An Automated System to Distribute Students to Clerkships.

Participating in clerkships with general practitioners (GPs) is integral to studying medicine. The students gain deep and valuable insights into the everyday working practice of GPs. The central challenge is organizing these clerkships to distribute the students to the participating doctors' offices. This process becomes even more complex and time-consuming if students can state their preferences. To support faculty staff and involve students in the process, we developed an application to support the distribution process via an automated system and applied it to allocate over 700 students over the course of 2.5 years.

Chiropractic management of a U.S. Veteran with myofascial pain and concurrent distal bimelic amyotrophy (Hirayama disease): a case report.

Background: Distal bimelic amyotrophy (DBMA) also known as Hirayama disease, is a rare, self-limiting motor neuron disease manifesting as atrophy of C7-T1 innervated muscles. We present a case report describing the chiropractic management of neck and thoracic pain in a patient with known DBMA. Case presentation: A 30 year-old black male U.S. veteran with DBMA presented with myofascial pain of the neck, shoulder, and back. A trial of chiropractic care was undertaken involving spinal manipulation of the thoracic spine and cervicothoracic region, manual and instrument-assisted soft tissue mobilization, and home exercise prescription. The patient reported modest improvement in pain intensity and did not experience any adverse events. Summary: This case presents the first documentation of chiropractic services in musculoskeletal pain management of a patient with concurrent DBMA. At this time there is no guidance in the existing body of literature for the safety and effectiveness of manual therapy in this population.

Contexte: La myélopathie cervicale basse, également connue sous le nom de maladie d'Hirayama, est une maladie rare et spontanément résolutive du motoneurone qui se manifeste par une atrophie des muscles innervés C7-T1. Nous présentons un rapport de cas décrivant la prise en charge chiropratique de douleurs cervicales et thoraciques chez un patient atteint d'une maladie d'Hirayama connue. Présentation du cas: Un vétéran américain noir de 30 ans, atteint de myélopathie cervicale basse, s'est présenté avec des douleurs myofasciales au cou, aux épaules et au dos. Un essai de soins chiropratiques a été entrepris comprenant des manipulations vertébrales de la colonne thoracique et de la région cervicothoracique, des mobilisations manuelles et instrumentales des tissus mous, et la prescription d'exercices à domicile. Le patient a fait état d'une amélioration modeste de l'intensité de la douleur et n'a pas ressenti d'effets indésirables. Résumé: Ce cas présente la première documentation des services chiropratiques dans la gestion de la douleur musculo-squelettique d'un patient souffrant d'une myélopathie cervicale basse. À l'heure actuelle, il n'existe pas d'orientation dans la littérature existante sur la sécurité et l'efficacité de la thérapie manuelle dans cette population.

Integrated clinical opportunities for training offered through US doctor of chiropractic programs.

OBJECTIVE: The primary objective of this study was to assess, summarize, and compare the current integrated clinical learning opportunities offered for students who matriculated in US doctor of chiropractic programs (DCPs). METHODS: Two authors independently searched all accredited DCP handbooks and websites for clinical training opportunities within integrated settings. The 2 data sets were compared with any discrepancies resolved through discussion. We extracted data for preceptorships, clerkships, and/or rotations within the Department of Defense, Federally Qualified Health Centers, multi-/inter-/transdisciplinary clinics, private/public hospitals, and the Veterans Health Administration. Following data extraction, officials from each DCP were contacted with a request to verify the collected data. RESULTS: Of the 17 DCPs reviewed, all but 3 offered at least 1 integrated clinical experience, while 41 integrated clinical opportunities were the most offered by a single DCP. There was an average of 9.8 (median 4.0) opportunities per school and an average of 2.5 (median 2.0) clinical setting types. Over half (56%) of all integrated clinical opportunities were within the Veterans Health Administration, followed by multidisciplinary clinic sites (25%). CONCLUSION: This work presents preliminary descriptive information of the integrated clinical training opportunities available through DCPs.

