Subsequent Outcomes Research Articles

Bendamustine Lymphodepletion (LD) Prior to Idecabtagene Vicleucel (Ide-cel) Is Associated with Inferior Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Background Chimeric antigen receptor therapy (CART) has revolutionized the management of RRMM. LD prior to CART cells modulates the immune environment creating optimal conditions for T cell expansion and subsequent efficacy. Fludarabine/cyclophosphamide (FLU/CY) is an effective LD regimen, and its use has been adopted widely prior to CART cells for all indications. Since the safety of FLU/CY is not established in patients with substantial renal impairment and given recent nationwide fludarabine shortage, alternative lymphodepletion strategies have been explored. Bendamustine (BENDA) has been shown to be a safe alternative with equivalent efficacy and reduced toxicity in non-Hodgkin's lymphoma (NHL). While its use has been extrapolated to RRMM, efficacy and long-term outcomes have not been examined. Methods We retrieved and analyzed data on sequential patients (pts) with RRMM treated with commercial Ide-cel at a single institution from its approval in 3/2021 until 5/2023. We captured baseline patient, disease and treatment characteristics. We used IgG (with monoclonal component deducted) and uninvolved FLC as indirect surrogate of CAR-T expansion and on target, off tumor killing of non-malignant plasma cells. We assessed cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) based on the American Society for Transplantation and Cellular Therapy criteria and disease responses using the International Myeloma Working Group response criteria. We graded hematologic toxicity using the Common Terminology Criteria for Adverse Events version 5.0. We compared efficacy between the cohorts using overall response rate (ORR) and progression-free survival (PFS), since overall survival is expected to be affected by choice of subsequent, often experimental therapies. Results We identified 28 pts with RRMM who met the inclusion criteria. Nine pts received alternative LD with BENDA (2 pts - renal dysfunction with creatinine clearance <30ml/min; 7 - fludarabine shortage) and 19 received FLU/CY as LD. Baseline characteristics are summarized in Table. Prior autologous stem cell transplant (ASCT) and prior B cell maturation antigen (BCMA) targeting therapy were more frequent in the FLU/CY cohort. Median absolute lymphocyte count (measured in 10^3/ cmm) prior to LD chemotherapy was similar in both cohorts (0.85 in BENDA vs 0.80 in FLU/CY). Median duration of absolute neutrophil count <1,000/μL was shorter in the BENDA cohort. The incidence of any grade CRS (56% vs. 90%, p=0.06) and tocilizumab use (56% vs. 84%, p=0.16) was lower with BENDA compared to FLU/CY. In the absence of ide-cel expansion data, we used nadir polyclonal IgG and uninvolved free light chain (uFLC) in the initial 90 days post CART cell infusion as surrogate of non-malignant plasma burden and therefore ide-cel expansion. We noted lower median uFLC and median IgG with FLU/CY vs. BENDA. The overall response rate was lower with BENDA (22%) vs. FLU/CY (79%, p=0.01). With median follow up of 4.8 mo., all pts in the BENDA cohort progressed with median PFS of 1.6 months vs 7.8 months for FLU/CY (p<0.001, Figure). The median OS for both cohorts is not yet reached. Conclusion: BENDA LD prior to ide-cel infusion results in suboptimal lymphodepletion and subsequent inferior outcomes including low rate of objective responses and decreased progression free survival. The inferior efficacy of BENDA as LD likely results from inferior ide-cel expansion and persistence resulting in less frequent and severe CRS and cytopenias and less suppression of unaffected immunoglobulins. Future efforts to study alternative lymphodepletion approaches is essential given inability to use fludarabine in patients with severe renal dysfunction and periods of critical drug shortages. While there is a need to develop alternatives for LD prior to ide-cel, BENDA is an inadequate substitute of FLU/CY.

