Long-Acting Cabotegravir/Rilpivirine Concentrations in Combination With Intravenous Rifampin: A Case Report.

As antiretroviral therapy advancements focus on long-acting medications, there is a need to assess the potential impact of drug-drug interactions. We present a real-world case of long-acting cabotegravir/rilpivirine co-administered with intravenous rifampin. The combination resulted in both cabotegravir and rilpivirine concentrations falling below 4 times the protein-adjusted IC90.

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience.

BACKGROUND: CD19 chimeric antigen receptor (CAR)-T cell therapy has emerged as an effective treatment in those with refractory or relapsed lymphoma. CD19 CAR-T cell therapy can cause direct and indirect toxic adverse effects and increased risk for infection. Infectious complications and optimal antimicrobial prophylaxis strategies are an ongoing area of investigation. METHODS: A single-center retrospective cohort study was conducted to review recipients of CD19 CAR-T cell therapy between April 2018 and December 2020. Patient characteristics and clinical outcomes were extracted from the electronic health records. RESULTS: Infectious complications were identified in 18/50 (36%) recipients with 31 episodes of infection. The median time to infection was 225 days (range 0-614). Bacterial infections were most common with bloodstream infection followed by sinusitis and skin and soft tissue infection. Eight viral infections were identified, most being respiratory viral illnesses. Two fungal infections were identified: Pneumocystis jirovecii pneumonia (PJP) and disseminated fusariosis. Seventeen infections (54.8%) were classified as severe: leading to death, requiring hospitalization, need for empiric intravenous antibiotics, or significant alteration in hospital course. No characteristics were found to be statistically significant risks for infection, although a trend toward significance was seen in prior autologous stem cell transplant recipients (p = .12) and those with recurrent neutropenia (p = .14). Three patients (6%) died from infection. CONCLUSION: Infections were common after CD19 CAR-T cell therapy and occurred beyond the first year. Further multicenter studies are needed to define infectious risks and optimize antimicrobial prophylaxis recommendations in recipients of CD19 CAR-T cell therapy.

Factors Associated With Disease-Modifying Therapy Adherence and Persistence in Multiple Sclerosis: A Scoping Literature Review.

BACKGROUND: Patients with multiple sclerosis (MS) receiving disease-modifying therapies (DMT) show published adherence rates of 27.0% to 93.8% and published persistence rates of 49.7% to 96.5%. Improvements in DMT adherence and persistence are key to optimizing MS care, and enhanced understanding could improve MS disease management and identify research gaps. This scoping literature review aims to examine the nature and findings of the literature evaluating factors associated with DMT adherence and persistence in patients with MS. METHODS: Eligible articles included in the literature review were quantitative clinical studies written in English, included adherence or persistence as primary outcomes, and accounted for covariates/confounders. The articles were assessed to identify factors associated with adherence/persistence and analyzed according to DMT type (self-injectable, oral, infusion). RESULTS: Fifty-eight studies (103,450 patients) were included. Study distribution by DMT type was self-injectable only (n = 41), oral only (n = 2), infusion only (n = 1), and more than 1 type (n = 14). Older age and previous DMT use were associated with increased adherence and/or persistence. Increased alcohol consumption, DMT adverse events, higher education, and higher body mass index were negatively associated with adherence and/or persistence. Greater number and severity of relapses was associated with increased adherence but decreased persistence. CONCLUSIONS: Most studies examined factors associated with adherence and persistence to self-injectable DMTs. These factors should be evaluated further for oral and infusion DMTs. Insights into the modifiable factors associated with adherence and persistence could guide treatment decisions and help improve adherence and clinical outcomes.

Expert Consensus Statement on Proficiency Standards for Dermoscopy Education in Primary Care.