Results of a phase Ib study of SB-121, an investigational probiotic formulation, a randomized controlled trial in participants with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by core impairments in social communication as well as restricted, repetitive patterns of behavior and/or interests. Individuals with ASD, which includes about 2% of the US population, have challenges with activities of daily living and suffer from comorbid medical and mental health concerns. There are no drugs indicated for the core impairments of ASD. As such, there is a significant need for the development of new medication strategies for individuals with ASD. This first-in-human placebo-controlled, double-blind, crossover study investigated the safety (primary objective) and efficacy of oral SB-121, a combination of L. reuteri, Sephadex® (dextran microparticles), and maltose administered once daily for 28 days in 15 autistic participants. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted. These results provide support for further clinical evaluation of SB-121 as a treatment in autistic patients. To evaluate the safety and tolerability of multiple doses of SB-121 in subjects with autism spectrum disorder. Single-center, randomized, placebo-controlled, double-blind, crossover trial. 15 patients with autism spectrum disorder were randomized and analyzed. Daily dosing of SB-121 or placebo for 28 days, followed by approximately a 14 day washout, then 28 days of dosing with other treatment. Incidence and severity of adverse events, presence of Limosilactobacillus reuteri and Sephadex® in stool, and incidence of bacteremia with positive L. reuteri identification. Additional outcomes include changes from baseline on cognitive and behavior tests as well as biomarker levels. Adverse event rates were similar between SB-121 and placebo, with most reported as mild. There were no severe or serious adverse events. No participants had features of suspected bacteremia or notable changes in vital signs, safety laboratory, or ECG parameters from baseline. There was a statistically significant increase from baseline in the Vineland-3 Adaptive Behavior Composite score (p = 0.03) during SB-121 treatment. There was a trend for increased social/geometric viewing ratio following SB-121 treatment compared to placebo. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted.Trial registration: clinicaltrials.gov Identifier: NCT04944901.

Clinician approaches to spinal manipulation for persistent spinal pain after lumbar surgery: systematic review and meta-analysis of individual patient data.

BACKGROUND: This review aimed to identify variables influencing clinicians' application of spinal manipulative therapy (SMT) for persistent spine pain after lumbar surgery (PSPS-2). We hypothesized markers of reduced clinical/surgical complexity would be associated with greater odds of applying SMT to the lumbar region, use of manual-thrust lumbar SMT, and SMT within 1-year post-surgery as primary outcomes; and chiropractors would have increased odds of using lumbar manual-thrust-SMT compared to other practitioners. METHODS: Per our published protocol, observational studies describing adults receiving SMT for PSPS-2 were included. PubMed, Web of Science, Scopus, OVID, PEDro, and Index to Chiropractic Literature were searched from inception to January 6, 2022. Individual patient data (IPD) were requested from contact authors when needed for selection criteria. Data extraction and a customized risk-of-bias rubric were completed in duplicate. Odds ratios (ORs) for primary outcomes were calculated using binary logistic regressions, with covariates including age, sex, symptom distribution, provider, motion segments, spinal implant, and surgery-to-SMT interval. RESULTS: 71 articles were included describing 103 patients (mean age 52 ± 15, 55% male). The most common surgeries were laminectomy (40%), fusion (34%), and discectomy (29%). Lumbar SMT was used in 85% of patients; and of these patients was non-manual-thrust in 59%, manual-thrust in 33%, and unclear in 8%. Clinicians were most often chiropractors (68%). SMT was used > 1-year post-surgery in 66% of cases. While no primary outcomes reached significance, non-reduced motion segments approached significance for predicting use of lumbar-manual-thrust SMT (OR 9.07 [0.97-84.64], P = 0.053). Chiropractors were significantly more likely to use lumbar-manual-thrust SMT (OR 32.26 [3.17-327.98], P = 0.003). A sensitivity analysis omitting high risk-of-bias cases (missing ≥ 25% IPD) revealed similar results. CONCLUSIONS: Clinicians using SMT for PSPS-2 most often apply non-manual-thrust SMT to the lumbar spine, while chiropractors are more likely to use lumbar-manual-thrust SMT relative to other providers. As non-manual-thrust SMT may be gentler, the proclivity towards this technique suggests providers are cautious when applying SMT after lumbar surgery. Unmeasured variables such as patient or clinician preferences, or limited sample size may have influenced our findings. Large observational studies and/or international surveys are needed for an improved understanding of SMT use for PSPS-2. Systematic review registration PROSPERO (CRD42021250039).

Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9orf72 disease.