Impact of Anticoagulation in Acquired Hemophilia a

Background Acquired Hemophilia A (AHA) is a rare autoimmune disorder that occurs due to the development of autoantibodies against factor VIII which leads to inhibition of the coagulation cascade and results in a propensity for hemorrhage. The estimated incidence is approximately 1.5 per million per year. It carries an exceptionally high morbidity and mortality rate, with severe or life-threatening hemorrhagic events occurring in 70-90% of cases, with 5-10% of these cases resulting in mortality. Several underlying conditions are associated with AHA, including autoimmune disorders, obstetrical and oncologic disease, and various medications, such as direct oral anticoagulants (DOACs) and antiplatelet therapy (APT), both of whose usage has increased significantly over the past decade. Objectives We aimed to evaluate whether patients prescribed an antiplatelet or anticoagulant at the time of diagnosis of AHA experienced more severe bleeding and worse clinical outcomes compared to those with AHA not prescribed an antiplatelet or anticoagulant. Methods This is a single-center retrospective study examining 16 individuals with AHA from April 2013 to April 2023. These individuals were categorized by the presence or absence of a prescribed anticoagulant and then further divided into class of anticoagulant (APT, DOAC or other oral anticoagulant (OAC), or exposure to both). Primary end points included the number of blood product transfusions received, hospital length of stay (LOS), need for intervention or procedure, and degree of hemoglobin (Hgb) drop from baseline. Continuous variables were compared using t-test or Wilcoxon rank-sum test while categorical variables were compared using the chi-square test or Fisher's exact test. Results Of the 16 individuals in our cohort, 9 were without prior exposure to anticoagulation or antiplatelet agents before the diagnosis of AHA while 7 were prescribed either an anticoagulant, antiplatelet agent, or both. Of those taking one of these classes of medications, 2 were prescribed OACs, 3 were prescribed APTs, and 2 were prescribed both classes. The mean baseline Hgb was similar in both groups, 12.84 for the non-exposed group and 12.92 for the exposed group, while mean Hgb at diagnosis was 9.55 and 8.81 for the non-exposed group and exposed group respectively (p-value 0.638). Median factor VIII titer inhibitors at diagnosis were 3.30 and 38.10 (p-value 0.124) for non-exposed and exposed groups, respectively. Mean hospitalization rates for non-exposed individuals versus exposed individuals were 5.0 and 7.0 (p-value 2.00) with a mean hospital LOS of 10.20 and 12.57 days (p-value 0.624) in the non-exposed and exposed group, respectively. The mean number of packed red blood cell (pRBC) transfusions needed during the index hospitalization was 1.6 and 3.0 (p-value 0.333) in the non-exposed group and exposed group respectively while the mean number of platelet transfusions were 4 and 6 in the non-exposed and exposed groups respectively. There was a statistically significant increase in intramuscular bleeding with a mean of 1.0 and 5.0 (p-value 0.035) in the non-exposed and exposed groups respectively. In each group there was only one individual who required procedural intervention. There was one death due to hemorrhage which occurred in the exposed group (p-value 0.467). Conclusions The increased rates of intramuscular bleeding in patients exposed to prior anticoagulation was statistically significant. Intramuscular hemorrhage is associated with increased morbidity due to the risk for compartment syndrome requiring surgical intervention. Our data demonstrates a trend towards the need for a longer hospitalization and more pRBC transfusions in individuals with prior exposure though notably, there is not an apparent increased trend for an increased rate of platelet transfusions. There is also a trend towards significance for higher factor VIII titer inhibitor levels in patients on anticoagulation at the time of diagnosis. While this study is limited in power by the sample size, there are no comparable studies to date examining the impact of anticoagulation on individuals with AHA. With the increasing rates of anticoagulation therapy, further investigation is needed on the impact of therapeutic anticoagulant or antiplatelet use prior to the diagnosis of AHA and subsequent clinical outcomes.

Antecedents and consequences of perpetrator-centric knowledge hiding within organizations: a cross-cultural meta-analytic review and implications for human resource management

As knowledge hiding has become an increasingly widespread phenomenon within organizations, there has been a dramatic increase in research on this topic over the past two decades. However, previous studies have provided inconsistent conclusions on why knowledge hiding occurs and how it affects the perpetrator’s subsequent work and well-being outcomes. As no reviews to date have focused on the knowledge hiding from the perpetrator’s perspective, this meta-analysis systematically synthesizes frequently studied antecedents and consequences of perpetrator-centric knowledge hiding. It also examines the moderating effects of cultural dimensions and causal directions on the consequences. Based on evidence from N = 193 sources with a total sample size of N = 68,113, this meta-analysis found significantly strong relationships between neuroticism, moral disengagement (hider’s factors), psychological contract breach, toxic leadership, leader-signaled knowledge hiding, perceived organizational politics (contextual factors) and knowledge hiding. The findings revealed that knowledge hiding had a medium-sized positive relationship with perpetrator psychological strain. It also uncovered the cross-cultural differences among the perpetrator-centric consequences. These findings helped answer the question of whether some common predictors or outcomes of knowledge hiding should be identified as outcomes or indicators. Finally, it provided suggestions for future research and human resource management (HRM) practices.

Use of Ponatinib Alone or Combined with Other Therapies in Relapsed/Refractory Ph-like Acute Lymphoblastic Leukemia. a Campus ALL Real-Life Study

