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Fungal diseases impact the lives of a millions of people across the globe, and with our current repertoire of therapeutic options dwindling, effective treatment strategies are urgently needed. Critically, the emergence of azole-resistant isolates in the clinic following prolonged treatment regimes, environmental fungicide exposure, and fungal evolution, threatens the outcome of current therapeutics, further endangering the survival of infected individuals. Here, we investigate the underpinnings of antifungal resistance using quantitative proteomics to discover protein-level signatures of fluconazole (FLC) resistance in the opportunistic human fungal pathogen, Cryptococcus neoformans . We explore ClpX, an ATP-dependent unfoldase, as a target to overcome FLC resistance and explore target efficacy through macrophage and murine models of cryptococcal infection. Here we show that disruption of ClpX, following gene deletion or targeted inhibition, re-introduces FLC susceptibility into resistant strains, rendering FLC treatment effective once again. Further, we identify and experimentally confirm mechanisms by which ClpX influences susceptibility to FLC, through association with both heme biosynthesis and ergosterol production. Overall, our results contribute to the understanding of mechanisms driving FLC resistance in a globally important fungal pathogen, and we provide avenues for targeting proteins as a therapeutic strategy to reverse antifungal resistance. Here, the authors reveal that the ATP-dependent unfoldase ClpX is a key driver of fluconazole resistance in Cryptococcus neoformans , and show that targeting ClpX restores drug susceptibility, offering a potential therapeutic strategy to reverse antifungal resistance and to render current drugs effective.

After 43 years of dormancy, Taal Volcano violently erupted in January 2020 forming a towering eruption plume. The fall deposits covered an area of 8605 km2, which includes Metro Manila of the National Capital Region of the Philippines. The tephra fall caused damage to crops, traffic congestion, roof collapse, and changes in air quality in the affected areas. In a tropical region where heavy rains are frequent, immediate collection of data is crucial in order to preserve the tephra fall deposit record, which is readily washed away by surface water runoff and prevailing winds. Crowdsourcing, field surveys, and laboratory analysis of the tephra fall deposits were conducted to document and characterize the tephra fall deposits of the 2020 Taal Volcano eruption and their impacts. Results show that the tephra fall deposit thins downwind exponentially with a thickness half distance of about 1.40 km and 9.49 km for the proximal and distal exponential segments, respectively. The total calculated volume of erupted fallout deposit is 0.057 km3, 0.042 km3, or 0.090 km3 using the exponential, power-law, and Weibull models, respectively, and all translate to a VEI of 3. However, using a probabilistic approach (Weibull method) with 90% confidence interval, the volume estimate is as high as 0.097 km3. With the addition of the base surge deposits amounting to 0.019 km3, the volume translates to a VEI of 4, consistent with the classification for the observed height and umbrella radius of the 2020 main eruption plume. VEI 4 is also consistent with the calculated median eruption plume height of 17.8 km and sub-plinian classification based on combined analysis of isopleth and isopach data. Phreatomagmatic activity originated from a vent located in Taal Volcano’s Main Crater Lake (MCL), which contained 42 million m3 of water. This eruptive style is further supported by the characteristics of the ash grain components of the distal 12 January 2020 tephra fall deposits, consisting dominantly of andesitic vitric fragments (83–90%). Other components of the fall deposits are lithic (7–11%) and crystal (less than 6%) grains. Further textural and geochemical analysis of these tephra fall deposits contributes to better understand the volcanic processes that occurred at Taal Volcano, one of the 16 Decade Volcanoes identified by the International Association of Volcanology and Chemistry of the Earth’s Interior (IAVCEI) because of its destructive nature and proximity to densely populated areas. The crowdsourcing initiative provided a significant portion of the data used for this study while at the same time educating and empowering the community to build resilience.

