A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

Pleiotropic brain function of whirlin identified by a novel mutation.

Despite some evidence indicating diverse roles of whirlin in neurons, the functional corollary of whirlin gene function and behavior has not been investigated or broadly characterized. A single nucleotide variant was identified from our recessive ENU-mutagenesis screen at a donor-splice site in whirlin, a protein critical for proper sensorineural hearing function. The mutation (head-bob, hb) led to partial intron-retention causing a frameshift and introducing a premature termination codon. Mutant mice had a head-bobbing phenotype and significant hyperactivity across several phenotyping tests. Lack of complementation of head-bob with whirler mutant mice confirmed the head-bob mutation as functionally distinct with compound mutants having a mild-moderate hearing defect. Utilizing transgenics, we demonstrate rescue of the hyperactive phenotype and combined with the expression profiling data conclude whirlin plays an essential role in activity-related behaviors. These results highlight a pleiotropic role of whirlin within the brain and implicate alternative, central mediated pathways in its function.

Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery.

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m6A writers Mettl3 and Mettl14, nor the m6A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

"Blue Scrub Lid Retraction": Changes in Eyelid Position on the Day of Surgery.

PURPOSE: The aim of this study is to test the hypothesis that margin-reflex distance 1 (MRD1) on the day of surgery will be higher than the MRD1 measured at the in-clinic consult visit among patients undergoing blepharoptosis repair due to an increased sympathetic drive. METHODS: Patients evaluated for involutional blepharoptosis repair were prospectively enrolled over a 12-month period in this single-center, self-controlled study. Three investigators independently determined MRD1 using cropped photos taken of patients at the in-clinic consult visit and on the day of surgery. A difference in height was tested for by using the 2-tailed Wilcoxon signed rank test. RESULTS: Evaluated in this study were 76 eyelids from 38 patients. Over 3-quarters of study participants had a higher MRD1 in the right and OSs on the day of surgery than at their in-clinic consultation visit (p < 0.001). The mean increase in MRD1 for the right eyelid and left eyelid was 1.0 mm (range: 0-3.15 mm) and 1.1 mm (range: 0-2.7 mm), respectively. CONCLUSIONS: In patients with involutional blepharoptosis, we conclude that MRD1 is higher on the day of surgery as compared with the in-clinic consult visit. This may be secondary to the stress of surgery and an associated increase in sympathetic drive. In some cases, this change in eyelid position led to resolution of apparent involutional ptosis altogether. Caution should be used when considering deferral of ptosis repair on the basis of exam findings present on the day of surgery.

Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

Efficacy of Ustekinumab and Vedolizumab Among Postoperative Crohn's Disease Patients as Postoperative Prophylaxis and Rescue Therapy: Real-world Data.

BACKGROUND: Almost half of patients with Crohn's disease (CD) require bowel surgeries in their lifetime. Due to the high risk of postoperative disease recurrence and high rate of previous antitumor necrosis factor (anti-TNF) failure, often alternative therapy options such as ustekinumab (UST) and vedolizumab (VDZ) are used. We aimed to evaluate the efficacy of UST and VDZ among postoperative CD patients as postoperative prophylaxis and rescue therapy. METHODS: Consented CD patients who underwent initial ileocecal resection and were treated with UST and VDZ were included in this study. Demographics, clinical characteristics, health care utilization, endoscopy scores, and surgery outcomes were collected. Postoperative early CD recurrence was defined as a Rutgeerts endoscopic score ≥i2 within the first 2 years. The rescue therapy group was defined as patients who received either UST or VDZ after having Rutgeerts endoscopic score ≥i2 postoperatively. RESULTS: During 2009 to 2019, 98 CD patients were treated with UST or VDZ postoperatively. Postoperative early recurrence rates were 5% (n = 1 out of 20) and 6% (1 out of 15) for the UST and VDZ groups, respectively. Two patients from the UST group and 1 patient from the VDZ group required bowel surgery during follow-up with median drug exposure of 51 (95% confidence interval [CI], 29-61) and 30 (95% CI, 14-63) months, respectively; 55% and 69% of patients had at least 1 point of improvement on postoperative endoscopic Rutgeerts score, respectively, for UST and VDZ. Only 3 out of 40 and 1 out of 23 patients required bowel surgery during follow-up while receiving UST and VDZ as rescue therapy. CONCLUSIONS: Both UST and VDZ were effective as postoperative therapies either as prophylaxis or rescue therapy.

This retrospective 11-year data examines the efficacy of ustekinumab and vedolizumab among postoperative Crohn's disease patients. When utilizing postoperative Rutgeerts score, this study confirms that both ustekinumab and vedolizumab were effective as postoperative therapies either as prophylaxis or rescue therapy.

Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Factors influencing patient decision-making to undergo shoulder arthroplasty.

