Objectives: Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Yet, data of which combinations are most effective is lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa.

Methods: We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, meropenem, minocycline, rifampicin, temocillin, thiamphenicol or trimethoprim by automated time-lapse microscopy using predefined cut-off values indicating inhibition of growth (≤10⁶ CFU/mL) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments.

Results: All strains were intermediate or resistant to polymyxin B, anti-pseudomonal β-lactams, ciprofloxacin and amikacin. Genes encoding β-lactamases (e.g., bla_PAO and bla_OXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol and trimethoprim. Time kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem.

Conclusion: Positive interactions were frequently found with the tested combinations, also against strains that harboured several resistance mechanisms to the single drugs and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.

Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA.

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 E. coli bloodstream infection isolates from Oxfordshire, UK, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity 23% (78/339)) but improved when genetic features associated with penicillinase hyper-production (e.g. promoter mutations, copy number estimates) were considered (sensitivity 82% (277/339); p<0.0001). Most discrepancies occurred in isolates with peri-breakpoint MICs. We investigated two potential causes; the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.

Periodontitis as a biofilm-associated inflammatory disease is highly prevalent worldwide. It severely affects oral health and yet closely links to systemic diseases like diabetes and cardiovascular disease. Porphyromonas gingivalis as a ‘keystone' periodontopathogen drives the shift of microbe-host symbiosis to dysbiosis, and critically contributes to the pathogenesis of periodontitis. Persisters are a tiny subset of biofilm-associated microbes highly tolerant to lethal treatment of antimicrobials, and notably metronidazole-tolerant P. gingivalis persisters have recently been identified by our group. This study further explored the interactive profiles of metronidazole-treated P. gingivalis persisters (M-PgPs) with human gingival epithelial cells (HGECs). P. gingivalis cells (ATCC 33277) at stationary phase were treated with lethal dosage of metronidazole (100 μg/ml, 6 hours) for generating M-PgPs. The interaction of M-PgPs with HGECs was assessed by microscopy, flow cytometry, cytokine profiling and qPCR. We demonstrated that the overall morphology and ultra-cellular structure of M-PgPs remained unchanged. Importantly, M-PgPs maintained the capabilities to adhere to and invade into HGECs. Moreover, M-PgPs significantly suppressed pro-inflammatory cytokine expression in HGECs at a comparable level with the untreated P. gingivalis cells, through the thermo-sensitive components. The present study reveals that P. gingivalis persisters induced by lethal treatment of antibiotics could maintain their capabilities to adhere to and invade into human gingival epithelial cells, and perturb the innate host responses. Novel strategies and approaches need to be developed for tackling P. gingivalis and favourably modulating the dysregulated immuno-inflammatory responses for oral/periodontal health and general wellbeing.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

KBP-7072 is a semi-synthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens including multidrug resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (IV) administration of single and multiple doses were investigated in animal models including during fed and fasted states and also evaluated the protein binding and excretion characteristics. In Sprague-Dawley (SD) rats, Beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after administration of single oral and IV and multiple oral doses. Oral bioavailability ranged from 12% to 32%. Mean T_max ranged from 0.5 to 4 hours, and mean half-life ranged from approximately 6 to 11 hours. Administration of oral doses in the fed state resulted in a marked reduction in C_max and AUC compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5 mg/kg oral dose of KBP-7072 in SD rats, cumulative excretion in feces was 64% and in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single and multiple ascending dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once daily oral and IV administration in clinical studies.

Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics such as bedaquiline and imipenem although in vitro data have questioned this combination. We report that the efficacy of the bedaquiline plus imipenem treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed at clearing the infection in the spleen.

Carbapenem pharmacokinetic profiles are significantly changed in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of Extracorporeal Membrane Oxygenation (ECMO) and Continuous Renal Replacement Therapy (CRRT). A two-compartment population PK model with Creatinine clearance (CrCL), body weight (WT), and ECMO as fixed effects was developed using the non-linear mixed effect model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant minimum inhibitory concentrations(MICs). The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750mg Q6h could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than that of non-ECMO patients, therefore dosage may need to be increased. The dosage may need adjustment for patients with CrCL ≤ 70ml/min, but dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients within the WT ranging from 50-80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, TDM should be carried out to optimize drug regimens.

Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA₄ receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients.

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on healthcare systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Disease of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of a β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy.