Histological analysis confirmed the resemblance of the ovarian structure and development of Panulirus longipes longipes to those of other palinurid species. The low incidence of inactive ovaries and the presence of developing ovaries at any time of the year indicate that this species breeds year round in Calatagan, Batangas, Philippines. Continuous breeding of the population is further ascertained by the incidence of egg-bearing females in the landed catch during practically all months from July 1982 to June 1984. Furthermore, the incidence of developing and redeveloping ovaries in egg-bearing females (44.0-81.2 mm CL) suggests that individuals can produce at least 2 broods in rapid succession particularly during the warmer months of March to May. The smallest females with eggs and mature ovaries were 41.8 and 41.4 mm CL size, respectively. The disproportionate increase in the growth of the third walking leg of the males relative to the females indicate that males reach first functional sexual maturity between 55.0-60.0 mm CL. The relationship between the total number of eggs (E) carried and the size of the female (CL) is expressed by the relationship: E = -291063 + 7387 CL over the size range 43.0-85.4 mm CL. Over this size range, the reproductive potential of P. longipes longipes is higher than that of closely related species belonging to the P. japonicus group. /// L'analyse histologique a confirmé la ressemblance de la structure de l'ovaire et du développement de Panulirus longipes longipes avec ceux des autres espèces de palinurides. La faible fréquence d'ovaires inactifs et la présence d'ovaires en cours de développement à tout moment de l'année indiquent que cette espèce se reproduit toute l'année à Calatagan, Batangas, Philippines. La reproduction en continu de la population est confirmée par la fréquence de femelles ovigères dans les prises débarquées pendant pratiquement tous les mois de juillet 1982 à juin 1984. De plus, la fréquence des ovaires en développement ou redéveloppement chez les femelles ovigères (44,0 à 81,2 mm CL) suggère que les individus peuvent produire au moins 2 pontes en succession rapide en particulier au cours des mois les plus chauds de mars à mai. Les plus petites femelles avec oeufs et ovaires à maturité mesuraient 41,8 et 41,4 mm CL, respectivement. La croissance disproportionée de la troisième patte ambulatoire des mâles comparée à celle des femelles indique que les mâles atteignent les premiers la maturité sexuelle fonctionnelle entre 55,0 et 60,0 mm CL. La relation entre le nombre d'oeufs (E) et la taille de la femelle (CL) est exprimée par: E = -291063 + 7387 CL pour la classe de taille 43,0-85,4 mm CL. Dans cette classe de taille, le potentiel reproductif de P. longipes longipes est supérieur à celui d'espèces proches appartenant au groupe P. japonicus.

Systemic lupus erythematosus (SLE) affects reproductive aged women. Issues regarding family planning are an important part of SLE patient care. Women with SLE can flare during pregnancy, in particular those who have active disease at conception or prior history of renal disease. These flares can lead to increased adverse pregnancy outcomes including fetal loss, pre-eclampsia, preterm birth and small for gestational aged infants. In addition, women with antiphospholipid antibodies can have thrombosis during pregnancy or higher rates of fetal loss. Women who have anti-Ro/SSA and anti-La/SSB antibodies need special monitoring as their offspring are at risk for congenital complete heart block and neonatal lupus. Ideally, SLE patients should have their disease under good control on medications compatible with pregnancy prior to conception. All patients with SLE should remain on hydroxychloroquine unless contraindicated. We recommend the addition of 81mg/d of aspirin at the end of the first trimester to reduce the risk of pre-eclampsia. The immunosuppressive azathioprine, tacrolimus and cyclosporine are compatible with pregnancy and lactation, mycophenolate mofetil (MMF)/mycophenolic acid are not. Providers should use glucocorticoids at the lowest possible dose. Methotrexate, leflunomide and cyclophosphamide are contraindicated in pregnancy and lactation. SLE patients on the biologics rituximab, belimumab and abatacept can continue these medications until conception and resume during lactation.