Introduction. Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) employed in relapsed/refractory (R/R) and, more recently, also in newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ph-like ALL is a genetically heterogenous subgroup that shares a common transcriptional profile, similar to that of true Ph+ ALL, though lacking the BCR::ABL1 rearrangement. Ph-like ALL is characterized by a poor prognosis, a high relapse rate and a worse overall survival if treated with standard chemotherapy. Several molecular pathways are involved, including JAK/STAT, CRLF2 and ABL-class mutations, providing a heterogeneous genetic landscape with very limited data on the subsequent clinical outcome. Few isolated cases of successful treatment of R/R Ph-like ALL with ponatinib have been reported, including also patients with lesions different from ABL-class mutations. Currently, ponatinib prescription in Italy is not allowed for Ph-like ALL. Patients and Methods. Between January 2019 and July 2023, 17 patients were candidate to receive ponatinib on a nominate compassionate use basis; data were collected in the context of the Campus ALL network in Italy. The criteria for inclusion were a diagnosis of Ph-like ALL, with either hematological or molecular evidence of disease, and a treatment period of at least 28 consecutive days of ponatinib. The Ph-like signature was based on the BCR/ABL1 like-predictor (Chiaretti et al, BJH 2018) and, whenever possible, targeted RNA sequencing. Final data were collected for 15 patients (2 patients were excluded due to a treatment period <28 days) treated with ponatinib either as a single agent or in association with immuno and/or chemotherapy. Results. All patients had common ALL. Eight of the 15 cases were classified as high risk or very high risk ALL at diagnosis; 10 were males, the median age was 28 years (14-66) and the median white blood count at diagnosis was 25.6 x10 9/l (2.7-317 x10 9/l). Targeted RNA sequencing was carried out in 10/15 cases: 7 presented gene fusions ( ABL-class mutations in 2, JAK2 mutations in 2, and CRLF2::P2RY8, IKZF1::DDC and RB1::RCBTB2 in 1 case each); 2 additional cases had a CRLF2 rearrangement, evaluated by FISH. Copy number aberrations analysis by multiplex ligation-dependent probe amplification (MLPA) technology was performed in 12/15 cases: 5 cases had a IKZF1 plus signature, 6 had a IZKF1 loss, while 1 case was IKZF1 wild type. Ponatinib was started in first (n=2) or second (n=5) hematologic relapse in 7 patients (46%), with 3 also having an extramedullary disease; 7 additional patients (46%) were treated in first (n=5) or second (n=2) minimal residual disease (MRD) persistence/recurrence; finally, 1 patient was refractory to 3 subsequent lines of treatment. In 8/15 patients ponatinib was used as single agent or in association with steroids or intrathecal chemotherapy only, in 4 it was administered in combination with chemotherapy and in 3 with blinatumomab; 7 patients started ponatinib after having failed an allogeneic transplant (6 hematologic relapses and 1 molecular relapse). A complete hematological and molecular remission (MRD- CR) was achieved in 6 patients (40%); notably, 4 of these 6 cases carried a gene fusion (1 JAK2 rearrangement, 1 ABL-class fusion, 1 IKZF1::DDC and 1 RB1::RCBTB2); 2 further patients in hematologic relapse at the start of treatment achieved a MRD+ CR (1 patient had a ABL-class gene fusion). Thus, the overall response rate was 53%. Four patients were refractory, while 2 maintained a stable disease. After ponatinib-based treatment, 6 patients were allografted and 1 received a CAR-T cell infusion. The toxicity profile was mild: 3 patients developed a transaminitis, 1 also had a fungal pneumonia, and 1 an increase in pancreatic enzymes. At a median follow-up of 3 months (1-5), 10 patients are alive, 8 being in continuous complete remission. Conclusions. Treatment with ponatinib showed promising results in terms of CR achievement in a heavily pre-treated population of Ph-like ALL patients, with an acceptable toxicity profile. In a pre-transplant setting, ponatinib was effective as a bridge to cellular therapies in 7 out of 8 patients as intention-to-treat (ITT), thus suggesting that this strategy may represent an effective bridge to further therapies. To our knowledge, this is the largest cohort of adult Ph-like ALL cases treated with ponatinib so far reported.

Outcomes of Patients with Newly Diagnosed Multiple Myeloma Experiencing Treatment Failure after Upfront Quadruplet Therapy and Autologous Stem Cell Transplantationgayathri Ravi 1, Susan Bal 1, Kelly Godby 1, Smith Giri 1, Clare Ubersax 1, Abigail Tucker 1, Luciano J Costa 1

Background The combination of a proteasome inhibitor (PI) an immunomodulatory agent (IMiD), an anti-CD38 monoclonal antibody (anti-CD38MoAb) and dexamethasone, i.e. quadruplet therapy (QUAD) leads to highest rate of complete responses (CR) and prolonged progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM) in the context of autologous stem cell transplantation (ASCT). While there are treatment failures reported after QUADs and they may be exquisitely challenging to treat the published literature in this setting is scarce. Methods We included all patients treated with QUADs between January 2016 and May 2023 with intention to proceed with ASCT to identify treatment failures and report outcomes. Treatment failures were classified into primary failure (PF) defined as lack of objective response after at least 4 QUAD cycles or progression during or within 60 days of completing QUAD therapy; early progression (EP), defined as disease progression 2-12 months of completing QUAD therapy, and late progression (LP) defined as disease progression > 12 months from completing QUAD therapy. For each of these groups we analyzed disease features, treatment refractoriness (as patients in EP and LP may have varying refractoriness depending on maintenance therapy received), response to subsequent therapy and outcomes- Overall response rates(ORR), Progression free survival(PFS) and Overall Survival(OS). Results We identified 248 sequential patients treated with QUADs, including 191 (77%) treated with daratumumab, bortezomib, lenalidomide and dexamethasone (D-VRd), and 57 (23%) treated with daratumumab, carfilzomib, lenalidomide and dexamethasone (D-KRd). Median follow up for all patients is 20.4 months (IQR 11.3-34.0) from onset of QUAD therapy. We found 11 patients with PF, 9 with EP and 11 with LP (Table) for a total of 31 treatment failures. Patients with QUAD failures were more likely to have ISS-3, R-ISS3 and 2+ high-risk chromosome abnormalities than the overall QUAD population. Median follow up from QUAD failure is 5.2 months for PF, 11.2 months for EP and 10.7 months for LP. All 31 patients with QUAD failure received subsequent therapy and 28 patients have > 1 month follow up enable assessment of response to subsequent therapy (Table). Cytotoxic chemotherapy was frequently used in patients with PF (60%) whereas anti-CD38 monoclonal Ab containing regimen was commonly used with increasing time from initial QUAD therapy reaching 89% in patients with LP. ORR to next line of therapy was 20% for PF, 33% for EP and 67% for LP. Of the 28 patients, 13(46%) participated in subsequent treatment clinical trial and 16(57%) received subsequent T-cell redirecting therapy either bispecific antibody or CAR-T cell therapy . Median PFS on next line of therapy was 2.4 months for PF, 3.7 months for EP and 7.4 months for LP. Median OS from QUAD failure was only 6.3 months for PF and 11.5 months for EP. No deaths (0/11) observed in LP group (Figure). Conclusions Multiple myeloma patients with delayed progression (>12 months) from end of QUADs have reasonable response to subsequent therapy. Despite access to experimental therapies including T-cell redirected therapies, patients with earlier failure of QUAD therapy (0-12 months) have poor response rates to subsequent treatments and significantly shorter survival. These findings highlight the urgent need for better predictive models to identify patients with QUAD failure and preemptively deploy treatments with novel mechanisms of action.

