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Fernand Bteich,1 Kush Desai,1 Chenxin Zhang,1,2 Anahat Kaur,3 Rachel A Levy,1 Lydia Bioh,1 Aaron Wang,1 Sharmin Sultana,1 Andreas Kaubisch,1 Milan Kinkhabwala,1,4 Sarah Bellemare,1,4 Shabnam Fidvi,5 Devaraju Kanmaniraja,5 Robert Berkenblit,5 Jee-Young Moon,1,2 Adebola Adedimeji,2 Clara Y Tow,6 Yvonne Saenger1 1Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA; 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; 3Department of Medicine, Division of Medical Oncology, Jacobi Medical Center, Bronx, NY, USA; 4Department of General Surgery, Division of Abdominal Transplantation, Montefiore Medical Center, Bronx, NY, USA; 5Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, USA; 6Department of Medicine, Division of Transplant Hepatology, Montefiore Medical Center, Bronx, NY, USACorrespondence: Yvonne Saenger, Montefiore Einstein Comprehensive Cancer Center, Department of Oncology, Albert Einstein College of Medicine, Golding Building, Room 701, 1300 Morris Park Avenue, Bronx, NY, 10461, USA, Tel +1 718-430-2715, Email yvonne.saenger@einsteinmed.eduBackground: : Incidence of hepatocellular cancer (HCC) in the Bronx is 61% higher than the rest of New York State. Underserved populations are not well represented in clinical trials of immune checkpoint inhibitors (ICI).Methods: Demographics were tabulated for 194 patients treated with ICI at the Montefiore-Einstein Comprehensive Cancer Center (MECCC) between 2017 and 2022. Categorical variables were analyzed by Chi-squared test, and survival was analyzed using Kaplan–Meier (KM) curves.Results: MECCC patients were 40.7% Hispanic and 20.6% Black, compared with 3% and 2%, respectively, in the landmark IMbrave 150 study. Median overall survival (mOS) on ICI was 9.0 months, 25.0 months for the 100 (51.5%) favorable-prognosis Child Pugh A (CPA) patients included in HCC clinical trials. Disease control rate (DCR) was 58.5% among 123 evaluable patients per mRECIST 1.1. Baseline liver function, as defined by CP and the Model for End-Stage Liver Disease-Sodium (MELD-Na), correlated with survival (p < 0.001). Hepatitis C Virus (HCV) and alcoholism were over-represented relative to National Cancer Institute (NCI) data (56.2% vs 4.7% and 38.7% vs 8.2%, respectively). HCV treatment correlated with prolonged survival in infected patients (p = 0.0017). AFP decline correlated with response (p = 0.001). Hispanic patients lived longer when clinical variables were controlled for (mOS 52 vs 23 months; p = 0.011).Conclusion: In an underserved HCC population, ICI yielded a DCR of 58.5% and low rates of severe toxicity. This work highlights ICI efficacy in minority groups, a need for earlier HCC diagnosis and for studies of genetic and environmental factors in Hispanics with HCC.Keywords: hepatocellular carcinoma, systemic therapy, immunotherapy, checkpoint inhibitors, minorities

Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE. ClinicalTrials.gov identifiers: LBSL02: NCT00071487; BLISS-52: NCT00424476; BLISS-76: NCT00410384. [ABSTRACT FROM AUTHOR]

Medicaid annuities are annuities that long-term care recipients use to shelter assets, thereby qualifying them early for Medicaid eligibility. As such, these annuities have the potential to increase Medicaid costs. This study estimates the cost of annuities to the Medicaid program. From a sample of Medicaid applications in five states, we found the rate at which annuities were used and simulated their cost to Medicaid. We estimated that in 2004, Medicaid annuities cost Medicaid about $197 million, which represented a small proportion of Medicaid's almost $50 billion cost for nursing home care. [ABSTRACT FROM AUTHOR]

Innovations in dosage forms and dose delivery systems across a wide range of medications offer substantial clinical advantages, including reduced dosing frequency and improved patient adherence; minimized fluctuation of drug concentrations and maintenance of blood levels within a desired range; localized drug delivery; and the potential for reduced adverse effects and increased safety. The advent of new large-molecule drugs for previously untreatable or only partially treatable diseases is stimulating the development of suitable delivery systems for these agents. Although advanced formulations may be more expensive than conventional dosage forms, they often have a more favorable pharmacologic profile and can be cost-effective. Inclusion of these dosage forms on drug formulary lists may help patients remain on therapy and reduce the economic and social burden of care. [ABSTRACT FROM AUTHOR]

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on Antiphospholipid Antibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previous stroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided. [ABSTRACT FROM AUTHOR]

