An Open-Label Phase I Study of Metformin and Nelfinavir in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma.

BACKGROUND: In preclinical models, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor shows synergistic therapeutic potential against multiple myeloma (MM). Thus, this study evaluated the safety and tolerability of repurposing metformin, a complex I inhibitor, and nelfinavir, a GLUT4 inhibitor, in combination with bortezomib for the treatment of relapsed/refractory MM that had progressed on all standard of care therapies. MATERIALS AND METHODS: This trial utilized a 3 + 3 dose escalation design with 3 dose levels planned for up to a maximum of 6 (21-day) cycles. Metformin and nelfinavir were administered for 14 of 21 days, and subQ bortezomib was administered to a portion of patients on days 1, 8, and 15. The primary objective was to determine the maximal tolerated dose, and the secondary objective was to evaluate the safety and overall response rate (ORR) of this combination. RESULTS: Nine patients were accrued with a median age of 65 (range: 42-81) and received a median of 7 prior lines of therapy (Range: 5-12). The first 3 patients received only metformin (500 mg BID) and nelfinavir (1250 mg BID) at the first dose level, with 1 patient experiencing an unconfirmed minimal response (MR) in the first cycle, 1 experiencing progressive disease after 1 cycle of treatment and 1 patient going off treatment prior to assessing response but with signs of progressive disease. Given the limited therapeutic activity, the upfront addition of bortezomib (1.3 mg/m2) was utilized for the subsequent 6 patients accrued. Three of these 6 patients went off study due to progressive disease, 1 patient achieved an unconfirmed partial response after 1 cycle of treatment but reported progressive disease in the subsequent cycle, 1 patient went off study to enter hospice, and the remaining patient experienced stable disease (SD) after receiving 6 cycles of clinical trial treatment. The study was closed before accrual to the next dose level was started. CONCLUSION: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of relapsed and refractory MM. This was an overall negative study with no ORR observed. Fortunately, 1 patient experienced an SD response, allowing this combination to stabilize their disease until another novel therapy on a clinical trial was available.

PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19).

PURPOSE: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

Comparison of quartz and sapphire optical chambers for infrared laser sealing of vascular tissues using a reciprocating, side-firing optical fiber: Simulations and experiments.

INTRODUCTION: Infrared (IR) lasers are being tested as an alternative to radiofrequency (RF) and ultrasonic (US) surgical devices for hemostatic sealing of vascular tissues. In previous studies, a side-firing optical fiber with elliptical IR beam output was reciprocated, producing a linear IR laser beam pattern for uniform sealing of blood vessels. Technical challenges include limited field-of-view of vessel position within the metallic device jaws, and matching fiber scan length to variable vessel sizes. A transparent jaw may improve visibility and enable custom treatment. METHODS: Quartz and sapphire square optical chambers (2.7 × 2.7 × 25 [mm3 ] outer dimensions) were tested, capable of fitting into a 5-mm-OD laparoscopic device. A 1470 nm laser was used for optical transmission studies. Razor blade scans and an IR beam profiler acquired fiber (550-µm-core/0.22NA) output beam profiles. Thermocouples recorded peak temperatures and cooling times on internal and external chamber surfaces. Optical fibers with angle polished distal tips delivered 94% of light at a 90° angle. Porcine renal arteries with diameters of 3.4 ± 0.7 mm (n = 13) for quartz and 3.2 ± 0.7 mm (n = 14) for sapphire chambers (p > 0.05), were sealed using 30 W for 5 s. RESULTS: Reflection losses at material/air interfaces were 3.3% and 7.4% for quartz and sapphire. Peak temperatures on the external chamber surface averaged 74 ± 8°C and 73 ± 10°C (p > 0.05). Times to cool down to 37°C measured 13 ± 4 s and 27 ± 7 s (p < 0.05). Vessel burst pressures (BP) averaged 883 ± 393 mmHg and 412 ± 330 mmHg (p < 0.05). For quartz, 13/13 (100%) vessels were sealed (BP > 360 mmHg), versus 9/14 (64%) for sapphire. Computer simulations for the quartz chamber yielded peak temperatures (78°C) and cooling times (16 s) similar to experiments. CONCLUSIONS: Quartz is an inexpensive material for use in a laparoscopic device jaw, providing more consistent vessel seals and faster cooling times than sapphire and current RF and US devices.

Combined Bilateral Salpingo-oophorectomy and Cesarean Delivery in BRCA1/2 Alteration Carriers : A Case Series.