Continuous and Placement Assessment Results as a Predictor of Student Achievement in Primary Schools

The purpose of this study was to explore the performance of out-of-school children in speed school and accelerated learning programs as a basis for success in primary schools. This research field has received very little attention. The continuous assessment and placement test results of students at risk were not used much in the literature, which this study aims to fill. The total number of students involved in the study was 624. The study used the continuous assessment average scores and placement test scores as predictor variables. The results show that the relationship between placement test and 1st-semester score in grade four was significant, r (196) = .501, p < .001. For the Accelerated Learning Program, the placement test and 1st-semester score in grade three were significant, r (111) = .413, p<.001. As a tool to forecast primary school students' future achievement, the teacher-made continuous assessment appears to be less useful than placement tests for children who come through speed school. Students from speed school backgrounds performed better than students from formal schools; students from accelerated learning program backgrounds performed almost similarly to students from formal schools except in environmental science. The study indicated that in grade four of formal primary school, continuous assessment was found to be poorly linked with student knowledge and skills. However, the results show that both comparisons found placement examinations to be a reliable indicator of children's achievement in primary schools. It can be concluded that students who joined grades three and four of formal school through speed school and an accelerated learning program are capable of achieving minimum learning competence in the subsequent educational outcomes in elementary grades.

Real-World Experience With CMV inSIGHT T Cell Immunity Testing in High-Risk Kidney and Pancreas Transplant Recipients.

Cytomegalovirus (CMV)-specific cell-mediated immunity is important for control of CMV after transplant. Assays exist to measure this, but their place in therapy is unclear, particularly in CMV high-risk recipients, without pretransplant exposure. The objective of this study was to evaluate predictive potential of a positive assay to determine freedom from DNAemia and describe subsequent 3-month CMV outcomes. Adult CMV high-risk kidney and/or pancreas transplant recipients were included if a CMV inSIGHT T Cell Immunity Panel (TCIP, Eurofins Viracor) was ordered and resulted between 1 August, 2019 and 30 July, 2022. Seventy-six patients were included in our study; 49 tested during prophylaxis and 27 during treatment. Most TCIP assays obtained in the prophylaxis cohort were negative (n = 46, 93.9%). Rate of post-TCIP CMV infection was 10.2%. In those tested during treatment, 33.3% were positive and rate of post-TCIP CMV recurrence was 22.2%. The positive predictive value of the assay to successfully predict immunity was 66.7% during both prophylaxis and treatment. There were 4 cases of TCIP predictive failure with progressive CMV replication. At time of replication, 2 patients had concomitant clinical confounders thought to influence immune control of viral replication. All patients had intensification of immunosuppression prior to recurrent replication, but after TCIP was collected. The data obtained from the TCIP are not static, immune control of CMV in latency can change and must be evaluated in clinical context. Timing of TCIP after transplant is significant, and patient-specific factors remain important to assess the likelihood of CMV in each unique patient-specific scenario. A CMV stewardship program can aid in application and interpretation of results.

Bacterial second messenger cyclic di-AMP in streptococci.

Cyclic dimeric adenosine monophosphate (c-di-AMP) has been well studied in bacteria, including those of the genus Streptococcus, since the first recognition of this dinucleotide in 2008. Streptococci possess a sole diadenylate cyclase, CdaA, and distinct c-di-AMP phosphodiesterases. Interestingly, cdaA is required for viability of some streptococcal species but not all when streptococci are grown in standard laboratory media. Bacteria of this genus also have distinct c-di-AMP effector proteins, diverse c-di-AMP-signaling pathways, and subsequent biological outcomes. In streptococci, c-di-AMP may influence bacterial growth, morphology, biofilm formation, competence program, drug resistance, and bacterial pathogenesis. c-di-AMP secreted by streptococci has also been shown to interact with the mammalian host and induces immune responses including type I interferon production. In this review, we summarize the reported c-di-AMP networks in seven species of the genus Streptococcus, which cause diverse clinical manifestations, and propose future perspectives to investigate the signaling molecule in these streptococcal pathogens.