Gastroesophageal reflux disease (GERD) is a major problem in primary care. More than 25% of the population experience GERD symptoms, and nonerosive forms of the disease are common. Conservative management is recommended. This review and case study presents conservative treatment options from the updated guidelines for the adult patient with GERD. [ABSTRACT FROM AUTHOR]

Consider race or ethnic background when choosing medications since both can affect disease pathophysiology and drug metabolism. Learning about the health beliefs of different groups may also improve adherence--and, thus, clinical outcomes. [ABSTRACT FROM AUTHOR]

AbstractEvaporation of fluid at micro and nanometer scale may be used to self-assemble nanometre-sized particles in suspension. Evaporating process can be used to gently control flow in micro and nanofluidics, thus providing a potential mean to design a fine pattern onto a surface or to functionalize a nanoprobe tip. In this paper, we present an original experimental approach to explore this open and rather virgin domain. We use an oscillating tip at an air liquid interface with a controlled dipping depth of the tip within the range of the micrometer. Also, very small dipping depths of a few ten nanometers were achieved with multi walls carbon nanotubes glued at the tip apex. The liquid is an aqueous solution of functionalized nanoparticles diluted in water. Evaporation of water is the driving force determining the arrangement of nanoparticles on the tip. The results show various nanoparticles deposition patterns, from which the deposits can be classified in two categories. The type of deposit is shown to be strongly dependent on whether or not the triple line is pinned and of the peptide coating of the gold nanoparticle. In order to assess the classification, companion dynamical studies of nanomeniscus and related dissipation processes involved with thinning effects are presented.

Abstract Background Recent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner. Results We have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface. Conclusions We provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.

Una proposta metodologica per favorire lo sviluppo di abilità logiche.

One of the major targets of antiphospholipid antibodies (aPL) is the placenta, the evolution of which during pregnancy has been well documented. Histopathological findings are related to gestational age, and several physiologic and pathologic alterations that occur during its development. The major findings in placentae from aPL positive patients are thrombosis, acute atherosis, a decreased number of syncytio-vascular membranes, increased number of syncytial knots and obliterative arteriopathy. These findings are not specific to the antiphospholipid syndrome (APS) and sometimes do not correlate with the fetal outcome. Histopathological study of placentae may elucidate mechanisms of action of aPL in fetal loss and other obstetric complications. In addition, it may assist in the investigation of the differential diagnosis between APS and pregnancy- induced hypertension. Immunohistochemical studies of local placental proteins contribute to this differential diagnosis. [ABSTRACT FROM PUBLISHER]

