip Outcome Tool-12 (iHOT-12), Modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADL) and Sport Specific (HOS-SS) subset scores. Demographics and outcome variables were analyzed using t tests or fixed effects modeling where appropriate. Data are currently being collected for hip arthroscopies performed through March 2022. Results: 58 patients met inclusion criteria consisting of 40 females (69%) and 18 males (31%). 34 patients (59%) had neuraxial anesthesia and 24 patients (41%) underwent general anesthesia. Almost all reported complications were perineal (n=4) or lateral femoral cutaneous nerve (n=7) paresthesias. 4 patients underwent revision hip arthroscopy, 2 underwent subsequent periacetabular osteotomy, and 2 converted to total hip arthroplasty. Anesthesia type had no effect on whether a complication was reported (P=0.938) or a subsequent ipsilateral hip surgery was performed (P=0.688). Patient reported outcome scores increased for all scales over the postoperative period for both anesthesia groups without a significant difference between them at any postoperative interval (P > 0.161). Conclusions: Patients undergoing neuraxial anesthesia for hip arthroscopy to treat FAIS have similar postoperative clinical and patient reported outcomes to those who undergo general anesthesia for the procedure.

A 42-year-old male patient presented with intermittent abdominal pain and gastrointestinal discomfort present for 4 years. Work-up included ultrasound and computed tomography, which identified a fat-containing splenic mass 5.6 cm in size. Due to recurrent symptoms, the patient sought medical care again. Subsequent images showed an increase in size to 7.6 cm, which was concerning for neoplasm. This was removed via open splenectomy, which was challenging due to intra-abdominal adhesions despite never having had any abdominal surgery. The patient’s recovery was uncomplicated. Pathologic assessment indicated that the mass was a myelolipoma. Extra-adrenal myelolipomas are rare and typically found within the retroperitoneum but are extremely rare within the spleen. This case report adds the 6th such case to the literature and demonstrates the need for it to remain in the differential diagnosis of patients with fatty splenic masses, as well as that splenectomy is an appropriate treatment.

Single-cell proteomics (SCP) is uniquely suited for cell-type characterization, trajectory-based inference, and microenvironment mapping. Evaluating biological hypotheses in these experiments requires labeled cells. Without a pre-measurement label, machine learning is used to identify features that characterize the cell types and classify unlabeled samples. Current implementations of annotation methods come with several statistical and computational disadvantages. First, machine-learning methods require complete data, leading to large amounts of missing-value imputation in SCP. Additionally, some machine-learning methods select features and classify samples via cross-sample comparisons, nullifying downstream cross-sample comparisons, like differential expression, through double dipping. Finally, measurements from different proteomic experiments are not directly comparable due to batch effects, significantly limiting the accuracy of classifiers trained on external data. Here we present NIFty, a top-scoring pairs based feature selection method, implemented in a full classification pipeline, that does not require pre-imputed data as input or employ circular analysis techniques, and overcomes batch effects without batch correction. When tested on imputed vs unimputed data, data with large batch effects, and multiclass data, NIFty successfully overcame the targeted classification challenges and comparably, or more accurately, classified the samples in the varied datasets.

We present a summary of gravitational-wave (GW) follow-up using the Las Cumbres Observatory global network of telescopes during the third (O3) and fourth (O4) observing runs of the GW detectors. As in O2, we implemented the Gehrels et al. 2016 galaxy-targeted strategy. Here we test its efficacy in O3 and O4 and analyze the Las Cumbres Observatory response time and depth for nine GW alerts that showed a possibility of having an electromagnetic counterpart (GW190425, GW190426_152155, S190510g, GW190728_064510, GW190814, S190822c, GW191216_213338, S240422ed and S250206dm). We find that Las Cumbres Observatory is able to begin observations in response to GW alerts within minutes of the alert, with the observations being deep enough to detect possible GW170817-like kilonovae out to a median distance of 250 Mpc. In this sense a global rapid-response network of telescopes like Las Cumbres is an excellent GW follow-up facility. However, the galaxy-targeted follow-up strategy was much less efficient in O3 and O4 than originally predicted, given the larger than assumed GW localizations. We conclude that coordination between various facilities to include both wide-field and rapid-response capabilities is required to achieve efficient and comprehensive follow-up of GW events.