'As CEO of Avast, I feel personally responsible and I would like to apologize to all concerned,' wrote Ondrej Vlcek following a PCMag-Motherboard investigation into the privacy risks around the data harvesting.

Jake Griggs, who will graduate Saturday with a 3.95 GPA with dual majors in management and political science, has been named Smeal’s spring 2020 management and organization student marshal.

A new protocol using aerosolized hydrogen peroxide to decontaminate N95 respirators could allow them to be safely reused in hospital settings. The protocol, optimized by a team of Penn State researchers, inactivates viruses without deforming or damaging the respirator and could help hospitals overcome the current respirator shortage due to the COVID-19 pandemic.

Olivia M. Vaz
Feb 1, 2020; 145:e20190620-e20190620
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Millicent Collins
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Hazleton native Megan Bobish has joined the Penn State Hazleton Athletics Department as the newest member of its team.

Google removes the free WireGuard app from the Play Store for having a donation button, reigniting a debate over whether its policy hurts the open-source community.

Two Penn State University Libraries employees at Berks Thun Library, Penn State Berks, have been awarded the American Library Association’s 2020 Emerging Technologies Section 2020 Best Emerging Technology Application (BETA) Award, which recognizes a technology application that directly benefits library users.

Hongyan “Red” Yuan, an instructional designer at Penn State Berks and member of the board of the Reading Chinese Association (RCA), recently helped to coordinate the donation of 1,500 surgical masks to Penn State Health St. Joseph.

Three Berks Thun Library employees received the 2020 Innovation in College Librarianship Award from the College Libraries Section of the Association of College & Research Libraries, a division of the American Library Association. The award honors librarians who demonstrate a capacity for innovation in working with or serving undergraduates or instructors in the areas of programs, services, and operations, or creating innovations for library colleagues that facilitate their ability to better serve the library’s community.

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Philip M. Farrell
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Richard A. Ehrenkranz
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Barbara J. Stoll
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National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents
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A new structure begins next year, incorporating UEFA Nations League-style groups in a two-season cycle.

Amid bad feelings between the union and district administrators, Cincinnati teachers overwhelmingly rejected a groundbreaking plan that would have based their pay on performance.

Instructions for using the new Alternative Grade Calculator and Request Tool in LionPATH are now available for undergraduates and students enrolled in the Graduate School.

At its final meeting of the 2019-20 academic year, the Penn State Faculty Senate passed landmark legislation updating its full-time faculty hiring policy for the first time in more than 20 years, as one step in continued efforts to advance the University’s commitment to diversity, equity and inclusion.

Denver Newsroom, Apr 28, 2020 / 05:17 pm (CNA).- Archbishop Michael Miller of Vancouver has announced that he is donating to the University of British Columbia’s research toward a COVID-19 vaccine.

“May the search for COVID-19 solutions also be a moment of solidarity, of collaboration, and of growing together as a visible sign to the world of the healing and reconciliation so needed right now,” Archbishop Miller said April 27 as reported by the B.C. Catholic.

Ryan Thomas, a special advisor to the archdiocese, told CNA that Archbishop Miller wanted to express, through his donation, the Catholic Church’s support for science and medicine that contribute to the common good.

“The Church— as Pope Francis has said from the beginning of his pontificate— is called to go out, we're called to engage, not called to retreat,” Thomas told CNA.

“From a scientific standpoint, that means identifying the research that is worthy of our investment, that meets the high standards that we have to protect life,” he said.

Thomas declined to specify the amount of the donation, but said that it was in the thousands of dollars.

The global effort to develop a COVID-19 vaccine includes at least 50 other research teams, the university says, many of which in the U.S. and Canada have received government funding and are being conducted by large pharmaceutical companies.

Pro-life leaders have warned in recent months that among the many COVID-19 vaccines currently in development worldwide, in some cases researchers are using old cell lines derived from the cells of aborted babies.

It was important to Archbishop Miller, Thomas said, that the Church be seen to be promoting research into a vaccine that Catholics can support in good conscience.

A group of Evangelical Christians and Catholics in Vancouver began to rally around the idea of supporting a vaccine that corresponded to Christian ethical standards, and eventually presented the idea of supporting UBC’s research to Archbishop Miller.

Thomas said Miller made sure to inquire about whether UBC’s vaccine research makes use of aborted fetal cells, which it does not.