Hexanucleotide G4C2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

Activity of Delafloxacin and Levofloxacin against Stenotrophomonas maltophilia at Simulated Plasma and Intrapulmonary pH Values.

Fluoroquinolones have become a popular treatment option for Stenotrophomonas maltophilia infections. Although levofloxacin is most commonly used, delafloxacin demonstrates comparable in vitro activity when evaluated under standard susceptibility testing conditions at neutral pH. At acidic pH, the activity of the anionic delafloxacin is improved, while the activity of the zwitterionic levofloxacin is reduced. Because the human respiratory tract has a pH of ~6.6 and is the most common site of S. maltophilia infection, it is vital to understand the activity of these agents in this environment. Therefore, levofloxacin and delafloxacin were tested against clinical S. maltophilia isolates via broth microdilution testing (n = 37) and time-kill analysis (n = 5) in neutral cation-adjusted Mueller-Hinton broth (CAMHB) (pH 7.3) and acidic CAMHB (aCAMHB) (pH 6.5). In CAMHB, MIC50 values were similar between levofloxacin and delafloxacin (8 mg/L versus 8 mg/L). In aCAMHB, levofloxacin MICs did not change, while delafloxacin MICs decreased by a median of 4 log2 dilutions (MIC50 values of 8 mg/L versus 0.25 mg/L). In time-kill analyses, levofloxacin and delafloxacin at the maximum drug concentration for the free drug (fCmax) were bactericidal against 3 and 2 isolates in CAMHB, respectively. In aCAMHB, levofloxacin was not bactericidal against any isolate, while delafloxacin was bactericidal against the same 2 isolates. Relative to CAMHB, levofloxacin activity was reduced by 2.5 log10 CFU/mL in aCAMHB, whereas delafloxacin activity was increased 2.7 log10 CFU/mL. Although the bactericidal activity of levofloxacin against S. maltophilia was attenuated in an acidic environment in this study, the increased potency of delafloxacin at pH 6.5 did not translate into improved bactericidal activity in time-kill analyses, compared to pH 7.3. IMPORTANCE Stenotrophomonas maltophilia most often infects the lungs, where the physiologic environment is naturally slightly acidic (pH ~6.6), compared to most parts of the body (such as the bloodstream), which have neutral pH values (~7.4). Pneumonia due to S. maltophilia is often treated with the antibiotic levofloxacin, despite the activity of levofloxacin being known to be impaired at acidic pH. Unfortunately, currently available methods for susceptibility testing of levofloxacin against S. maltophilia are performed at a neutral pH and therefore may not accurately represent the activity of levofloxacin at the site of infection in the lungs. A similar but newer antibiotic in the same class as levofloxacin, namely, delafloxacin, is not affected by being in an acidic environment and may actually work better at lower pH values. Therefore, the purpose of this study was to investigate whether one drug might be better than the other in this setting by testing each agent's ability to kill S. maltophilia at pH 7.3 and pH 6.5. These findings could then be used to design confirmatory studies that may ultimately impact which drug is given to patients with lung infections due to S. maltophilia.

Wheat Stem Rust Back in Europe: Diversity, Prevalence and Impact on Host Resistance.

The objective of this study was to investigate the re-emergence of a previously important crop pathogen in Europe, Puccinia graminis f.sp. tritici, causing wheat stem rust. The pathogen has been insignificant in Europe for more than 60 years, but since 2016 it has caused epidemics on both durum wheat and bread wheat in local areas in southern Europe, and additional outbreaks in Central- and West Europe. The prevalence of three distinct genotypes/races in many areas, Clade III-B (TTRTF), Clade IV-B (TKTTF) and Clade IV-F (TKKTF), suggested clonal reproduction and evolution by mutation within these. None of these genetic groups and races, which likely originated from exotic incursions, were detected in Europe prior to 2016. A fourth genetic group, Clade VIII, detected in Germany (2013), was observed in several years in Central- and East Europe. Tests of representative European wheat varieties with prevalent races revealed high level of susceptibility. In contrast, high diversity with respect to virulence and Simple Sequence Repeat (SSR) markers were detected in local populations on cereals and grasses in proximity to Berberis species in Spain and Sweden, indicating that the alternate host may return as functional component of the epidemiology of wheat stem rust in Europe. A geographically distant population from Omsk and Novosibirsk in western Siberia (Russia) also revealed high genetic diversity, but clearly different from current European populations. The presence of Sr31-virulence in multiple and highly diverse races in local populations in Spain and Siberia stress that virulence may emerge independently when large geographical areas and time spans are considered and that Sr31-virulence is not unique to Ug99. All isolates of the Spanish populations, collected from wheat, rye and grass species, were succesfully recovered on wheat, which underline the plasticity of host barriers within P. graminis. The study demonstrated successful alignment of two genotyping approaches and race phenotyping methodologies employed by different laboratories, which also allowed us to line up with previous European and international studies of wheat stem rust. Our results suggest new initiatives within disease surveillance, epidemiological research and resistance breeding to meet current and future challenges by wheat stem rust in Europe and beyond.