FUNCTIONAL STATE OF THE PINEAL GLAND IN WOMEN WITH THREATENED ABORTION IN THE FIRST TRIMESTER – FURTHER PROSPECTS OF PREGNANCY

Melatonin is an important hormone for normal pregnancy development, but the infl uence of serotonin remains poorlyunderstood. Low melatonin production can lead to spontaneous abortion by stimulating progesterone secretion and inhibiting prostaglandin synthesis. Melatonin has an eff ect on the induction and blocking of apoptosis of the villous cytotrophoblast and promotes the development of the syncytiotrophoblast. Analysis of the frequency of positive pregnancy showed a signifi cant impact on the course of pregnancy and childbirth, compliance with sleep and rest also contribute to a positive eff ect, but there is no general concept, which makes the subject relevant.The aim of the study. To evaluate the functional state of the pineal gland, in particular, the amount of melatonin and serotonin in the blood of pregnant women at 10-12 weeks of gestation with a threat of abortion, which was manifested by bloody discharge or formation of retrochorionic hematoma, and the consequences of pregnancy.Materials and methods. Two groups were formed: I main group – 40 pregnant women with a threat of abortion and formation of retrochorionic hematoma, II control group – 44 healthy pregnant women. Obstetric examination, enzyme- linked immunosorbent assay for determination of melatonin, serotonin, chorionic gonadotropin, and ultrasound were performed. Informed consent of pregnant women was obtained with adequate explanation of the purpose, objectives, methods and scope of laboratory and instrumental research methods. The study protocol was approved by the Commission on Biomedical Ethics of the Bukovinian State Medical University, 2015 (minutes of the Commission meeting No 2 from the 19.10.2023 year). The study was conducted in accordance with the basic provisions of GCP (1996), the Convention of the Council of Europe on Human Rights and Biomedicine (April 4, 1997), the Declaration of Helsinki of the World Medical Association for the Ethical Principles of Scientifi c Medical Research Involving Human Subjects (1964-2008), the Order of the Ministry of Health of Ukraine 690 of September 23, 2009 (as amended by the Order of the Ministry of Health of Ukraine 523 of July 12, 2012). Statistical analysis was performed using generally accepted methods of variance statistics. Reliability was assessed by Student’s t-test. Diff erences were considered signifi cant if the signifi cance level was p≤0.05. We also performed correlation analysis in Microsoft Excel, using the method of squares (Pearson’s method) to determine the correlation coeffi cient. The work is a fragment of the research work of the Department of Obstetrics and Gynecology, UDC 618.1-053.34 + 618.1-0536 /.8]. –07-084-08 «Prevention, diagnosis and treatment of disorders of the perinatal period and reproductive system of women and adolescent girls» (No. 201110Н, state registration number 0111U006499. The term of implementation is 02.2011-12.2015).Results of the study. According to the obtained results, retrochorionic hematoma up to 1 cm is detected three times more often than over 1 cm, while the level of melatonin is not signifi cantly lower, but with retrochorionic hematoma over 1 cm a signifi cant decrease is observed in cases of further normal pregnancy and childbirth. With further complications of pregnancy in retrochoroidal hematoma up to 1 cm, there is a signifi cant signifi cant decrease in melatonin (p ˂ 0.001), in contrast to retrochoroidal hematoma over 1 cm, where no signifi cant diff erence was found in the complicated course of pregnancy (p > 0.05). Serotonin levels were elevated in all subgroups regardless of hematoma size and subsequent pregnancy outcome. Conclusions. In case of threatened abortion in the fi rst trimester with formation of retrochorionic hematoma, the risk ofcomplicated pregnancy remains in 60.87 % of cases. Determination of pineal hormones revealed a signifi cant increase inserotonin with a simultaneous signifi cant decrease in melatonin, while maintaining a positive relationship between the hormones, indicating a disruption of melatonin synthesis in the central nervous system. This is confi rmed by the normal level of chorionic gonadotropin and the preservation of embryonic viability. Since the disruption of hormone formation in the pineal gland has been established, adherence to the recommendations for adequate rest may positively aff ect the further outcome of pregnancy and childbirth.

Prevalence of mycophenolate mofetil discontinuation and subsequent outcomes in pediatric kidney transplant recipients: A PNRC study.

Mycophenolate Mofetil (MMF) is an effective immunosuppressant used in kidney transplant recipients to prevent acute rejection. Complications such as diarrhea, leukopenia, and infections may necessitate the reduction or discontinuation of MMF. The objective of the study was to investigate the prevalence, timing, and reasons for MMF discontinuation and its association with outcomes in pediatric kidney transplant recipients. Seven Pediatric Nephrology Research Consortium (PNRC) centers participated in a retrospective analysis of kidney transplant recipients <21 years of age. Characteristics and outcomes of patients in whom MMF was discontinued were compared to those who continued taking MMF throughout the first 2 years post-transplant. The study population included 288 participants (mean age 11.2 years) from 7 North American transplant centers. MMF was discontinued in 93/288 (32%) of participants. Common reasons for discontinuation included infections (35%), diarrhea (32%), leukopenia (15%), and others (18%). Increased cumulative alloimmunity (55% vs. 42%, p = .02), increased number of hospitalizations (82% vs. 67%, p = .01), and viral replications (79% vs. 47%, p < .0001) were observed in the MMF discontinuation group compared to the continuation group. Greater eGFR decline also occurred in the MMF discontinuation group over 2 years of follow-up (-7 vs. -1 mL/min/1.73 m2 , p = .05). Almost a third of pediatric kidney transplant recipients who begin MMF for maintenance immunosuppression have it discontinued within the first 2 years post-transplant, and this subset of patients is more likely to experience adverse outcomes. New strategies are needed to manage MMF therapy and improve post-transplant outcomes.

Intraoperative radiotherapy in breast cancer: Alterations to the tumor microenvironment and subsequent biological outcomes (Review).