Dr. Wilf Jefferies, the project’s lead researcher, told CNA via email that his research team is currently in the process of validating the potency of vaccine candidates in preclinical trials, in order to assess their potential toxicity before trying them in human subjects.

The UBC lab is using immune-boosting components called adjuvants in its vaccine candidate, with the hopes of reducing the dosage of vaccine required for complete protection against the disease. In addition, Jefferies hopes that UBC’s vaccine will continue to provide protection against COVID-19 even if the virus mutates over time.

“I am heartened by the unity and kindness that is being demonstrated during this pandemic,” Jefferies told CNA.

“I think the response by the archdiocese is an affirmative and practical way to address the critical need in our society to develop a vaccine...I am sincerely humbled by the support we have received from the archdiocese and from other groups and individuals.”

So far, Jefferies’ lab has received grants from the government-funded Michael Smith Health Research Foundation and the Sullivan Urology Foundation affiliated with the University of British Columbia, as well as a number of private donations.

There are at least 1,000 clinical trials currently taking place around the world to test potential COVID-19 vaccines.

A group of pro-life leaders in a letter to the Trump administration earlier this month reiterated that development of a COVID-19 vaccine should avoid unethical links to abortion.

“No American should be forced to choose between being vaccinated against this potentially deadly virus and violating his or her conscience,” reads the April 17 letter to Dr. Stephen M. Hahn, commissioner of the U.S. Food and Drug Administration.

“Fortunately, there is no need to use ethically problematic cell lines to produce a COVID vaccine, or any vaccine, as other cell lines or processes that do not involve cells from abortions are available and are regularly being used to produce other vaccines,” it continued.

The letter’s signers include Archbishop Joseph Naumann of Kansas City in Kansas, chair of the U.S. Conference of Catholic Bishops’ Committee on Pro-Life Activities; the heads of three other bishops’ conference committees; and leaders of many other Catholic and non-Catholic groups.

The Pontifical Academy for Life has noted that Catholics have an obligation to use ethically-sourced vaccines when available, and have an obligation to speak up and request the development of new cell lines that are not derived from aborted fetuses.

The 2008 Vatican document Dignitatis personae strongly criticized aborted fetal tissue research. However, as regards common vaccines, such as those for chicken pox and measles, mumps, and rubella (MMR), that may be derived from cell lines of aborted babies, the Vatican said they could be used by parents for “grave reasons” such as danger to their children’s health.

In a 2017 document on vaccines, the academy noted a “moral obligation to guarantee the vaccination coverage necessary for the safety of others… especially the safety of more vulnerable subjects such as pregnant women and those affected by immunodeficiency who cannot be vaccinated against these diseases.”

 

Bridget O’Donnell, assistant director of student engagement at Penn State Brandywine, has been recognized as Advisor of the Year by the Association for the Promotion of Campus Activities.

The Salt Path

The Ratline: Love, Lies and Justice on the Trail of a Nazi Fugitive

NATURE BOOK

Michael Mann, distinguished professor of atmospheric sciences and director of Penn State's Earth System Science Center at Penn State, has been elected to the National Academy of Sciences, recognizing distinguished and continuing achievements in original research. Membership in the NAS is one of the highest honors given to a scientist or engineer in the United States.

Bernadette Lear, Penn State University Libraries behavioral sciences and education librarian and coordinator of library instruction at the Penn State Harrisburg Library, has been elected vice chair/chair elect of the Library History Round Table, a membership group of the American Library Association.

The arts, geography, economics, and foreign languages will lose their place in the testing line-up as the National Assessment of Educational Progress is being streamlined to cut costs.

The Coronavirus and International Affairs Roundtable, taking place 9:30 a.m. Friday, April 17, via Zoom, will bring together experts in law and international affairs from Asia, Europe, the Middle East, North America, and the Caribbean to discuss the broader impact of COVID-19.

Rebecca Mattson, head of faculty and research services for the H. Laddie Montague Jr. Law Library, Penn State University Libraries, and professor of legal research at Penn State Law at University Park, has been elected vice chair/chair elect of the Research Instruction and Patron Services Special Interest Section of the American Association of Law Libraries.

As the coronavirus pandemic continues to impact communities throughout Pennsylvania, Penn State staff members are fighting food insecurity by donating to food banks and organizations across the state.