Background: Disease remission or low disease activity are key treatment targets for patients with systemic lupus erythematosus (SLE). Pivotal trials of belimumab were conducted before the introduction of these targets. In this study, we aimed to pool data across trials to assess attainment of remission and low disease activity in a large, racially and culturally diverse patient population with SLE., Methods: In this integrated post-hoc analysis, we pooled data from five phase 3 trials of belimumab (BLISS-76 [NCT00410384], BLISS-52 [NCT00424476], BLISS-NEA [NCT01345253], BLISS-SC [NCT01484496], and EMBRACE [NCT01632241]), in patients with active, autoantibody-positive SLE. Patients were randomly assigned to receive belimumab (10 mg/kg per month intravenously or 200 mg per week subcutaneously) or placebo, plus standard therapy. The proportion of patients with Definitions of Remission in SLE (DORIS) remission and lupus low disease activity state (LLDAS) were analysed every 4 weeks from week 4 to week 52 for belimumab versus placebo, using modified Poisson regression adjusted for trial variance, in all patients and in subgroups per baseline SLE Disease Activity Index-2000 score (<10 or ≥10); anti-double stranded DNA positivity (yes or no); low complement 3 (C3) or C4 levels (yes or no); anti-dsDNA positivity or low C3 or C4 levels (yes and no); prednisone-equivalent dose (≤7·5 mg per day or >7·5 mg per day); antimalarial use (yes or no); and by race (Black African ancestry or African American, Asian, Indigenous American, or White)., Findings: Data for 3086 patients (1869 in the belimumab group and 1217 in the placebo group) were analysed. 2913 (94%) of 3086 patients were women and 173 (6%) were men, and the median age was 36 years (IQR 28-45). The proportion of patients with DORIS remission was significantly higher in the belimumab group than the placebo group at weeks 28, 48, and 52 (week 52: 148 [8%] of 1869 participants vs 68 [6%] of 1217 participants; risk ratio 1·51 [95% CI 1·15-1·99]; p=0·0055). The proportion of patients who attained LLDAS was higher in the belimumab group than the placebo group at weeks 8, 24, 32-52 (week 52: 322 [17%] of 1869 participants vs 125 [10%] of 1217 participants; 1·74 [1·44-2·12]; p<0·0001). A higher proportion of patients had DORIS remission at week 52 in the belimumab group than the placebo group among all baseline subgroups denoting high disease activity, with the exception of those on a prednisone-equivalent dose higher than 7·5 mg per day in whom there was no difference for DORIS remission with belimumab versus placebo. The proportion of patients with LLDAS was significantly higher among patients in the belimuab group than those who received placebo from week 44 in all baseline subgroups denoting high disease activity or earlier in some subgroups, and the differences were maintained at week 52., Interpretation: In adults with active SLE, belimumab plus standard therapy yielded greater benefit than placebo plus standard therapy in attaining DORIS remission (for which low rates were attained in both groups) and LLDAS, with differences observed as early as week 28 for DORIS remission and week 8 for LLDAS., Funding: Swedish Rheumatism Association, King Gustaf V's 80-year Foundation, Swedish Society of Medicine, Nyckelfonden, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and the Karolinska Institutet., Competing Interests: Declaration of interests IP reports grants and speaker honoraria from Amgen, AstraZeneca, Aurinia, BMS, Eli Lilly, Gilead, GSK, Janssen, Novartis, Otsuka, and Roche. MZ reports speaker honoraria from Eli Lilly, AstraZeneca, and GSK. AA has received consulting fees from AbbVie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer, and UCB. RvV reports grants from Pfizer and Roche; consulting fees from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, Janssen, Pfizer, Sanofi, Servier, UCB, and Vielabio; and speaker honoraria from AbbVie, Galapagos, GSK, Janssen, Pfizer, UCB, and Roche. MN reports grants from Janssen Pharmaceuticals; and consulting fees and speaker honoraria from AstraZeneca, Boehringer Ingelheim, GSK, and Janssen Pharmaceuticals. RAL, CH, MK, HAQ, and DC are employees of GSK and hold stocks and shares in the company. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The 2023 American College of Rheumatology/EULAR antiphospholipid syndrome (APS) classification criteria development, which aimed to identify patients with high likelihood of APS for research, employed a four-phase methodology. Phase I and II resulted in 27 proposed candidate criteria, which are organized into laboratory and clinical domains. Here, we summarize the last stage of phase III efforts, employing a consensus-based multicriteria decision analysis (MCDA) to weigh candidate criteria and identify an APS classification threshold score., Methods: We evaluated 192 unique, international real-world patients referred for "suspected APS" with a wide range of APS manifestations. Using proposed candidate criteria, subcommittee members rank ordered 20 representative patients from highly unlikely to highly likely to have APS. During an in-person meeting, the subcommittee refined definitions and participated in an MCDA exercise to identify relative weights of candidate criteria. Using consensus decisions and pairwise criteria comparisons, 1000Minds software assigned criteria weights, and we rank ordered 192 patients by their additive scores. A consensus-based threshold score for APS classification was set., Results: Premeeting evaluation of 20 representative patients demonstrated variability in APS assessment. MCDA resolved 81 pairwise decisions; relative weights identified domain item hierarchy. After assessing 192 patients by weights and additive scores, the Steering Committee reached consensus that APS classification should require separate clinical and laboratory scores, rather than a single-aggregate score, to ensure high specificity., Conclusion: Using MCDA, candidate criteria preliminary weights were determined. Unlike other disease classification systems using a single-aggregate threshold score, separate clinical and laboratory domain thresholds were incorporated into the new APS classification criteria., (© 2024 American College of Rheumatology.)