BACKGROUND: Primary care providers (PCPs) frequently address dermatologic concerns and perform skin examinations during clinical encounters. For PCPs who evaluate concerning skin lesions, dermoscopy (a noninvasive skin visualization technique) has been shown to increase the sensitivity for skin cancer diagnosis compared with unassisted clinical examinations. Because no formal consensus existed on the fundamental knowledge and skills that PCPs should have with respect to dermoscopy for skin cancer detection, the objective of this study was to develop an expert consensus statement on proficiency standards for PCPs learning or using dermoscopy. METHODS: A 2-phase modified Delphi method was used to develop 2 proficiency standards. In the study's first phase, a focus group of PCPs and dermatologists generated a list of dermoscopic diagnoses and associated features. In the second phase, a larger panel evaluated the proposed list and determined whether each diagnosis was reflective of a foundational or intermediate proficiency or neither. RESULTS: Of the 35 initial panelists, 5 PCPs were lost to follow-up or withdrew; 30 completed the fifth and last round. The final consensus-based list contained 39 dermoscopic diagnoses and associated features. CONCLUSIONS: This consensus statement will inform the development of PCP-targeted dermoscopy training initiatives designed to support early cancer detection.

Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary.

People with multiple sclerosis (also shortened to MS) may have difficulties staying on treatment due to side effects. Cladribine tablets, approved for treating relapsing forms of MS, are given by mouth for four short periods over two years. The benefit of convenient dosing may be lost if side effects prevent people with MS from finishing their treatment. This is the summary of a study that examined side effects from cladribine tablets treatment in the first 12 weeks of two clinical studies called CLARITY and ORACLE-MS. Overall, 34.7% of participants who took cladribine tablets experienced drug-related side effects compared to 23.2% of participants who took placebo. Most side effects were mild and were seen in 54.8% of participants taking cladribine tablets and 59.1% taking the placebo. A low number of participants discontinued treatment due to side effects (1.6% of participants who took cladribine tablets; 1.4% of participants who took placebo). The researchers concluded that cladribine tablets are well-tolerated and people with MS are likely to complete the full treatment course. ClinicalTrials.gov NCT numbers: CLARITY study - NCT00213135 and ORACLE-MS study - NCT00725985.

Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis.

BACKGROUND: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. OBJECTIVE: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. METHODS: This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. RESULTS: By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). CONCLUSION: Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation.

Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets.

Cladribine tablets (CladT) preferentially reduce B and T lymphocyte levels. As aging is associated with a decline in immune function, the effect of CladT on lymphocyte levels may differ by age. This post hoc analysis combined data from the Phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies to examine the effect of age (≤50 or >50 years) on lymphopenia following CladT 3.5 mg/kg (CladT3.5; cumulative dose over 2 years) treatment over 96 weeks. Both CladT3.5 and placebo were given over Weeks 1 and 5 (Year 1 treatment) and Weeks 48 and 52 (Year 2 treatment) from the start of the studies. Absolute lymphocyte count (ALC) and levels of lymphocyte subsets were examined in 1564 patients (Age ≤50 [placebo: N=566; CladT3.5: N=813]; Age >50 [placebo: N=75; CladT3.5: N=110]). In both age groups, following CladT3.5 treatment, nadir for ALC occurred at Week 9 (8 weeks following start of Year 1 treatment) and Week 55 (7 weeks following start of Year 2 treatment) of the 96-week period; for CD19+ B lymphocytes, nadir occurred at Week 9 (Year 1) and Week 52 (Year 2). For CD4+ T lymphocytes, nadir occurred at Week 16 (Year 1) in both age groups, and at Weeks 60 and 72 (Year 2) in the Age ≤50 and >50 groups, respectively. Nadir for CD8+ T lymphocytes occurred at Week 16 (Year 1) and Week 72 (Year 2) in the Age ≤50 group and levels remained in the normal range; nadir occurred at Week 9 (Year 1) and Week 96 (Year 2) in the Age >50 group. Lymphocyte recovery began soon after nadir following CladT3.5 treatment and median levels reached normal range by end of the treatment year in both age groups. By Week 96, ~25% of patients treated with CladT3.5 reported ≥1 episode of Grade ≥3 lymphopenia (Gr≥3L). The rate of certain infections was numerically higher in older versus younger patients who experienced Gr≥3L. In conclusion, CladT3.5 had a similar effect on ALC and lymphocyte subsets in both younger and older patient groups.