BACKGROUND: The cumulative lifetime risk of ovarian cancer is 16-68% and 11-30% in female BRCA1 and BRCA2 gene alteration carriers, respectively. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only proven way to reduce ovarian cancer mortality. We report a series of patients who underwent risk-reducing surgery at the time of planned obstetric-indicated cesarean delivery. CASES: This is a case series of four women carrying a pathogenic germline BRCA1 or BRCA2 gene alteration who underwent RRSO at the time of cesarean delivery between March 1, 2018, and March 31, 2022. All women were referred during pregnancy to the University College London Hospitals Familial Cancer Clinic for consideration of RRSO at the time of obstetric-indicated cesarean delivery. Women were considered eligible for RRSO if they had a proven pathogenic germline alteration, would have completed childbearing after the cesarean delivery, and were older than age 35 or 40 years with BRCA1 or BRCA2 alterations, respectively. Operating time, blood loss, transfusion requirements, length of hospital stay, complications, and ability to breastfeed were assessed and, where possible, compared with the institutional means for similar patients who underwent cesarean delivery only, to determine whether RRSO was associated with increased morbidity. Women were contacted 11-59 months postprocedure to assess satisfaction. The mean blood loss was 687 mL (range 400-1,000 mL), mean operating time was 68 minutes, mean length of hospital stay was 3 days, and mean change in hemoglobin was -1 g/dL. No patient required a transfusion, had internal organ damage, returned to the operating room, or was readmitted. One of two women with intact breast tissue successfully breastfed, and the other chose to bottle feed. The mean contemporaneous institutional blood loss for cesarean delivery was not significantly different at 681 mL for singleton pregnancies and 872 mL for twin pregnancies. All four women reported a high level of satisfaction with the combined procedure. CONCLUSION: Our results show that RRSO can be performed at the time of cesarean delivery with high patient satisfaction. This approach can be offered to appropriately counseled individuals, with the benefit of avoiding the need for two separate procedures, with potentially reduced patient morbidity and health care costs.

Use of super resolution reconstruction MRI for surgical planning in Placenta accreta spectrum disorder: Case series.

INTRODUCTION: Comprehensive imaging using ultrasound and MRI of placenta accreta spectrum (PAS) aims to prevent catastrophic haemorrhage and maternal death. Standard MRI of the placenta is limited by between-slice motion which can be mitigated by super-resolution reconstruction (SRR) MRI. We applied SRR in suspected PAS cases to determine its ability to enhance anatomical placental assessment and predict adverse maternal outcome. METHODS: Suspected PAS patients (n = 22) underwent MRI at a gestational age (weeks + days) of (32+3±3+2, range (27+1-38+6)). SRR of the placental-myometrial-bladder interface involving rigid motion correction of acquired MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume, was achieved in twelve. 2D MRI or SRR images alone, and paired data were assessed by four radiologists in three review rounds. All radiologists were blinded to results of the ultrasound, original MR image reports, case outcomes, and PAS diagnosis. A Random Forest Classification model was used to highlight the most predictive pathological MRI markers for major obstetric haemorrhage (MOH), bladder adherence (BA), and placental attachment depth (PAD). RESULTS: At delivery, four patients had placenta praevia with no abnormal attachment, two were clinically diagnosed with PAS, and six had histopathological PAS confirmation. Pathological MRI markers (T2-dark intraplacental bands, and loss of retroplacental T2-hypointense line) predicting MOH were more visible using SRR imaging (accuracy 0.73), in comparison to 2D MRI or paired imaging. Bladder wall interruption, predicting BA, was only easily detected by paired imaging (accuracy 0.72). Better detection of certain pathological markers predicting PAD was found using 2D MRI (placental bulge and myometrial thinning (accuracy 0.81)), and SRR (loss of retroplacental T2-hypointense line (accuracy 0.82)). DISCUSSION: The addition of SRR to 2D MRI potentially improved anatomical assessment of certain pathological MRI markers of abnormal placentation that predict maternal morbidity which may benefit surgical planning.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

Sperm chromatin structure and reproductive fitness are altered by substitution of a single amino acid in mouse protamine 1.

Conventional dogma presumes that protamine-mediated DNA compaction in sperm is achieved by electrostatic interactions between DNA and the arginine-rich core of protamines. Phylogenetic analysis reveals several non-arginine residues conserved within, but not across species. The significance of these residues and their post-translational modifications are poorly understood. Here, we investigated the role of K49, a rodent-specific lysine residue in protamine 1 (P1) that is acetylated early in spermiogenesis and retained in sperm. In sperm, alanine substitution (P1(K49A)) decreases sperm motility and male fertility-defects that are not rescued by arginine substitution (P1(K49R)). In zygotes, P1(K49A) leads to premature male pronuclear decompaction, altered DNA replication, and embryonic arrest. In vitro, P1(K49A) decreases protamine-DNA binding and alters DNA compaction and decompaction kinetics. Hence, a single amino acid substitution outside the P1 arginine core is sufficient to profoundly alter protein function and developmental outcomes, suggesting that protamine non-arginine residues are essential for reproductive fitness.