Purpose of this Review Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy over the past decade. Unfortunately, immune related adverse events (irAEs) are common, including rheumatologic adverse events. These rheumatologic irAEs include de novo rheumatoid arthritis-like presentations or flares of pre-existing rheumatoid arthritis, collectively called ICI-associated rheumatoid arthritis. In this article we review the different mechanisms of disease activity and management approaches including use of conventional (cs) DMARDs and biologic (b) DMARDs in this patient population. Other forms of ICI-induced inflammatory arthritis e.g., PMR-like or Spondylarthritis-type IA, are beyond the scope of this review. Recent Findings The heterogeneous presentations of inflammatory arthritis in patients receiving immune checkpoint inhibitors has made this a challenging area to study. Nonetheless, recent studies are providing better understanding on the mechanisms of de novo disease and flares in patients with rheumatoid arthritis. About half of patients with pre-existing rheumatoid arthritis flare after receiving checkpoint inhibitors. Persistent arthritis is often encountered in patients receiving combination immune checkpoint inhibitors. Outcomes on overall survival do not differ in rheumatoid arthritis patients receiving checkpoint inhibitors compared to their non-arthritis counterparts. Summary Rheumatologist play a critical role in the management of active rheumatoid arthritis induced by checkpoint inhibitors. Collaboration with oncology colleagues will continue to be a crucial component in providing quality care to these patients. While the use of glucocorticoids is often the first line therapy for active inflammatory arthritic disease, we recommend earlier consideration of DMARDs just as we inverted the treatment pyramid several decades ago, for rheumatoid arthritis.

Background:sAnti-nuclear antibodies (ANA) are common in systemic rheumatic diseases, non-rheumatic autoimmune diseases and the general population. In clinical practice, testing for ANA can inform further clinical diagnoses even in the absence of symptoms to suggest SLE or connective tissue disease. This study was undertaken to evaluate whether ANA testing result informed clinical diagnosis.Objectives:1). Determine the frequency of ANA testing in an academic medical center, 2). Determine the demographics and principal diagnoses of people undergoing ANA testing in an academic medical center, and 3) Determine the impact of positive ANA determinations on diagnosis and patient care.Methods:The UT Southwestern Medical Center IRB approved this study. Data were obtained by SQL queries of the Epic electronic health record. The study population included all patients for whom an ANA was ordered at UT Southwestern Medical Center January 1, 2010 to June 30, 2017. The titer and pattern of the ANA as well as the results of ENA or anti-dsDNA testing were documented. Patient characteristics included age and sex. Encounter characteristics included the date of testing, frequency of testing, primary encounter diagnosis, and provider specialty. Chart review was performed by a board-certified rheumatologist in patients who had a change in diagnosis after a positive ANA.Results:During the study period, a total of 33,270 ANA tests were ordered in 28,659 unique patients. 22,529 of the ANAs were tested in outpatients, representing 0.7% of all office visits during this time. Forty-nine percent of the ANA tests were positive at a titer of 1:80 or greater; slightly more women (51%) had a positive ANA (≥1:80) than did men (43%). 54.5% of the positive ANA in women were 1:320 or greater vs. 41.6% in men (p<0.0001). In 118 patients with a positive ANA, ICD 9 coding changed from a non-rheumatic disease diagnosis to a rheumatic disease diagnosis after ANA testing. Chart review showed that 26 of these patients had testing for joint pain. In 7 the note described this as inflammatory, while in 19 it was not specified. In five of the seven patients with a prior diagnosis of rheumatoid arthritis, the diagnosis was changed to SLE, and one was changed to Sicca syndrome. The 19 with non-inflammatory arthritis were diagnosed UCTD (7), with sicca or Sjögren’s (6), drug induced SLE (1) and SLE (3) although none of these fulfilled the 2019 EULAR/ACR criteria. 16 patients had a prior diagnosis of SLE that was confirmed. 14 had a initial diagnosis of “positive ANA” and 13 had their diagnosis changed to a systemic rheumatologic disease (SLE, incomplete SLE, Sjögren’s syndrome, UCTD, or systemic sclerosis). 9 patients had autoimmune liver disease confirmed and 8 had confirmed dermatomyositis. In 1 of 12 patients that carried a diagnosis of rheumatologic disorder (MCTD or Sjögrens) the diagnosis was changed to SLE while the other 11 had the diagnosis stay the same. In most of the remaining patients with either symptoms specific to SLE (pleurisy, pancytopenia, or non-specific hearing loss), the diagnosis was changed to UCTD or sicca syndrome.Conclusion:ANA testing in the inpatient and outpatient setting is common. Diagnoses precipitating testing are most often non-rheumatic conditions. A positive ANA result changed the clinical diagnosis in a small percentage of patients and rarely informed treatment.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:David Karp Support to university from UCB, Eli Lilly, Genentech, Bristol-Myers Squibb, Novartis, and Biogen., Bonnie Bermas: None declared, Shivani Kottur: None declared.