Clinical Characteristics and Outcome of Staphylococcus aureus Prostate Abscess, Ten-Year Experience at a Tertiary Care Center.

BACKGROUND: Prostatic abscess (PA) is an uncommon infection that is generally secondary to Escherichia coli and other members of the Enterobacteriaceae family. In recent years, although rare, more reports of Staphylococcus aureus (S. aureus) PA have been reported, especially with increasing reports of bacteremia associated with injection drug use (IDU). METHODS: This was a retrospective review of adult patients admitted to a tertiary care hospital between 2008 and 2018 and who had a diagnosis of S. aureus PA. RESULTS: Twenty-one patients were included. Average age was 46 years. Fourteen (67%) presented with genitourinary concerns. Main risk factors included concurrent skin or soft tissue infections in 52%, history of genitourinary disease or instrumentation in 48%, IDU in 38%, and diabetes mellitus in 38%. Methicillin-resistant staphylococcus aureus (MRSA) was identified in 57% and concomitant bacteremia in 81% of patients. Surgical or a radiologically guided drainage was performed in 81% of patients. Antibiotic treatment duration ranged from 3 to 8 weeks. Six patients were lost to follow-up. Clinical resolution was observed in the remaining 15 (81%) patients who had follow-up. CONCLUSIONS: S. aureus prostate abscess (PA) continues to be a rare complication of S.aureus infections. MRSA is the culprit in most published reports. In high risk patients with persistent bacteremia physicians need to consider the prostate as a site of infection.

Impact of Shared Decision Making on Disease-Modifying Drug Adherence in Multiple Sclerosis.

BACKGROUND: Shared decision making (SDM) and adherence to treatment are an integral part of multiple sclerosis (MS) care. A collaborative process, SDM actively involves the patient, the health care provider, and an extended network in making treatment decisions. Adherence to disease-modifying drug therapies in patients with MS presents an ongoing challenge for patients and health care providers due to the chronic nature of this disease. This narrative review aims to explore the impact of SDM on adherence based on existing literature and to identify new approaches to optimizing adherence. METHODS: A search was conducted using medical subject heading terms, including decision-making, adherence, shared decision-making, compliance, and patient-centered care. RESULTS: Shared decision making between patients and clinicians promotes adherence to the treatment plan in MS. A proactive SDM approach is based on patient preferences, education, and engagement. Providing credible and accurate sources of information is essential for improving patient engagement. Home monitoring, computerized models, and active patient engagement are a few new approaches to improve adherence in patients with MS. CONCLUSIONS: Shared decision-making interventions can have a positive effect on patient adherence to disease-modifying drug therapy in MS care. A range of new strategies is emerging that may help promote optimal disease management.

Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress.

Pathogenic fungi, including Candida glabrata, develop strategies to grow and survive both in vitro and in vivo under azole stress. However, the mechanisms by which yeast cells counteract the inhibitory effects of azoles are not completely understood. In the current study, it was demonstrated that the expression of the ergosterol biosynthetic genes ERG2, ERG3, ERG4, ERG10, and ERG11 was significantly upregulated in C. glabrata following fluconazole treatment. Inhibiting ergosterol biosynthesis using fluconazole also increased the expression of the sterol influx transporter AUS1 and the sterol metabolism regulators SUT1 and UPC2 in fungal cells. The microarray study quantified 35 genes with elevated mRNA levels, including AUS1, TIR3, UPC2, and 8 ERG genes, in a C. glabrata mutant strain lacking ERG1, indicating that sterol importing activity is increased to compensate for defective sterol biosynthesis in cells. Bioinformatic analyses further revealed that those differentially expressed genes were involved in multiple cellular processes and biological functions, such as sterol biosynthesis, lipid localization, and sterol transport. Finally, to assess whether sterol uptake affects yeast susceptibility to azoles, we generated a C. glabrata aus1∆ mutant strain. It was shown that loss of Aus1p in C. glabrata sensitized the pathogen to azoles and enhanced the efficacy of drug exposure under low oxygen tension. In contrast, the presence of exogenous cholesterol or ergosterol in medium rendered the C. glabrata AUS1 wild­type strain highly resistant to fluconazole and voriconazole, suggesting that the sterol importing mechanism is augmented when ergosterol biosynthesis is suppressed in the cell, thus allowing C. glabrata to survive under azole pressure. On the basis of these results, it was concluded that sterol uptake and sterol biosynthesis may act coordinately and collaboratively to sustain growth and to mediate antifungal resistance in C. glabrata through dynamic gene expression in response to azole stress and environmental challenges.