Intraoperative radiotherapy (IORT) is a precise, single high‑dose irradiation directly targeting the tumor bed during surgery. In comparison with traditional external beam RT, it minimizes damage to other normal tissues, ensures an adequate dose to the tumor bed and results in improved cosmetic outcomes and quality of life. Furthermore, IORT offers a shorter treatment duration, lower economic costs and therapeutic efficacy comparable with traditional RT. However, its relatively higher local recurrence rate limits its further clinical applications. Identifying effective radiosensitizing drugs and rational RT protocols will improve its advantages. Furthermore, IORT may not only damage DNA to directly kill breast tumor cells but also alter the tumor microenvironment (TME) to exert a sustained antitumor effect. Specific doses of IORT may exert anti‑angiogenic effects, and consequently antitumor effects, by impacting post‑radiation peripheral blood levels of vascular endothelial growth factor and delta‑like 4. IORT may also modify the postoperative wound fluid composition to continuously inhibit tumor growth, e.g. by reducing components such as microRNA (miR)‑21, miR‑221, miR‑115, oncostatin M, TNF‑β, IL‑6 and IL‑8, and by elevating levels of components such as miR‑223, to inhibit the ability of postoperative wound fluid to induce proliferation, invasion and migration of residual cancer cells. IORT can also modify cancer cell glucose metabolism to inhibit the proliferation of residual tumor cells. In addition, IORT can induce a bystander effect, eliminating the postoperative wound fluid‑induced epithelial‑mesenchymal transition and tumor stem cell phenotype. Insights gained at the molecular level may provide new directions for identifying novel therapeutic targets and approaches. A more comprehensive understanding of the effects of IORT on the breast cancer (BC) TME may further its clinical application. Hence, the present article reviews the primary effects of IORT on BC and its impact on the TME, aiming to offer fresh research perspectives for relevant professionals.

Treatment of intrahepatic cholangiocarcinoma: evidence for the role of percutaneous ablation

Intrahepatic cholangiocarcinoma (iCCA) is a rare cancer with generally poor prognosis. In this narrative review, we examine the role of thermal ablation and summarize the current literature. Radiofrequency ablation (RFA) and microwave ablation (MWA) are both safe and well-tolerated as a minimally invasive local curative treatment option for patients suffering from primary and secondary liver tumors. Both methods can be used in patients with medical morbidities that would preclude surgery, as well as individuals with anatomical or functional constraints that impede liver resection. In unresectable iCCA, the median OS after conventional percutaneous US- or CT-guided RFA and MWA is between 20 and 39 months and 10 and 28 months, respectively. In recurrent iCCA, percutaneous RFA and MWA achieved a median OS of 21-27 months and 21-31 months, respectively. These data are comparable to long-term outcomes after surgical resection (SR), with the number of nodules and tumor size affecting prognosis. Stereotactic radiofrequency ablation (SRFA) allows for effective treatment of large and multiple iCCA nodules within one session and achieves short- and long-term results in inoperable patients compared with resection. With the addition of SRFA as an alternative treatment option, the proportion of patients who can be treated with curative treatment has significantly increased. In the absence of prospective trials comparing thermal ablation and surgical resection, we recommend a patient-specific decision-making process. Future research to identify technical and clinical prognostic criteria, as well as molecular markers of tumor biology, may help select patients for ablation and subsequent outcomes.

Trajectories of psychopathology among young people related to outcomes in young adulthood

Abstract What does young adulthood look like for individuals who had mental health problems across childhood? Using the Growing Up in Ireland cohort (born in 1998 and studied from ages 9 to 20) we explored the association between mental health problems between ages 9 and 13, and subsequent poor outcomes in the same individuals at ages 17-20. We consider educational/economic outcomes, health service use, poor mental and physical health, social isolation, substance abuse, and subjective wellbeing in young adults. In a previous study that used latent class modelling, we identified four groups which captured mental health in a general population sample of children. Between ages 9 and 13, children could be grouped into: a low symptoms group (∼65%), an ‘externalising’ group with ADHD or conduct symptoms (∼20%), an ‘internalising’ group with depressive, anxiety or peer issues (∼10%), or a group showing many combined mental health symptoms (∼2%). All mental health problem groups had elevated odds across all 7 adverse outcomes in young adulthood. The 5 areas of young adult functioning most related to childhood mental health were: education/economics, subjective wellbeing, mental health, social isolation and substance abuse. Poor educational/economic outcomes were as likely as poor mental health (OR ∼ 2) in individuals with childhood psychopathology. The 3 childhood problem groups showed different risk profiles in young adulthood. For instance, the childhood internalising group had lower odds of substance abuse than all other groups, but had the highest odds of poor physical health by adulthood. Findings point to the need for a wider range of preventative supports for children and adolescents with a history of mental health problems, beyond just mental health support. These include interventions to improve physical health, treat substance abuse, reduce social isolation, and improve adverse educational and economic outcomes.

Amphetamine Positivity Prior to Burn Surgery Does not Adversely Affect Intraoperative Outcomes.