Long-acting reversible contraceptives (LARCs) are effective contraceptive methods for adolescents. This study describes the initiation and continuation of LARC care to adolescents at school-based health centers (SBHCs) during the COVID-19 pandemic. Participants received contraceptive care in New York City SBHCs from April 2021-June 2022. LARC initiation, LARC discontinuation, and total contraceptive visits were measured monthly. During the study period, the SBHCs provided 1,303 contraceptive visits, including 77 LARC initiations. Among LARC initiations, six-month continuation probability was 79.3 % (95 %CI: 69.0-91.1). SBHCs play an important role in providing adolescents contraceptive services, particularly LARC care, when other health care systems are disrupted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria., Competing Interests: Competing interests: ADA has received consulting fees from AbbVie, Amgen, Aurinia, AstraZeneca, BMS and GSK; and has been an investigator for GSK, Janssen, Pfizer, UCB, Vielo, AstraZeneca and Eli Lilly. RAF has received research support from GSK and is an advisory board member for GSK. MD has received consulting fees from Aurinia, AstraZeneca, Biogen, Gilead, Pfizer and GSK. ASB has received consulting fees from Alexion, Principio, Calliditas, Aurinia, Catalyst, Travere, GSK, Visterra, Silence, Novo Nordisk, Otsuka, ChemoCentrx and Novartis. AS has received research grant support from GSK, Novartis and Pfizer; and has been an advisory board and speaker bureau member for GSK. M-HZ has been a consultant or advisory board member for GSK, AstraZeneca, Roche, Novartis, Bayer and BeiGene. INB is a National Institute for Health Research (NIHR) Senior Investigator and is funded by the NIHR Manchester Biomedical Research Centre (NIHR 203308). His institution has received research grants from GSK and Genzyme/Sanofi and consultancy fees from GSK, UCB, Eli Lilly, BMS, Merck Serono, Aurinia and IL-TOO. He has received speaker fees from GSK, AstraZeneca and UCB. RvV has received consulting fees from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, Janssen, Pfizer, Sanofi, Servier, UCB and Vielabio; speaker honoraria from AbbVie, Galapagos, GSK, Janssen, Pfizer and UCB; and support for educational programmes and institutional grants from Pfizer and Roche. MBU has received research grant support from GSK and has been an advisory board and speaker bureau member for GSK, and an advisory board member for AstraZeneca, Eli Lilly and UCB. MD was an employee of GSK at the initial time of writing, and held a stock and shares in the company. MK, BR, AC and RAL are employees of GSK and hold stocks and shares in the company., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease, carries high risk of organ damage and burden to healthcare systems. SLE disease modification aims to reduce disease activity with minimal treatment toxicity and preventing or minimizing organ damage development. This real-world study utilizing healthcare administrative claims data assessed organ damage development, associated costs and healthcare resource utilization (HCRU) in patients with SLE in Germany., Methods: Claims data from January 1, 2007, to December 31, 2017, were obtained from the Betriebskrankenkassen German Sickness Fund Database. Adults (> 18 years) with a confirmed SLE diagnosis between January 1, 2009, and December 31, 2014, (inclusion period) were included. The index date was calculated based on the first recorded SLE diagnosis during this period. Patients were propensity score-matched (1:3) to a comparator cohort without SLE by age, sex, and comorbidities (Charlson comorbidity index). Organ damage was identified using an algorithm developed based on conditions described in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), using ICD-10-GM diagnostic codes, healthcare procedures, and/or treatments., Results: 2121 patients with SLE and 6308 comparator patients were included (mean follow-up time: 6.4 years). Organ damage prevalence increased from 60.5% at baseline to 83.0% during 6 years of follow-up in all patients with SLE, while 17.0% of patients with SLE did not develop organ damage. Patients with newly confirmed SLE diagnosis without organ damage at baseline were nearly twice as likely to develop organ damage within 5 years versus the comparator cohort (52.0% vs. 27.0%). Total annual costs per patient-year for patients with SLE with organ damage were more than double those of patients with SLE without organ damage; both the number of inpatient admissions and length of stay were higher., Conclusions: The application of a recently developed algorithm allowed us to use claims data to elucidate SLE organ damage, and its associated high clinical and economic burden, in a large, representative sample in Germany. To our knowledge, this is the first European analysis of its kind involving a broad cohort of patients with SLE treated in the routine care setting., (© 2024. The Author(s).)

Background: Racial and ethnic disparities in pain management are well documented. Differences in pain assessment and management by language have not been studied in the postoperative setting in gynecologic surgery., Objective: This study aimed to investigate the association between language and immediate postoperative pain management by comparing pain assessments and perioperative opioid use in non-English speakers and English speakers., Study Design: This was a retrospective cohort study comparing perioperative outcomes between non-English-speaking patients and English-speaking patients who had undergone a gynecologic oncology open surgery between July 2012 and December 2020. The primary language was extracted from the electronic medical record. Opioid use is expressed in oral morphine equivalents. Proportions are compared using chi-square tests, and mean values are compared using 2-sample t tests. Although interpreter services are widely available in our institution, the use of interpreters for any given inpatient-provider interaction is not documented., Results: Between 2012 and 2020, 1203 gynecologic oncology patients underwent open surgery, of whom 181 (15.1%) were non-English speakers and 1018 (84.9%) were English speakers. There was no difference between the 2 cohorts concerning body mass index, surgical risk score, or preoperative opioid use. Compared with the English-speaking group, the non-English-speaking group was younger (57 vs 54 years old, respectively; P <.01) and had lower rates of depression (26% vs 14%, respectively; P <.01) and chronic pain (13% vs 6%, respectively; P <.01). Although non-English-speaking patients had higher rates of hysterectomy than English-speaking patients (80% vs 72%, respectively; P =.03), there was no difference in the rates of bowel resections, adnexal surgeries, lengths of surgery, intraoperative oral morphine equivalents administered, blood loss, use of opioid-sparing modalities, lengths of hospital stay, or intensive care unit admissions. In the postoperative period, compared with English-speaking patients, non-English-speaking patients received fewer oral morphine equivalents per day (31.7 vs 43.9 oral morphine equivalents, respectively; P <.01) and had their pain assessed less frequently (7.7 vs 8.8 checks per day, respectively; P <.01) postoperatively. English-speaking patients received a median of 19.5 more units of oral morphine equivalents daily in the hospital and 205.1 more units of oral morphine equivalents at the time of discharge ( P =.02 and P =.04, respectively) than non-English-speaking patients. When controlling for differences between groups and several factors that may influence oral morphine equivalent use, English-speaking patients received a median of 15.9 more units of oral morphine equivalents daily in the hospital cohort and similar oral morphine equivalents at the time of discharge compared with non-English-speaking patients., Conclusion: Patients who do not speak English may be at risk of undertreated pain in the immediate postoperative setting. Language barrier, frequency of pain assessments, and provider bias may perpetuate disparity in pain management. Based on this study's findings, we advocate for the use of regular verbal pain assessments with language-concordant staff or medical interpreters for all postoperative patients., (© 2024 The Authors.)