The role of continental subduction in mantle metasomatism and carbon recycling revealed by melt inclusions in UHP eclogites.

Subduction is the main process that recycles surface material into the mantle. Fluids and melts derived by dehydration and partial melting reactions of subducted continental crust, a major reservoir of volatiles (i.e., H2O and CO2) and incompatible elements, can substantially metasomatize and refertilize the mantle. Here, we investigate glassy inclusions of silicate melt of continental origin found in Variscan ultrahigh-pressure eclogites to assess the continental crust contribution to mantle metasomatism and the journey of volatiles, carbon in particular, to the deep roots of mountain belts. We argue that the melt preserved in these inclusions is the agent responsible for mantle metasomatism and subsequent ultrapotassic magmatism in the Variscides. We propose that continental subduction can redistribute a substantial volume of carbon in the continental lithosphere, which is subsequently transferred to the continental crust during postcollisional magmatism and stored for a time length longer than that of the modern carbon cycle.

Hypertensive disorders of pregnancy and long-term cardiovascular health: FIGO Best Practice Advice.

Hypertensive disorders of pregnancy (HDP) are the most common causes of maternal and perinatal morbidity and mortality. They are responsible for 16% of maternal deaths in high-income countries and approximately 25% in low- and middle-income countries. The impact of HDP can be lifelong as they are a recognized risk factor for future cardiovascular disease. During pregnancy, the cardiovascular system undergoes significant adaptive changes that ensure adequate uteroplacental blood flow and exchange of oxygen and nutrients to nurture and accommodate the developing fetus. Failure to achieve normal cardiovascular adaptation is associated with the development of HDP. Hemodynamic alterations in women with a history of HDP can persist for years and predispose to long-term cardiovascular morbidity and mortality. Therefore, pregnancy and the postpartum period are an opportunity to identify women with underlying, often unrecognized, cardiovascular risk factors. It is important to develop strategies with lifestyle and therapeutic interventions to reduce the risk of future cardiovascular disease in those who have a history of HDP.

The challenges of obesity for fertility: A FIGO literature review.

Obesity has been linked to infertility through several mechanisms, including at a molecular level. Those living with obesity face additional barriers to accessing fertility treatments and achieving a successful pregnancy, which can contribute to their economic and psychosocial stressors. There is scope to further improve care for people living with obesity and infertility with empathy, via a multidisciplinary approach.

Management of obesity across women's life course: FIGO Best Practice Advice.

Obesity is a chronic, progressive, relapsing, and treatable multifactorial, neurobehavioral disease. According to the World Health Organization, obesity affects 15% of women and has long-term effects on women's health. The focus of care in patients with obesity should be on optimizing health outcomes rather than on weight loss. Appropriate and common language, considering cultural sensitivity and trauma-informed care, is needed to discuss obesity. Pregnancy is a time of significant physiological change. Pre-, ante-, and postpartum clinical encounters provide opportunities for health optimization for parents with obesity in terms of, but not limited to, fertility and breastfeeding. Pre-existing conditions may also be identified and managed. Beyond pregnancy, women with obesity are at an increased risk for gastrointestinal and liver diseases, impaired kidney function, obstructive sleep apnea, and venous thromboembolism. Gynecological and reproductive health of women living with obesity cannot be dismissed, with accommodations needed for preventive health screenings and consideration of increased risk for gynecologic malignancies. Mental wellness, specifically depression, should be screened and managed appropriately. Obesity is a complex condition and is increasing in prevalence with failure of public health interventions to achieve significant decrease. Future research efforts should focus on interprofessional care and discovering effective interventions for health optimization.

Using FIGO Nutrition Checklist counselling in pregnancy: A review to support healthcare professionals.

The period before and during pregnancy is increasingly recognized as an important stage for addressing malnutrition. This can help to reduce the risk of noncommunicable diseases in mothers and passage of risk to their infants. The FIGO Nutrition Checklist is a tool designed to address these issues. The checklist contains questions on specific dietary requirements, body mass index, diet quality, and micronutrients. Through answering these questions, awareness is generated, potential risks are identified, and information is collected that can inform health-promoting conversations between women and their healthcare professionals. The tool can be used across a range of health settings, regions, and life stages. The aim of this review is to summarize nutritional recommendations related to the FIGO Nutrition Checklist to support healthcare providers using it in practice. Included is a selection of global dietary recommendations for each of the components of the checklist and practical insights from countries that have used it. Implementation of the FIGO Nutrition Checklist will help identify potential nutritional deficiencies in women so that they can be addressed by healthcare providers. This has potential longstanding benefits for mothers and their children, across generations.