The treatment of burn patients using amphetamines is challenging due hemodynamic liabilty and altered physiology. Wide variation exists in the operative timing for this patient population. We hypothesize that burn excision in patients admitted with amphetamine positivity is safe regardless of timing. Data from two verified burn centers between 2017 and 2022 with differing practice patterns in operative timing for amphetamine-positive patients. Center A obtains toxicology only on admission and proceeds with surgery based on hemodynamic status and operative urgency, whereas Center B sends daily toxicology until a negative test results. The primary outcome was the use of vasoactive agents during the index operation, modeled using logistic regression adjusting for burn severity and hospital days to index operation. Secondary outcomes included death and inpatient complications. A total of 270 patients were included, and there were no significant differences in demographics or burn characteristics between centers. Center A screened once and Center B obtained a median of four screens prior to the surgery. The adjusted OR of requiring vasoactive support intraoperatively was not associated with negative toxicology result (P = .821). Having a body surface area burned >20% conferred a significantly higher risk of vasoactive support (adj. OR 13.42 [3.90-46.23], P < .001). Mortality, number of operations, stroke, and hospital length of stay were similar between cohorts. Comparison between two verified burn centers indicates that waiting until a negative amphetamine toxicology result does not impact intraoperative management or subsequent burn outcomes. Serial toxicology tests are unnecessary to guide operative timing of burn patients with amphetamine use.

Pregnancy Rates after Hysteroscopic Endometrial Polypectomy versus Endometrial Curettage Polypectomy: A Retrospective Study.

Background and Objectives: A relationship between endometrial polypectomy and in vitro fertilization (IVF) pregnancy outcomes has been reported; however, only a few studies have compared polyp removal techniques and pregnancy rates. We investigated whether different polypectomy techniques with endometrial curettage and hysteroscopic polypectomy for endometrial polyps affect subsequent pregnancy outcomes. Materials and Methods: Data from 434 patients who had undergone polypectomy for suspected endometrial polyps using transvaginal ultrasonography before embryo transfer in IVF at four institutions between January 2017 and December 2020 were retrospectively analyzed. Overall, there were 157 and 277 patients in the hysteroscopic (mean age: 35.0 years) and curettage (mean age: 37.3 years) groups, respectively. Single-blastocyst transfer cases were selected from both groups and age-matched to unify background factors. Results: In the single-blastocyst transfer cases, 148 (mean age: 35.0 years) and 196 (mean age: 35.9 years) were in the hysteroscopic and curettage groups, respectively, with the 148 cases matched by age. In these cases, the pregnancy rates for the first embryo transfer were 68.2% (odds ratio (OR): 2.14) and 51.4% (OR: 1.06) in the hysteroscopic and curettage groups, respectively; the resulting OR was 2.03. The pregnancy rates after up to the second transfer were 80.4% (OR: 4.10) and 68.2% (OR: 2.14) in the hysteroscopic and curettage groups, respectively, in which the OR was 1.91. The live birth rates were 66.2% (OR: 1.956) and 53.4% (OR: 1.15) in the hysteroscopic and curettage groups, respectively, in which the odds ratio was 1.71. These results show the effectiveness of hysteroscopic endometrial polypectomy compared to polypectomy with endometrial curettage. No significant difference was found regarding the miscarriage rates between the two groups. Conclusions: Hysteroscopic endometrial polypectomy resulted in a higher pregnancy rate in subsequent embryo transfer than polypectomy with endometrial curettage. Therefore, establishing a facility where polypectomy can be performed hysteroscopically is crucial.

Enteric Infection at Flare of Inflammatory Bowel Disease Impacts Outcomes at 2 Years.

Outcomes of inflammatory bowel disease (IBD) following flare complicated by enteric infection (EI) are limited by follow-up duration and insufficient assessment of the role of non-Clostridioides difficile pathogens. We compared 2-year IBD outcomes following flare with and without EI. We performed a retrospective cohort study of adults evaluated with stool PCR testing for IBD flare. Subjects were stratified by presence of EI at flare and were matched for age, sex, and date to those without EI. The primary outcome was a composite of steroid-dependent IBD, colectomy, and/or IBD therapy class change/dose escalation at 2 years. Additional analyses were performed by dividing the EI group into C. difficile infection (CDI) and non-CDI EI, and further subdividing non-CDI EI into E. coli subtypes and other non-CDI EI. We identified 137 matched subjects, of whom 62 (45%) had EI (40 [29%] CDI; 17 [12%] E. coli). Enteric infection at flare was independently associated with the primary outcome (adjusted odds ratio, 4.14; 95% confidence interval [CI], 1.62-11.5). After dividing EI into CDI and non-CDI EI, only CDI at flare was independently associated with the primary outcome (adjusted odds ratio, 4.04; 95% CI, 1.46-12.6). After separating E. coli subtypes from non-CDI EI, E. coli infection and CDI at flare were both independently associated with the primary outcome; other EI was not. Enteric infection at flare-specifically with CDI-is associated with worse IBD outcomes at 2 years. The relationship between E. coli subtypes at flare and subsequent IBD outcomes requires further investigation.