Objective: To assess the impact of an evidence-informed protocol for management of placenta accreta spectrum (PAS)., Methods: This was a retrospective cohort study of patients who underwent cesarean hysterectomy (c-hyst) for suspected PAS from 2012 to 2022 at a single tertiary care center. Perioperative outcomes were compared pre- and post-implementation of a standardized Multidisciplinary Approach to the Placenta Service (MAPS) protocol, which incorporates evidence-informed perioperative interventions including preoperative imaging and group case review. Intraoperatively, the MAPS protocol includes placement of ureteral stents, possible placental mapping with ultrasound, and uterine artery embolization by interventional radiology. Patients suspected to have PAS on prenatal imaging who underwent c-hyst were included in the analysis. Primary outcomes were intraoperative complications and postoperative complications. Secondary outcomes were blood loss, need for ICU, and length of stay. Proportions were compared using Fisher's exact test, and continuous variables were compared used t -tests and Mood's Median test., Results: There were no differences in baseline demographics between the pre- ( n  = 38) and post-MAPS ( n  = 34) groups. The pre-MAPS group had more placenta previa (95% pre- vs. 74% post-MAPS, p  = 0.013) and prior cesarean sections (2 prior pre- vs. 1 prior post-MAPS, p  = 0.012). The post-MAPS group had more severe pathology (PAS Grade 3 8% pre- vs. 47% post-MAPS, p  = 0.001). There were fewer intraoperative complications (39% pre- vs.3% post-MAPS, p  < 0.001), postoperative complications (32% pre- vs.12% post-MAPS, p  = 0.043), hemorrhages >1l (95% pre- vs.65% post-MAPS, p  = 0.001), ICU admissions (59% pre- vs.35% post-MAPS, p  = 0.04) and shorter hospital stays (10 days pre- vs.7 days post-MAPS, p  = 0.02) in the post-MAPS compared to pre-MAPS patients. Neonatal length of stay was 8 days longer in the post-MAPS group (9 days pre- vs. 17 days post-MAPS, p  = 0.03). Subgroup analyses demonstrated that ureteral stent placement and uterine artery embolization (UAE) may be important steps to reduce complications and ICU admissions. When comparing just those who underwent UAE, patients in the post-MAPS group experienced fewer hemorrhages greater five liters (EBL >5l 43% pre- vs.4% post-MAPS, p  = 0.007)., Conclusion: An evidence-informed approach to management of PAS was associated with decreased complication rate, EBL >1l, ICU admission and length of hospitalization, particularly for patients with severe pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Levy, Diala, Rothschild, Correa, Lehrman, Markley, Poder, Rabban, Chen, Gras, Sobhani, Cassidy and Chapman.)