Pregnancy as an opportunity to prevent type 2 diabetes mellitus: FIGO Best Practice Advice.

Gestational diabetes (GDM) impacts approximately 17 million pregnancies worldwide. Women with a history of GDM have an 8-10-fold higher risk of developing type 2 diabetes and a 2-fold higher risk of developing cardiovascular disease (CVD) compared with women without prior GDM. Although it is possible to prevent and/or delay progression of GDM to type 2 diabetes, this is not widely undertaken. Considering the increasing global rates of type 2 diabetes and CVD in women, it is essential to utilize pregnancy as an opportunity to identify women at risk and initiate preventive intervention. This article reviews existing clinical guidelines for postpartum identification and management of women with previous GDM and identifies key recommendations for the prevention and/or delayed progression to type 2 diabetes for global clinical practice.

Human DNA ligases I and III have stand-alone end-joining capability, but differ in ligation efficiency and specificity.

Double-strand DNA breaks (DSBs) are toxic to cells, and improper repair can cause chromosomal abnormalities that initiate and drive cancer progression. DNA ligases III and IV (LIG3, LIG4) have long been credited for repair of DSBs in mammals, but recent evidence suggests that DNA ligase I (LIG1) has intrinsic end-joining (EJ) activity that can compensate for their loss. To test this model, we employed in vitro biochemical assays to compare EJ by LIG1 and LIG3. The ligases join blunt-end and 3'-overhang-containing DNA substrates with similar catalytic efficiency, but LIG1 joins 5'-overhang-containing DNA substrates ∼20-fold less efficiently than LIG3 under optimal conditions. LIG1-catalyzed EJ is compromised at a physiological concentration of Mg2+, but its activity is restored by increased molecular crowding. In contrast to LIG1, LIG3 efficiently catalyzes EJ reactions at a physiological concentration of Mg2+ with or without molecular crowding. Under all tested conditions, LIG3 has greater affinity than LIG1 for DNA ends. Remarkably, LIG3 can ligate both strands of a DSB during a single binding encounter. The weaker DNA binding affinity of LIG1 causes significant abortive ligation that is sensitive to molecular crowding and DNA terminal structure. These results provide new insights into mechanisms of alternative nonhomologous EJ.

Response to photic stimulation as a measure of cortical excitability in epilepsy patients.

Studying states and state transitions in the brain is challenging due to nonlinear, complex dynamics. In this research, we analyze the brain's response to non-invasive perturbations. Perturbation techniques offer a powerful method for studying complex dynamics, though their translation to human brain data is under-explored. This method involves applying small inputs, in this case via photic stimulation, to a system and measuring its response. Sensitivity to perturbations can forewarn a state transition. Therefore, biomarkers of the brain's perturbation response or "cortical excitability" could be used to indicate seizure transitions. However, perturbing the brain often involves invasive intracranial surgeries or expensive equipment such as transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups, or animal model studies. Photic stimulation is a widely used diagnostic technique in epilepsy that can be used as a non-invasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans. This involves changing the frequency of strobing light, sometimes triggering a photo-paroxysmal response (PPR), which is an electrographic event that can be studied as a state transition to a seizure state. We investigate alterations in the response to these perturbations in patients with genetic generalized epilepsy (GGE), with (n = 10) and without (n = 10) PPR, and patients with psychogenic non-epileptic seizures (PNES; n = 10), compared to resting controls (n = 10). Metrics of EEG time-series data were evaluated as biomarkers of the perturbation response including variance, autocorrelation, and phase-based synchrony measures. We observed considerable differences in all group biomarker distributions during stimulation compared to controls. In particular, variance and autocorrelation demonstrated greater changes in epochs close to PPR transitions compared to earlier stimulation epochs. Comparison of PPR and spontaneous seizure morphology found them indistinguishable, suggesting PPR is a valid proxy for seizure dynamics. Also, as expected, posterior channels demonstrated the greatest change in synchrony measures, possibly reflecting underlying PPR pathophysiologic mechanisms. We clearly demonstrate observable changes at a group level in cortical excitability in epilepsy patients as a response to perturbation in EEG data. Our work re-frames photic stimulation as a non-invasive perturbation paradigm capable of inducing measurable changes to brain dynamics.