Issues regarding pregnancy in women with systemic lupus erythematosus (SLE) and Sjogren's Syndrome (SS) are an important part of disease management. SLE impacts women during their peak reproductive years while SS occurs more frequently at the tail end of this period.Maternal risksBetter disease control of SLE in general has improved the course of SLE during pregnancy. Nonetheless, pregnancy SLE flare rate still approaches 60 percent. Fortunately, only one-fifth of these flares will be severe. Common disease manifestations during pregnancy include lupus nephritis, cutaneous disease, arthritis and thrombocytopenia. The type of organ-system involvement in the pre-conception period may predict disease symptoms during pregnancy. Risks for flare during pregnancy include active disease in the six months preceding conception and any history of renal disease. Low complement levels and hematologic abnormalities also portend worse pregnancy outcome. Preeclampsia, eclampsia and HELLP syndrome are increased in lupus pregnancies, with 25 percent of women with SLE developing preeclampsia. Preeclampsia can be difficult to distinguish from SLE flare as both conditions are associated with hypertension, edema, proteinuria and low platelet counts. Elevated liver function tests and uric acid levels, an acellular urine sediment and onset after 34 weeks suggest preeclampsia, whereas low complement levels, rising anti-dsDNA antibody titers, low white blood cell count, an active urine sediment and onset prior to 20 weeks gestation are more indicative of a lupus flare. Higher rates of thrombosis, cesarean section and maternal mortality occur in women with SLE when compared to controls. SLE patients with pulmonary hypertension, prior cerebral vascular event or myocardial infarction are at the highest risk for maternal mortality. Limited data precludes conclusions regarding the maternal risks in SS pregnancy other than an apparent increase in cesarean section rate.Fetal risksIncreased rates of miscarriage and stillbirths are reported in SLE pregnancy with and without the presence of antiphospholipid antibodies (aPLs). Preterm premature rupture of the membranes (PPROM) with preterm birth also occurs with higher frequency in SLE pregnancies. Reports for the incidence of small for gestational age infants (SGA) in SLE varies from the background rate of 5% to an increased rate of 30%. There is conflicting data on whether SS causes increased fetal loss. In women with SLE and/or SS, the presence of anti-SS-A/anti-Ro and anti-SS-B /anti-La antibodies is associated with a 10-15% risk of neonatal lupus (cardiac, cutaneous, hematologic and hepatic manifestations) and a 2% risk of congenital complete heart block in the offspring. Risk of the latter increases to 17% in a subsequent pregnancy.Management/TreatmentWomen with SLE and SS should be co-managed by a team that includes a maternal-fetal medicine and rheumatology specialist who are familiar with the management of these disorders during pregnancy. For women with SLE, baseline laboratory testing should be done prior to pregnancy or early in the first trimester. This evaluation should include a complete blood count, liver function tests, assessment of renal function including urine protein testing, uric acid level, anti-dsDNA titer, complement levels and testing for anti-SS-A/anti-Ro and anti-SS-B /anti-La and antiphospholipid antibodies. Patients with SS should also be assessed for the presence of anti-SS-A/anti-Ro and anti-SS-B /anti-La antibodies. Regular monitoring with laboratory testing should be tailored to the individual's clinical situation and antibody status. Treatment strategies should focus on disease control prior to conception. Certain medications commonly used for SLE disease management such as methotrexate, leflunomide, mycophenolate mofetil, cyclophosphamide, belimumab, and rituximab, are contraindicated during pregnancy. Other immunosuppressive agents such as cyclosporine, azathioprine, and tacrolimus are considered compatible with pregnancy. Glucocorticoids can be used during pregnancy although they carry an increased risk of cleft palate formation with first trimester exposure, and PPROM, gestational diabetes and hypertension when used throughout pregnancy. Transitioning women to medications that are compatible with pregnancy should occur six months prior to conception to ensure that patients are stable on their anticipated pregnancy regimen. Hydroxychloroquine use during pregnancy should be encouraged in SLE patients as the data suggest that this medication improves pregnancy outcome. Hydroxychloroquine should also be considered for all anti-SSA/anti-Ro and anti-SSB /anti-La positive mothers to reduce the risk of congenital complete heart block.Disclosure of InterestNone declared