Background: Data on belimumab efficacy in patients with lupus nephritis (LN) according to diagnosis duration or induction therapy are limited. Post hoc analyses of the phase 3, randomized, double-blind BLISS-LN study (GSK BEL114054; NCT01639339) were performed to assess belimumab efficacy on kidney-related outcomes in newly diagnosed and relapsed LN subgroups and according to the use of glucocorticoid (GC) pulses at induction., Methods: BLISS-LN randomized 448 patients with active LN to monthly intravenous belimumab 10 mg/kg or placebo plus standard therapy. Post hoc analyses assessed primary efficacy renal response (PERR) and complete renal response (CRR) at week 104, time to kidney-related event or death and time to first LN flare from week 24 in newly diagnosed and relapsed patients and patients with/without GC pulses at induction., Results: A greater proportion of patients achieved a PERR with belimumab versus placebo in the newly diagnosed {69/148 [46.6%] versus 55/148 [37.2%]; odds ratio [OR] 1.36 [95% confidence interval (CI) 0.85-2.20]} and relapsed [27/75 (36.0%) versus 17/75 (22.7%); OR 2.31 (95% CI 1.07-5.01)] subgroups. Similarly for CRR [newly diagnosed: 50/148 (33.8%) versus 36/148 (24.3%); OR 1.49 (95% CI 0.88-2.51) and relapsed: 17/75 (22.7%) versus 8/75 (10.7%); OR 3.11 (95% CI 1.16-8.31)]. The probability of kidney-related event or death, or LN flare was lower with belimumab versus placebo in both subgroups. Belimumab was associated with improved kidney outcomes versus placebo with or without GC pulses at induction., Conclusion: Data suggest consistent benefits of belimumab on kidney outcomes for newly diagnosed and relapsed patients, and irrespective of GC pulses at induction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Introduction: Lupus nephritis (LN) treatment aims to control and prevent flares and irreversible kidney damage. Around 30% of patients are unresponsive to treatment; however, real-world LN treatment patterns have not been reported. Objectives of this retrospective cohort study (GSK 209758) were to quantify the time to switching/re-initiating induction therapy in patients with LN initiating immunosuppressant therapy and conversion from induction to maintenance immunosuppressant therapy, and to assess corticosteroid use., Methods: Patients with LN initiating induction or maintenance immunosuppressant therapy were identified using claims data. Patients were followed up from the index date (immunosuppressant initiation date) until treatment discontinuation, death, disenrollment, administrative censoring, or the end of follow-up period. The cumulative incidence of switching/re-initiating induction therapy and conversion to maintenance therapy was estimated using outpatient pharmacy claims and procedure codes. Corticosteroid use was estimated using pharmacy claims; a mean daily dose of ≥ 7.5 mg/day was considered high., Results: In total, 5000 patients with LN contributed 5516 treatment episodes (induction cohort, N = 372; maintenance cohort, N = 5144). In the induction cohort, the cumulative incidence (95% confidence interval) of switching between induction therapies was 24.6% (20.1-30.0) at 12 months, while 59.6% (52.4-66.1) of patients converted to maintenance therapy at 12 months. In the maintenance cohort, 21.2% (19.9-22.5) re-initiated induction therapy at 12 months. Oral corticosteroid use decreased during the follow-up in both cohorts, but 21.5% of patients remained on a high dose at 12 months in the induction cohort, while 15.8% in the maintenance cohort were taking a high dose at 24 months., Conclusions: Around a quarter of patients with LN initiating immunosuppressant therapy switched within 12 months, while a fifth re-initiated induction therapy within 12 months. Use of high corticosteroid doses were observed during 24 months of follow-up. These data suggest that many patients do not respond to existing standard LN therapies., (© 2023. The Author(s).)

Objective: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR., Methods: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard., Results: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-β 2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%., Conclusion: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research., (© 2023 American College of Rheumatology.)

Objective: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR., Methods: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard., Results: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-β 2 -glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%., Conclusion: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research., Competing Interests: Competing interests: RAL is an employee of GlaxoSmithKline., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can lead to irreversible organ damage (OD). Data describing the patient burden of OD, as compared with SLE without OD, are limited. Objective: To develop a comprehensive conceptual model describing the burden experienced by patients living with SLE-associated OD. Methods: There were three phases to this qualitative study. First, a targeted literature review was conducted to inform a draft conceptual model. Second, key opinion leaders (KOLs) were interviewed to assess the draft conceptual model and help shape patient interview materials. Third, patients of different demographic backgrounds from across the United States were interviewed individually to gather their perspectives on living with SLE-associated OD. Data from concept elicitation interviews with KOLs and patients were coded and analyzed using NVivo software to identify the key concepts of the overall patient burden of SLE-associated OD. Findings from the KOL and patient interviews were used to finalize the conceptual model. Results: KOLs highlighted that SLE-associated OD carried a higher rate of mortality than SLE alone. Participants with SLE-associated OD (n = 40) experienced detrimental impacts across 4 areas of their lives: physical, cognitive, psychosocial functioning, and economic and work-related well-being. Physical impacts were described by all participants, often affecting their ability to perform everyday tasks. Many also described deterioration of cognitive functioning. Almost all participants experienced emotional impacts and challenges to their relationships and social lives resulting from living with SLE-associated OD. Additionally, SLE-associated OD imposed an economic burden including increased healthcare costs. SLE-associated OD had a more severe and debilitating impact on all aspects of the patient's quality of life than SLE prior to OD development, including further limitations in activities of daily living after the development of OD. Discussion: Study findings guided the development of a comprehensive conceptual model that fully represents the patient experience of living with SLE-associated OD, highlighting the additional burden of OD when compared with SLE alone. Conclusions: The conceptual model will inform improvements in disease management, which may result in better patient outcomes and aid development of clinical outcome assessments of disease burden., Competing Interests: L.B. and A.M.F. are current employees of QualityMetric, and C.U.F. is a former employee of QualityMetric. QualityMetric received funding from GSK to conduct this research. W.H.C., R.A.L., and D.C. are employees of GSK and hold stocks and shares in the company. K.G. is a former employee of GSK and holds stocks and shares in the company.