A Framework of Care in Multiple Sclerosis, Part 2: Symptomatic Care and Beyond.

The Consortium of Multiple Sclerosis Centers (CMSC) convened a Framework Taskforce composed of a multidisciplinary group of clinicians and researchers to examine and evaluate the current models of care in multiple sclerosis (MS). The methodology of this project included analysis of a needs assessment survey and an extensive literature review. The outcome of this work is a two-part continuing education series of articles. Part 1, published previously, covered the updated disease phenotypes of MS along with recommendations for the use of disease-modifying therapies. Part 2, presented herein, reviews the variety of symptoms and potential complications of MS. Mobility impairment, spasticity, pain, fatigue, bladder/bowel/sexual dysfunction, cognitive dysfunction, and neuropsychiatric issues are examined, and both pharmacologic and nonpharmacologic interventions are described. Because bladder and bowel symptoms substantially affect health-related quality of life, detailed information about elimination dysfunction is provided. In addition, a detailed discussion about mental health and cognitive dysfunction in people with MS is presented. Part 2 concludes with a focus on the role of rehabilitation in MS. The goal of this work is to facilitate the highest levels of independence or interdependence, function, and quality of life for people with MS.

CME/CNE Article: A Framework of Care in Multiple Sclerosis, Part 1: Updated Disease Classification and Disease-Modifying Therapy Use in Specific Circumstances.

Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org. TARGET AUDIENCE: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). LEARNING OBJECTIVES: Apply new information about MS to a comprehensive individualized treatment plan for patients with MSIntegrate the team approach into long-term planning in order to optimize rehabilitation care of patients with MSAccreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NPA designates this enduring material for 1.0 Continuing Nursing Education credit. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has received royalties from Springer Publishing and has received intellectual property rights from Biogen. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Scott D. Newsome, DO, MSCS (author), has served on scientific advisory boards for Biogen, Genentech, Novartis, and Genzyme, and has performed contracted research (institution received funds) for Biogen, Genentech, and Novartis. Philip J. Aliotta, MD, MSHA, CHCQM, FACS (author), has served on speakers' bureaus for Astellas Pharma, Actavis, Augmenix, and Allergan and has performed contracted research for Allergan. Jacquelyn Bainbridge, PharmD (author), has disclosed no relevant financial relationships. Susan E. Bennett, PT, DPT, EdD, NCS, MSCS (author), has served on speakers' bureaus for Acorda Therapeutics, Biogen, and Medtronic; has received consulting fees from and performed contracted research for Acorda Therapeutics; and is chair of the Clinical Events Committee at Innovative Technologies. Gary Cutter, PhD (author), has participated on Data and Safety Monitoring Committees for AMO Pharma, Apotek, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck, Merck/Pfizer, Opko Biologics, Neuren, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), and NICHD (OPRU Oversight Committee); has received consulting fees from and/or served on speakers' bureaus and scientific advisory boards for Cerespir, Genzyme, Genentech, Innate Therapeutics, Janssen Pharmaceuticals, Klein-Buendel Incorporated, MedImmune, Medday, Nivalis, Novartis, Opexa Therapeutics, Roche, Savara, Somahlution, Teva Pharmaceuticals, Transparency Life Sciences, and TG Therapeutics; and is President of Pythagoras, Inc., a private consulting company located in Birmingham, AL. Kaylan Fenton, CRNP, APNP, MSCN (author), has disclosed no relevant financial relationships. Fred Lublin, MD (author), has received consulting fees/fees for non-CME/CE activities from Bayer HealthCare Pharmaceuticals, Biogen, EMD Serono, Novartis, Teva Neuroscience, Actelion, Sanofi/Genzyme, Acorda, Questcor/Mallinckrodt, Roche/Genentech, MedImmune, Osmotica, Xenoport, Receptos/Celgene, Forward Pharma, Akros, TG Therapeutics, AbbVie, Toyama, Amgen, Medday, Atara Biotherapeutics, Polypharma, Pfizer, Johnson & Johnson, Revalesio, Coronado Bioscience, and Bristol-Myers Squibb; has served on speakers' bureaus for Genentech/Roche and Genzyme/Sanofi; has performed contracted research for Acorda, Biogen, Novartis, Teva Neuroscience, Genzyme, Xenoport, and Receptos; is the co-chief editor of Multiple Sclerosis and Related Disorders; and has an ownership interest in Cognition Pharmaceuticals. Dorothy Northrop, MSW, ACSW (author), has disclosed no relevant financial relationships. David Rintell, EdD (author), has received consulting fees from Novartis and has served as a patient education speaker for Teva Neuroscience. He started as a salaried employee of Sanofi Genzyme in November 2015. Dr. Rintell's work on this project was completed before he became a salaried employee of Sanofi Genzyme.Bryan D. Walker, MHS, PA-C (author), has served on scientific advisory boards for EMD Serono and Sanofi Genzyme and owns stock in Biogen. Megan Weigel, DNP, ARNP-C, MSCN (author), has received consulting fees from Mallinckrodt, Genzyme, and Genentech, and has served on speakers' bureaus for Bayer Corp, Acorda Therapeutics, Teva Neuroscience, Biogen, Mallinckrodt, Genzyme, Novartis, and Pfizer. Kathleen Zackowski, PhD, OTR, MSCS (author), has performed contracted research for Acorda Therapeutics. David E. Jones, MD (author), has received consulting fees from Biogen and Novartis, and has performed contracted research for Biogen. One anonymous peer reviewer for the IJMSC has performed contracted research (institution received funds) for Novartis, Chugai, and Biogen. Another reviewer has received consulting fees and served on speakers' bureaus for Biogen, Sanofi Genzyme, Genentech, EMD Serono, and Novartis. The third reviewer has disclosed no relevant financial relationships. Lori Saslow, MS (medical writer), has disclosed no relevant financial relationships. The staff at the IJMSC, CMSC, NPA, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Note: Disclosures listed for authors are those applicable at the time of their work on this project and within 12 months previously. Financial relationships for some authors may have changed in the interval between the time of their work on this project and publication of the article. Funding/Support: Funding for the Framework of Care consensus conference was provided by the Consortium of Multiple Sclerosis Centers, Mallinckrodt Pharmaceuticals, and Mylan Pharmaceuticals. Method of Participation: Release Date: December 1, 2016 Valid for Credit Through: December 1, 2017 In order to receive CME/CNE credit, participants must: Review the CME/CNE information, including learning objectives and author disclosures.Study the educational content.Complete the post-test and evaluation, which are available at http://www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities.

Surgical Outcomes in a Large, Clinical, Low-Dose Computed Tomographic Lung Cancer Screening Program.