Synergy between inhibitors of two mitotic spindle assembly motors undermines an adaptive response.

Mitosis is the cellular process that ensures accurate segregation of the cell's genetic material into two daughter cells. Mitosis is often deregulated in cancer; thus drugs that target mitosis-specific proteins represent attractive targets for anticancer therapy. Numerous inhibitors have been developed against kinesin-5 Eg5, a kinesin essential for bipolar spindle assembly. Unfortunately, Eg5 inhibitors (K5Is) have been largely ineffective in the clinic, possibly due to the activity of a second kinesin, KIF15, that can suppress the cytotoxic effect of K5Is by driving spindle assembly through an Eg5-independent pathway. We hypothesized that pairing of K5Is with small molecule inhibitors of KIF15 will be more cytotoxic than either inhibitor alone. Here we present the results of a high-throughput screen from which we identified two inhibitors that inhibit the motor activity of KIF15 both in vitro and in cells. These inhibitors selectively inhibit KIF15 over other molecular motors and differentially affect the ability of KIF15 to bind microtubules. Finally, we find that chemical inhibition of KIF15 reduces the ability of cells to acquire resistance to K5Is, highlighting the centrality of KIF15 to K5I resistance and the value of these inhibitors as tools with which to study KIF15 in a physiological context.

Positional aphasia as a manifestation of syndrome of the trephined: illustrative case.

BACKGROUND: The authors report a case of a 66-year-old male who presented acutely with a subdural hematoma who was managed operatively with craniotomy. His course was complicated by a postoperative epidural hematoma, which, on the basis of intraoperative findings at the second surgery, was managed with evacuation of the hematoma and removal of the bone flap. OBSERVATIONS: The patient's subsequent recovery was remarkable for a reproducible positional aphasia in the early postoperative period with an ultimate diagnosis of syndrome of the trephined. The patient's cerebral edema permitted early autologous cranioplasty, which resulted in resolution of the patient's symptoms. LESSONS: The authors believe this case to be the first described of isolated positional aphasia as a manifestation of syndrome of the trephined. Recognition and treatment of the syndrome resulted in a positive patient outcome.

Phase 2 trial of ixazomib, cyclophosphamide, and dexamethasone for previously untreated light chain amyloidosis.

Bortezomib, a proteasome inhibitor (PI), has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and is often used in combination with cyclophosphamide and dexamethasone. Ixazomib is the first oral PI to be approved in routine practice but has not yet been evaluated in the upfront treatment setting. Newly diagnosed AL amyloidosis patients with measurable disease and adequate organ function were enrolled. The primary objective was to determine the hematologic response rate of ixazomib in combination with cyclophosphamide and dexamethasone. Treatment was given for 12 cycles, followed by ixazomib maintenance until progression. Thirty-five patients were included; their median age was 67 years, and 69% were male. Major organ involvement included heart (66%) and kidneys (54%). A median of 4 induction cycles (range, 1-12) were administered. The overall hematologic response to induction was 63% and included complete response in 11.4% and very good partial response in 37.1% of patients. One patient was upstaged to complete response during maintenance. The most common reason for going off study was the institution of alternate therapy (61%). With a median follow-up of 29.7 months for the living patients, the 2-year progression-free survival and overall survival were 74% and 78%, respectively. The median time to alternate therapy was 7.5 months. Grade ≥3 hematologic and nonhematologic adverse events occurred in 23% and 49% of patients. Given ixazomib's favorable toxicity profile, which is an important advantage for the typically frail AL population, further evaluation of ixazomib in other combinations in the upfront setting is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01864018.

The effect of the delta SARS-CoV-2 variant on maternal infection and pregnancy.

A greater proportion of pregnant women with COVID-19 have mild disease compared with their non-pregnant counterparts. Paradoxically, however, they are at higher risk of developing severe disease, requiring respiratory support and admission to intensive care. The delta SARS-Cov-2 variant is associated with increased risk of hospitalization and morbidity in unvaccinated pregnant populations. However, it is not known whether the worse pregnancy outcomes associated with the delta variant are due to a direct effect of the virus on the pregnancy, or whether this effect is mediated through more severe maternal infection. Here, we synthesize studies of COVID-19 pregnancies, focusing on the different routes of SARS-CoV-2 infection of lung and placenta, and the mechanisms of syncytial formation for each SARS-CoV-2 variant. To delineate COVID-19 complications in pregnant women, future studies should explore whether the delta variant causes greater placental infection compared to other variants and contributes to increased syncytial formation.