Preconception laparoscopic cervical cerclage for prevention of mid-trimester pregnancy loss and preterm birth: A 6-year study

ObjectiveTo evaluate surgical results and pregnancy outcomes of preconception laparoscopic cervical cerclage (LCC) in women with cervical insufficiency. Study designWe conducted an observational study in consecutive women who had preconception LCC. Data was prospectively collected from 55 women at high risk of second trimester miscarriage and extreme preterm delivery due to cervical insufficiency who underwent pre-conception LCC between January 2017 – December 2021. This included patient demographics and relevant obstetric & gynaecological history, previous cervical cerclage, operative complications and subsequent pregnancy outcomes. All women included in study had at least one previous unsuccessful transvaginal cervical cerclage. The surgeries were conducted in private tertiary hospital in Hyderabad, India. The follow-up was until December 2022. The primary outcome was neonatal survival. Surgical morbidity and complications were also recorded. ResultsThere were 49 pregnancies of which 46 progressed beyond first trimester. 4.34 % (2/46) were delivered between 28 and 33 weeks due to preterm premature rupture of membranes (PPROM). 13.04 % (6/46) including 5 women with pregnancy complications and one with unicornuate uterus needed delivery between 34 and 36 weeks. 82.60 % (38/46) women were delivered at or beyond 37 weeks of pregnancy. In those who carried pregnancy beyond first trimester, live-birth rate and neonatal survival rate were 100 %. All neonates had favourable outcome with no long-term morbidity. There were no intraoperative or immediate postoperative complications. Two women had long-term complication in the form of tape erosion needing further surgery. ConclusionsThis study provides evidence that LCC improves pregnancy outcomes significantly in those with cervical weakness, without increasing the safety risk.

Systemic Immune-Inflammation Index Predicts the Prognosis of Traumatic Brain Injury

ObjectiveSystemic inflammation following traumatic brain injury (TBI) has been extensively studied over the past decades, as it contributes significantly to the pathophysiological injury mechanisms and subsequent poor outcomes. Systemic immune-inflammation (SII) index is a novel biomarker of systemic inflammatory response. However, its predictive value regarding TBI prognosis in clinical practice remains insufficiently investigated. MethodsA total of 102 TBI patients admitted to Nanjing Drum Tower Hospital from July 2019 to February 2022 were enrolled. We employed various statistical analyses to evaluate the correlation between inflammatory indicators upon admission and patient prognosis, compared the predictive accuracy of these indicators, and generated ROC analysis to test their prognostic performance. ResultsThe SII index, platelet count (PLT), absolute lymphocyte count (ALC), and neutrophil/lymphocyte ratio (NLR) were capable of distinguishing TBI prognosis according to univariate logistic regression models (P<0.05). Multivariate logistic regression models revealed that increased SII index, PLT, and NLR upon admission were independent predictors of poor TBI prognosis (P<0.05). ROC analysis further demonstrated that the SII index (AUC=0.845, 95% CI 0.769-0.921, P=0.000) exhibited higher predictive ability than the NLR (AUC=0.694, 95% CI 0.591-0.796, P=0.001). ConclusionsOur findings suggested that increased SII index during the early stages of TBI was an independent risk factor for poor prognosis with satisfactory predictive value. The SII index provides a reliable, convenient, and cost-effective prognostic model to evaluate systemic inflammation after TBI and identify patients at risk of poor outcomes, thereby offering valuable guidance for clinical practice.

From Incidental Exposure to COVID-19 Coping: The Influence of Expression and Perceived Networks on Social Media and Messaging Apps

ABSTRACTResearch has established the important role of incidental exposure in facilitating political learning, participation, as well as attitude polarization. Extending this line of work to public health crisis contexts, this study examines how pro-attitudinal and counter-attitudinal incidental exposures predict individuals’ expressive behaviors on social media and messaging apps (e.g. WhatsApp and LINE), and the subsequent coping outcomes during the COVID-19 pandemic. Analysis of an online survey in Taiwan showed that incidental exposure was related to expressive behaviors on social media and LINE, which in turn predicted coping outcomes, regardless of whether the information affirmed or undermined individuals’ opinions. However, the relationships between pro-attitudinal but not counter-attitudinal incidental exposure and expressive behaviors varied by perceived network homogeneity both on social media and LINE.

Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial

IntroductionInfants who are born from mothers with HIV (infants who are HIV exposed but uninfected; iHEU) are at higher risk of morbidity and display multiple immune alterations compared to infants who are HIV-unexposed (iHU). Easily implementable strategies to improve immunity of iHEU, and possibly subsequent clinical health outcomes, are needed. iHEU have altered gut microbiome composition and bifidobacterial depletion, and relative abundance of Bifidobacterium infantis has been associated with immune ontogeny, including humoral and cellular vaccine responses. Therefore, we will assess microbiological and immunological phenotypes and clinical outcomes in a randomized, double-blinded trial of B. infantis Rosell®-33 versus placebo given during the first month of life in South African iHEU.MethodsThis is a parallel, randomised, controlled trial. Two-hundred breastfed iHEU will be enrolled from the Khayelitsha Site B Midwife Obstetric Unit in Cape Town, South Africa and 1:1 randomised to receive 8 × 109 CFU B. infantis Rosell®-33 daily or placebo for the first 4 weeks of life, starting on day 1–3 of life. Infants will be followed over 36 weeks with extensive collection of meta-data and samples. Primary outcomes include gut microbiome composition and diversity, intestinal inflammation and microbial translocation and cellular vaccine responses. Additional outcomes include biological (e.g. gut metabolome and T cell phenotypes) and clinical (e.g. growth and morbidity) outcome measures.DiscussionThe results of this trial will provide evidence whether B. infantis supplementation during early life could improve health outcomes for iHEU.Ethics and disseminationApproval for this study has been obtained from the ethics committees at the University of Cape Town (HREC Ref 697/2022) and Seattle Children’s Research Institute (STUDY00003679).Trial registrationPan African Clinical Trials Registry Identifier: PACTR202301748714019. Clinical.trials.gov: NCT05923333.Protocol Version: Version 1.8, dated 18 July 2023.