Objective: To generate comparative efficacy evidence of belimumab versus anifrolumab in SLE that can inform treatment practices., Methods: The SLE Responder Index (SRI)-4 response at 52 weeks of belimumab versus anifrolumab was evaluated with an indirect treatment comparison. The evidence base consisted of randomised trials that were compiled through a systemic literature review.A feasibility assessment was performed to comprehensively compare the eligible trials and to determine the most appropriate indirect treatment comparison analysis method. A multilevel network meta-regression (ML-NMR) was implemented that adjusted for differences across trials in four baseline characteristics: SLE Disease Activity Index-2K, anti-double-stranded DNA antibody positive, low complement (C)3 and low C4. Additional analyses were conducted to explore if the results were robust to different sets of baseline characteristics included for adjustment, alternative adjustment methods and changes to the trials included in the evidence base., Results: The ML-NMR included eight trials: five belimumab trials (BLISS-52, BLISS-76, NEA, BLISS-SC, EMBRACE) and three anifrolumab trials (MUSE, TULIP-1, TULIP-2). Belimumab and anifrolumab were comparable in terms of SRI-4 response (OR (95% credible interval), 1.04 (0.74-1.45)), with the direction of the point estimate slightly favouring belimumab. Belimumab had a 0.58 probability of being the more effective treatment. The results were highly consistent across all analysis scenarios., Conclusions: Our results suggest that the SRI-4 response of belimumab and anifrolumab are similar at 52 weeks in the general SLE population, but the level of uncertainty around the point estimate means we cannot rule out the possibility of a clinically meaningful benefit for either treatment. It remains to be seen if specific groups of patients could derive a greater benefit from anifrolumab or from belimumab, and there is certainly an unmet need to identify robust predictors towards more personalised selection of available biological agents in SLE., Competing Interests: Competing interests: BN, PS, MS and AM are employees of Evidera, a part of Thermo Fisher Scientific. MP has received grant/research support from AstraZeneca, Aurinia, Eli Lilly, Exagen, GSK, Janssen and Thermo Fisher. MP has also received consulting fees from the BPR Scientific Advisory Committee, Alexion, Amgen, AnaptysBio, Argenx, AstraZeneca, Aurinia, AxDev, Biogen, Boston Pharmaceuticals, Caribou Biosciences, CVS Health, Eli Lilly, Gilead Biosciences, GSK, Idorsia Pharmaceuticals, Janssen, Kezar Life Sciences, Kira Pharmaceuticals, Momenta Pharmaceuticals, Nimbus Lakshmi, Proviant, Sanofi, SinoMab and UCB. MP has received speakers’ fees from Aurinia, MedShr and Arthros-FocusMedEd, and has received consulting fees for participation in a data safety monitoring board or advisory board for EMD Serono, Emergent Biosolutions, IQVIA and PPD Development. GKB has received consulting fees from Pfizer, Lilly and Novartis, and has received honorary fees from GSK, AstraZeneca, Pfizer, Novartis, Aenorasis, AbbVie and Lilly. GKB has also received a research grant from Pfizer. AHJK has received research support to Washington University from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant number P30 AR073752), National Center for Advancing Translational Sciences (grant number UL1 TR002345), Leona M. and Harry B. Helmsley Charitable Trust, Rheumatology Research Foundation, and National Multiple Sclerosis Society, GSK, and Foghorn Therapeutics. AHJK has performed consultancy for Alexion Pharmaceuticals, ANI Pharmaceuticals, AstraZeneca, Aurinia Pharmaceuticals, Exagen Diagnostics, GSK, Kypha and Pfizer unrelated to this work. AHJK has received payment or honoraria (for lectures, presentations, speakers bureaus, manuscript writing or educational events) from AstraZeneca, Aurinia Pharmaceuticals, Exagen Diagnostics and GSK. AHJK has participated on a data safety monitoring board or advisory board for National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases. AHJK has been a board member for the Rheumatology Research Foundation Scientific Advisory Board and the Lupus Foundation of America-Heartland Chapter, and president of the St Louis Rheumatology Association. AHJK is the inventor of patent number 11029318 with Kypha unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Washington University, its affiliated academic health care centers, or the National Institutes of Health. AF has received honoraria and consulting fees from GSK, Aenorasis and AstraZeneca. AF has been a paid speaker for AbbVie, Amgen, Pfizer, Lilly, Genesis-Pharma, Novartis, UCB and Boehringer-Ingelheim. RAL, DC and NB are employees of GSK and hold stocks and shares in GSK., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Implementation support through coaching-such as with embedded fidelity assessment, performance feedback, modeling, and alliance building-has been empirically supported as a way to increase and sustain interventionists' fidelity levels. However, education research consistently shows that practitioners struggle to monitor and improve interventionists' fidelity using implementation support strategies. One explanation for this type of implementation research-to-practice gap is that evidence-based coaching strategies have significant limitations with respect to their usability, feasibility, and adaptability. This study is the first to experimentally evaluate an evidence-based set of adaptable materials and procedures designed to assess and support the intervention fidelity of school-based interventions. Using a randomized multiple-baseline-across-participants design, we examined the extent to which these materials and procedures would influence intervention adherence and quality of an evidence-based reading intervention. Across all nine interventionist participants, data revealed that the implementation strategies meaningfully improved intervention adherence and quality, and high levels of intervention fidelity maintained 1 month after removing the support procedures. Findings are discussed with respect to how these materials and procedures address a critical need within school-based research and practice as well as how they may help to inform and address the implementation research-to-practice gap in education., (Copyright © 2023 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.)