Purpose of Review This article will review the current understanding of the immunologic changes that occur during pregnancy. It will discuss the impact of pregnancy on the disease activity of autoimmune or inflammatory rheumatic diseases (AIRD). Lastly, it will highlight the most recent data on pre-conception and pregnancy management practices that can improve pregnancy outcomes in autoimmune patients. Recent Findings Pregnancy is an immunologically complex and dynamic state that may affect the activity of AIRDs, with more patients having active disease during pregnancy than previously thought. Uncontrolled inflammatory diseases are associated with poor pregnancy outcomes such as preeclampsia, small for gestational age infants, and prematurity. Pre-conception counseling and early pregnancy planning discussions can help ensure optimal disease control and medication management prior to attempting conception. Summary Adequate control of AIRDs on pregnancy-compatible medications during the pre-conception, pregnancy, and postpartum periods is required for optimal pregnancy outcomes.

Pediatric patients often have poor pregnancy outcomes. Systemic lupus erythematosus predominantly impacts women in their second to fourth decade of life, with childhood-onset disease being particularly aggressive. Reproductive issues are an important clinical consideration for pediatric patients with systemic lupus erythematosus (SLE), as maintaining good disease control and planning a pregnancy are important for maternal and fetal outcomes. In this clinical review, we will consider the safety of medications in managing childhood-onset SLE during conception, pregnancy, and breastfeeding. The developing fetus is at highest risk for teratogenicity from maternal medications during the period of critical organogenesis, which occurs between the first 3–8 weeks following conception. Medications known to be teratogenic, leading to a specific pattern of malformations, include mycophenolic acid, methotrexate, and cyclophosphamide. These should be discontinued prior to a planned pregnancy or as soon as pregnancy is suspected. Hydroxychloroquine is safe and should be continued throughout pregnancy and breastfeeding in those without contraindications to it. Azathioprine and calcineurin inhibitors are felt to be compatible with pregnancy in usual doses and may be used prior to and throughout pregnancy and lactation. Non-fluorinated corticosteroids including methylprednisolone and prednisone are inactivated by the placenta and can be used if needed for maternal indication during gestation. Addition of aspirin may be considered around the 12th week of gestation for prevention of pre-eclampsia. Illustrative cases are presented that demonstrate management of adolescents with childhood-onset SLE through conception, pregnancy, and breastfeeding.

Immune checkpoint inhibitors (ICIs) have revolutionized oncology treatment. However, their success is mitigated by the recognition that ICI-induced immune-related adverse events (irAEs) pose considerable challenges to patients and clinicians. These autoimmune toxicities are heterogeneous, unpredictable, and reflect a disease state resulting from a change in the immune system of patients. This contrasts with the typical acute nature of toxicities from chemotherapy and molecularly targeted oncology therapies. Management is further complicated by the extended bioavailability of these agents in patients as well as the persistence of autoimmune pathology. Currently, irAE treatment remains suboptimal in many areas, as many expert guidelines remain vague on the optimal selection, dosing, and duration of steroids and the use of other immunosuppressive agents. This coupled with delays in diagnosis and difficulties for patients accessing effective irAE treatment results in barriers to effective irAE care. The latter is complicated by the lack of US Food and Drug Administration-approved irAE treatments that lead to insurance denials, as well as the high cost of biological immunosuppressant therapies. Fortunately, rheumatologists and other subspecialists with expertize in the management of chronic autoimmune conditions have become more involved in irAE diagnosis and management and may help navigate treatment. In this commentary, we discuss these issues and propose potential solutions to advance the field.