On-line Sequencing of CRISPR Guide RNAs and Their Impurities via the Use of Immobilized Ribonuclease Cartridges Attached to a 2D/3D-LC-MS System.

In this study, for the first time, the automated digestion and sequencing of an RNA molecule via the use of immobilized RNase cartridges attached to a multidimensional liquid chromatography (LC)-mass spectrometry (MS) system are presented. We first developed an on-line digestion-HILIC two-dimensional (2D)-LC-MS method in order to sequence CRISPR guide RNAs for gene editing. Three RNases (T1, A, and U2) were immobilized on polyetheretherketone cartridges, and their performance was evaluated. Ultrafast digestions were performed within 2.3 min with the on-line approach versus 30 min via the conventional off-line approach. The higher sequence coverage was achieved by the RNase T1 (71%), which is the same as the off-line mode. A 20-fold reduction in the gRNA sample amount was achieved with the on-line digestion approach (6.5 µg) in comparison to that with the off-line approach (130 µg). In the second step, a three-dimensional (3D)-LC-MS method was developed for the sequencing of fractions collected on-line across the main peak and the partially separated tail by the reference ion-pairing RPLC method. Additional insights were gained in order to better understand the cause of the main peak tailing.

Clinical decision-making for spinal manipulation for persistent spinal pain following lumbar surgery: a protocol for a systematic review and meta-analysis of individual participant data.

INTRODUCTION: There are limited available research and guidance regarding the use of spinal manipulative therapy (SMT) in patients with low back-related symptoms following lumbar spine surgery, a condition called persistent spinal pain syndrome type 2 (PSPS-2). This publication outlines a review protocol to identify and synthesise individual participant data (IPD) to examine associations between patient, clinical and surgical variables and SMT application in adults with PSPS-2. METHODS AND ANALYSIS: PubMed, OVID, Web of Science, Scopus, PEDro, Index to Chiropractic Literature and KoreaMed will be searched from inception to 1 January 2022 without language restrictions. Case reports, series, observational studies and cases from grey literature of adults receiving SMT for PSPS-2 will be included. Two investigators will independently screen citations, abstracts and full-text articles. A risk-of-bias assessment will be performed in duplicate to rate cases according to exposure and outcome ascertainment and data completeness. Data extraction will be performed in duplicate and missing IPD will be requested from corresponding authors. Multiple binary logistic regression will be used to identify independent predictors of the use of lumbar-SMT, lumbar-manual-thrust SMT and SMT within 1-year postsurgery. Patient, clinical and surgical variables will be summarised using descriptive statistics, while SMT-related outcomes (lumbar-SMT, lumbar-manual-thrust SMT and 1-year surgery-to-SMT interval) will be described using adjusted ORs with 95% CIs. ETHICS AND DISSEMINATION: This study was deemed not human subjects research by the University Hospitals' institutional review board. The results of this review will be disseminated at conferences and/or published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021250039.

Discovery of florylpicoxamid, a mimic of a macrocyclic natural product.

Natural products have routinely been used both as sources of and inspiration for new crop protection active ingredients. The natural product UK-2A has potent anti-fungal activity but lacks key attributes for field translation. Post-fermentation conversion of UK-2A to fenpicoxamid resulted in an active ingredient with a new target site of action for cereal and banana pathogens. Here we demonstrate the creation of a synthetic variant of fenpicoxamid via identification of the structural elements of UK-2A that are needed for anti-fungal activity. Florylpicoxamid is a non-macrocyclic active ingredient bearing two fewer stereocenters than fenpicoxamid, controls a broad spectrum of fungal diseases at low use rates and has a concise, scalable route which is aligned with green chemistry principles. The development of florylpicoxamid represents the first example of using a stepwise deconstruction of a macrocyclic natural product to design a fully synthetic crop protection active ingredient.

Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity.

BACKGROUND: Following the introduction of fenpicoxamid, a natural product-based fungicide targeting the Qi site of mitochondrial cytochrome bc1 complex, a second generation fully synthetic picolinamide, florylpicoxamid, was discovered and its biological activity and attributes were characterized. RESULTS: In vitro fungal growth inhibition assays and in planta glasshouse biological activity evaluations showed florylpicoxamid was active against 21 different plant pathogenic fungi within the phyla Ascomycota and Basidiomycota. Among the pathogens evaluated, florylpicoxamid was most potent against Zymoseptoria tritici, the causal organism of wheat leaf blotch, providing 80% growth inhibition in vitro at 0.0046 mg L-1 and 80% disease control in planta at 0.03 mg L-1 when applied as a preventative treatment. Florylpicoxamid was more efficacious than epoxiconazole, fluxapyroxad, and benzovindiflupyr versus a Z. tritici wild-type isolate when applied as curative and preventative treatments, with superior 10-day curative reachback activity. Analytical studies and in planta tests demonstrated that florylpicoxamid partitioned into plants quickly and showed good systemicity and translaminar activity on both monocot and dicot plants. No cross-resistance was observed between florylpicoxamid and strobilurin or azole fungicides. Florylpicoxamid exerts its preventative effect by preventing spore germination on the leaf surface and curative activity by arresting mycelial growth and pycnidia development in leaf tissue. CONCLUSIONS: With strong broad spectrum fungicidal activity, florylpicoxamid delivers an innovative solution for growers to sustain high productivity and quality of many crops, and also provides a new option for developing effective strategies for fungicide resistance management. © 2021 Society of Chemical Industry.

Living-Related Donor Kidney Transplant in a Patient With Single Ventricle and Fontan Circulation.

The hemodynamic profile of the Fontan circulation presents challenges that raise questions about candidacy for organ transplantation. We report a case of a 24-year-old male with double-inlet right ventricle and aortic atresia, who suffered bilateral renal cortical necrosis due to neonatal cardiovascular shock, received a live-donor kidney transplant from his mother at age 17, and has diminished yet stable renal function seven years posttransplant.

Lithium tracer diffusion in LiNi0.33Mn0.33Co0.33O2 cathode material for lithium-ion batteries.

The LiNi0.33Mn0.33Co0.33O2 compound is one of the most interesting cathode materials for Li-ion batteries. Li diffusion in this material directly influences charging/discharging times (and consequently power densities), maximum capacities, stress formation and possible side reactions. In the present study Li tracer self-diffusion is investigated in polycrystalline sintered bulk samples with an average grain size of about 50 nm in the temperature range between 110 and 350 °C. For analysis, stable 6Li tracers are used in combination with Secondary Ion Mass Spectrometry (SIMS). The diffusivities can be described by the Arrhenius law with an activation enthalpy of (0.85 ± 0.03) eV, which is interpreted as the migration energy of a single Li vacancy. Lithium diffuses via structural vacancies whose concentration is fixed by a Li deficiency of about 10%. An extrapolation of the diffusivities to room temperature gives significantly lower values than the diffusivities obtained by electrochemical measurements in literature.

The Gill-Oxygen Limitation Theory and size at maturity/maximum size relationships for salmonid populations occupying flowing waters.