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Premise: Fungaria are an underutilized resource for understanding fungal biodiversity. The effort and cost of producing DNA barcode sequence data for large numbers of fungal specimens can be prohibitive. This study applies a modified metabarcoding approach that provides a labor-efficient and cost-effective solution for sequencing the fungal DNA barcodes of hundreds of specimens at once., Methods: We applied a two-step PCR approach using nested, barcoded primers to sequence the fungal nrITS2 region of 766 macrofungal specimens using the Illumina platform. The specimens represent a broad taxonomic sampling of the Dikarya. Of these, 382 Lactarius specimens were analyzed to identify molecular operational taxonomic units (MOTUs) using a phylogenetic approach. The raw sequences were trimmed, filtered, assessed, and analyzed using the DADA2 amplicon de-noising toolkit and Biopython. The sequences were compared to the NCBI and UNITE databases and Sanger nrITS sequences from the same specimens., Results: The taxonomic identities derived from the nrITS2 sequence data were >90% accurate across all specimens sampled. A phylogenetic analysis of the Lactarius sequences identified 20 MOTUs., Discussion: The results demonstrate the capacity of these methods to produce nrITS2 sequences from large numbers of fungarium specimens. This provides an opportunity to more effectively use fungarium collections to advance fungal diversity identification and documentation., (© 2023 The Authors. Applications in Plant Sciences published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Objective: Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab., Methods: Data collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively., Results: Among 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data., Conclusions: Observations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use., Competing Interests: Competing interests: KG, MKh, RAL, AL, RM, MBC, KW, JHNH, HQ, PJ and DAR are employees of GSK and hold shares in the company. KG is a previous employee of Novartis and holds shares in the company. At the time of the study, MKu, PM and JMP were employees of GSK and hold shares in the company. MP received grant support from GSK and is a member of the BPR Scientific Advisory Committee. HL received royalties/licences from UpToDate Inc (Wolters Kluwer Health), has received consulting fees from AMAG Pharmaceuticals and is a member of the BPR Scientific Advisory Committee. KS is employed by the University of North Carolina at Chapel Hill to assist GSK with research. HT is a member of the BPR Scientific Advisory Committee and a GSK retiree. MEBC received grants from GSK and UCB, and acted as a consultant to GSK and UCB. RAL is the guarantor., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lupus is a complex disease that is often difficult to diagnose. Risks of diagnostic delays include non-specific signs and symptoms that mimic other diseases and a lack of diagnostic criteria and referral pathways for non-specialists. To address these issues, we convened a series of virtual meetings with members of our Addressing Lupus Pillars for Health Advancement clinical care team. Meeting participants included lupus physicians, treatment developers from biotechnology, patient advocacy group representatives from the Lupus Foundation of America and advocacy/government consultants. Causes and consequences of ambiguity in diagnosis and diagnostic delays were evaluated through historical, experiential and evidence-based accounts (survey data, literature reviews and patient testimonials). Discussions highlighted the need for a clearer understanding of the definition of lupus, the natural history of the disease and the need for advancements in biotechnology to support an accurate and timely diagnosis with the potential development of a lupus spectrum., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)