BACKGROUND: Lung cancer screening with low-dose computed tomography is proven to reduce lung cancer mortality among high-risk patients. However, critics raise concern over the potential for unnecessary surgical procedures performed for benign disease as a result of screening. We reviewed our outcomes in a large clinical lung cancer screening program to assess the number of surgical procedures done for benign disease, as we believe this is an important quality metric. METHODS: We retrospectively reviewed our surgical outcomes of consecutive patients who underwent low-dose computed tomography lung cancer screening from January 2012 through June 2014 using a prospectively collected database. All patients met the National Comprehensive Cancer Network lung cancer screening guidelines high-risk criteria. RESULTS: There were 1,654 screened patients during the study interval with clinical follow-up at Lahey Hospital & Medical Center. Twenty-five of the 1,654 (1.5%) had surgery. Five of 25 had non-lung cancer diagnoses: 2 hamartomas, 2 necrotizing granulomas, and 1 breast cancer metastasis. The incidence of surgery for non-lung cancer diagnosis was 0.30% (5 of 1,654), and the incidence of surgery for benign disease was 0.24% (4 of 1,654). Twenty of 25 had lung cancer, 18 early stage and 2 late stage. There were no surgery-related deaths, and there was 1 major surgical complication (4%) at 30 days. CONCLUSIONS: The incidence of surgical intervention for non-lung cancer diagnosis was low (0.30%) and is comparable to the rate reported in the National Lung Screening Trial (0.62%). Surgical intervention for benign disease was rare (0.24%) in our experience.

Milbemycin A4 oxime as a probe of azole transport in Candida glabrata.

Azole resistance in Candida glabrata, a pathogenic yeast, has prompted studies of compounds that have therapeutic potential by reversing azole resistance. Milbemycin A4 oxime blocked azole efflux and enhanced azole susceptibility fourfold in 28 clinical isolates of C. glabrata. Specificity of the milbemycin A4 oxime effect depended on the drug transporter and the substrate being effluxed. The major effect of milbemycin A4 oxime was inhibition of azole and rhodamine 6G efflux by the ATP-binding cassette (ABC) transporters CgCDR1 and PDH1. Milbemycin A4 oxime effect did not extend to oligomycin, transported by the ABC transporter YOR1 or to benomyl, transported by the major facilitator superfamily transporter, CgFLR1. Milbemycin A4 oxime did not suppress transcription of CgCDR1 but increased CgCDR1 expression 126-fold. Selectivity of the effect is compatible with the concept that milbemycin A4 oxime may interact directly with one or more drug-binding sites of the major azole transporters.

Toggling between gamma-frequency activity and suppression of cell assemblies.

Gamma (30-80 Hz) rhythms in hippocampus and neocortex resulting from the interaction of excitatory and inhibitory cells (E- and I-cells), called Pyramidal-Interneuronal Network Gamma (PING), require that the I-cells respond to the E-cells, but don't fire on their own. In idealized models, there is a sharp boundary between a parameter regime where the I-cells have weak-enough drive for PING, and one where they have so much drive that they fire without being prompted by the E-cells. In the latter regime, they often de-synchronize and suppress the E-cells; the boundary was therefore called the "suppression boundary" by Börgers and Kopell (2005). The model I-cells used in the earlier work by Börgers and Kopell have a "type 1" phase response, i.e., excitatory input always advances them. However, fast-spiking inhibitory basket cells often have a "type 2" phase response: Excitatory input arriving soon after they fire delays them. We study the effect of the phase response type on the suppression transition, under the additional assumption that the I-cells are kept synchronous by gap junctions. When many E-cells participate on a given cycle, the resulting excitation advances the I-cells on the next cycle if their phase response is of type 1, and this can result in suppression of more E-cells on the next cycle. Therefore, strong E-cell spike volleys tend to be followed by weaker ones, and vice versa. This often results in erratic fluctuations in the strengths of the E-cell spike volleys. When the phase response of the I-cells is of type 2, the opposite happens: strong E-cell spike volleys delay the inhibition on the next cycle, therefore tend to be followed by yet stronger ones. The strengths of the E-cell spike volleys don't oscillate, and there is a nearly abrupt transition from PING to ING (a rhythm involving I-cells only).