The slowing of growth as fish age has long been believed to be related to energy expenditure for maturation, and this rationalization has been used to explain why, across nearly all fish species, the relationship between size at first maturity (Lm ) and maximum (Lmax ) or asymptotic length (L∞ ) is relatively constant. In contrast, the Gill-Oxygen Limitation Theory (GOLT) postulates that (a) fish growth slows because as they grow, their two-dimensional ability to extract oxygen from the water diminishes relative to their three-dimensional weight gain, and (b) they can only invest energy for maturation if oxygen supply at their size at first maturity (Qm ) exceeds that needed for maintenance metabolism (Q∞ ). It has been reported previously across dozens of marine fish species that the relationship between Qm and Q∞ is linear and, further, it can be mathematically converted to Lm vs. L∞ by raising both terms to the power of D (the gill surface factor), resulting in a slope of 1.36. If the GOLT is universal, a similar slope should exist for Lm D vs. L∞ D relationships for freshwater species across multiple individual populations that reside in disparate habitats, although to our knowledge this has never been evaluated. For analysis, we used existing data from previous studies conducted on 51 stream-dwelling populations of redband trout Oncorhynchus mykiss gairdneri, Yellowstone cutthroat trout O. clarkii bouvieri and mountain whitefish Prosopium williamsoni. The resulting Lm D vs. L∞ D slopes combining all data points (1.35) or for all species considered separately (range = 1.29-1.40) were indeed equivalent to the slope originally produced for the marine species from which the GOLT-derived relationship was first reported. We briefly discuss select papers both supporting and resisting various aspects of the GOLT, note that it could potentially explain shrinking sizes of marine fish, and call for more concerted research efforts combining laboratory and field expertise in fish growth research.

In Vitro Pharmacodynamic Analyses Help Guide the Treatment of Multidrug-Resistant Enterococcus faecium and Carbapenem-Resistant Enterobacter cloacae Bacteremia in a Liver Transplant Patient.

BACKGROUND: Infections due to multidrug-resistant pathogens are particularly deadly and difficult to treat in immunocompromised patients, where few data exist to guide optimal antimicrobial therapy. In the absence of adequate clinical data, in vitro pharmacokinetic (PK)/pharmacodynamic (PD) analyses can help to design treatment regimens that are bactericidal and may be clinically effective. METHODS: We report a case in which in vitro pharmacodynamic analyses were utilized to guide the treatment of complex, recurrent bacteremias due to vancomycin-, daptomycin-, and linezolid-resistant Enterococcus faecium and carbapenem-resistant Enterobacter cloacae complex in a liver transplant patient. RESULTS: Whole-genome sequencing revealed unique underlying resistance mechanisms and explained the rapid evolution of phenotypic resistance and complicated intrahost genomic dynamics observed in vivo. Performing this comprehensive genotypic and phenotypic testing and time-kill analyses, along with knowledge of institution and patient-specific factors, allowed us to use precision medicine to design a treatment regimen that maximized PK/PD. CONCLUSIONS: This work provides a motivating example of clinicians and scientists uniting to optimize care in the era of escalating antimicrobial resistance.

Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. III. Impact of modifications to the macrocycle isobutyryl ester position.

BACKGROUND: Fenpicoxamid (Inatreq™ active), a new fungicide under development by Corteva Agriscience™, Agriculture Division of DowDuPont, is an isobutyryl acetal derivative of the antifungal antibiotic UK-2A. SAR studies around the picolinamide ring and benzyl substituents attached at positions 3 and 8, respectively, of the UK-2A bislactone macrocycle have recently been documented. This study focuses on replacement of the isobutyryl ester group in the 7 position. RESULTS: Thirty analogs, predominantly esters and ethers, were prepared and evaluated for inhibition of mitochondrial electron transport and in vitro growth of Zymoseptoria tritici, Leptosphaeria nodorum, Pyricularia oryzae and Ustilago maydis. Aliphatic substituents containing four to six carbon atoms deliver strong intrinsic activity, the pivaloate ester (IC50 1.44 nM) and the n-butyl, 1-Me-propyl, 3,3-diMe-propyl and 2-c-propyl propyl ethers (IC50 values = 1.08, 1.14, 1.15 & 1.32 nM, respectively) being the most active derivatives. QSAR modelling identified solvation energy (Esolv ) and critical packing parameters (vsurf_CP) as highly significant molecular descriptors for explaining relative intrinsic activity of analogs. Activity translation to fungal growth inhibition and disease control testing was significantly influenced by intrinsic activity and physical properties, the cyclopropanecarboxylate ester (log D 3.67, IC50 3.36 nM, Z. tritici EC50 12 µg L-1 ) showing the strongest Z. tritici activity in protectant tests. CONCLUSIONS: Substitution of the isobutyryl ester group of UK-2A generates analogs that retain strong antifungal activity against Z. tritici and other fungi. © 2019 Society of Chemical Industry.

Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model.

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.