Aims: Shoulder arthroplasty is effective in the management of end-stage glenohumeral joint arthritis. However, it is major surgery and patients must balance multiple factors when considering the procedure. An understanding of patients' decision-making processes may facilitate greater support of those considering shoulder arthroplasty and inform the outcomes of future research. Methods: Participants were recruited from waiting lists of three consultant upper limb surgeons across two NHS hospitals. Semi-structured interviews were conducted with 12 participants who were awaiting elective shoulder arthroplasty. Transcribed interviews were analyzed using a grounded theory approach. Systematic coding was performed; initial codes were categorized and further developed into summary narratives through a process of discussion and refinement. Data collection and analyses continued until thematic saturation was reached. Results: Two overall categories emerged: the motivations to consider surgery, and the information participants used to inform their decision-making. Motivations were, broadly, the relief of pain and the opportunity to get on with life and regain independence. When participants' symptoms and restrictions prevented them enjoying life to a sufficient extent, this provided the motivation to proceed with surgery. Younger participants tended to focus on maintaining employment and recreational activities, and older patients were eager to make the most of their remaining lifetime. Participants gathered information from a range of sources and were keen to optimize their recovery where possible. An important factor for participants was whether they trusted their surgeon and were prepared to delegate responsibility for elements of their care. Conclusion: Relief of pain and the opportunity to get on with life were the primary reasons to undergo shoulder arthroplasty. Participants highlighted the importance of the patient-surgeon relationship and the need for accurate information in an accessible format which is relevant to people of different ages and functional demands.

Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma.

BACKGROUND: Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy. METHODS: 84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC. RESULTS: Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts. CONCLUSIONS: Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

Cyprocide selectively kills nematodes via cytochrome P450 bioactivation.

Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.

Defining and Addressing Research Priorities in Cancer Cachexia through Transdisciplinary Collaboration.

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

Understanding hepatitis C virus (HCV) health literacy and educational needs among people in prison to enhance HCV care in prisons.

BACKGROUND: Hepatitis C virus (HCV) is a significant concern within prison populations. Provision of HCV testing and treatment for people in prison is expanding and a key component of global elimination efforts. Despite growing service availability, several challenges remain in HCV testing and treatment engagement during incarceration. The PIVOT study demonstrated that a 'one-stop-shop' intervention (point-of-care HCV RNA testing, Fibroscan®, nurse-led clinical assessment, and fast-tracked direct-acting antiviral prescription) enhanced HCV testing and treatment at a reception prison in Australia. Utilising Squier et al's Health Literacy Skills Framework, this analysis aimed to understand HCV health literacy and educational needs among people at a reception prison in Australia. METHODS: Semi-structured interviews were conducted with twenty-four male PIVOT study participants. Purposive sampling ensured comparable representation of those with: 1) prior HCV testing history (standard pathology / no prior testing), and 2) injecting drug use history (IDU; ever / never). RESULTS: Varied HCV health literacy levels and educational needs were evident amongst people in prison. Whilst those with multiple incarceration episodes and IDU history (prior knowledge) appeared to have stronger HCV health literacy than those without, substantial gaps in HCV health literacy were evident. Knowledge of HCV transmission risks in prison was high, and most understood the importance of HCV testing and treatment in prison (comprehension), but ability to engage with HCV testing and treatment services, participation in safe injecting behaviours (health-related behaviours), and knowledge of re-infection and re-treatment, within the context of the prison environment, were suboptimal. There was a general desire for increased HCV education in prison. CONCLUSION: Gaps in HCV health literacy among people in prison were evident, indicating opportunities for improvement. A targeted HCV education program for people in prison, addressing the gaps identified in this analysis, may enhance HCV testing, treatment, and prevention by fostering stronger HCV health literacy among people in prison.

Morphology and vocalization comparison of the Houston Toad and the Dwarf American Toad: implications for their historic range.

Documenting changes in the distribution and abundance of a given taxon requires historical data. In the absence of long-term monitoring data collected throughout the range of a taxon, conservation biologists often rely on preserved museum specimens to determine the past or present, putative geographic distribution. Distributional data for the Houston Toad (Anaxyrus houstonensis) has consistently been confounded by similarities with a sympatric congener, the Dwarf American Toad (A. americanus charlesmithi), both in monitoring data derived from chorusing surveys, and in historical data via museum specimens. In this case, misidentification can have unintended impacts on conservation efforts, where the Houston Toad is federally endangered, and the Dwarf American Toad is of least concern. Previously published reports have compared these two taxon on the basis of their male advertisement call and morphological appearance, often with the goal of using these characters to substantiate their taxonomic status prior to the advent of DNA sequencing technology. However, numerous studies report findings that contradict one another, and no consensus on the true differences or similarities can be drawn. Here, we use contemporary recordings of wild populations of each taxon to test for quantifiable differences in male advertisement call. Additionally, we quantitatively examine a subset of vouchered museum specimens representing each taxon to test previously reported differentiating morphometric characters used to distinguish among other Bufonids of East-Central Texas, USA. Finally, we assemble and qualitatively evaluate a database of photographs representing catalogued museum vouchers for each taxon to determine if their previously documented historic ranges may be larger than are currently accepted. Our findings reveal quantifiable differences between two allopatric congeners with respect to their male advertisement call, whereas we found similarities among their detailed morphology. Additionally, we report on the existence of additional, historically overlooked, museum records for the Houston Toad in the context of its putative historic range, and discuss errors associated with the curation of these specimens whose identity and nomenclature have not been consistent through time. These results bookend decades of disagreement regarding the morphology, voice, and historic distribution of these taxa, and alert practitioners of conservation efforts for the Houston Toad to previously unreported locations of occurrence.

Generalized nonlinearity in animal ecology: Research, review, and recommendations.

Generalized linear models (GLMs) are an integral tool in ecology. Like general linear models, GLMs assume linearity, which entails a linear relationship between independent and dependent variables. However, because this assumption acts on the link rather than the natural scale in GLMs, it is more easily overlooked. We reviewed recent ecological literature to quantify the use of linearity. We then used two case studies to confront the linearity assumption via two GLMs fit to empirical data. In the first case study we compared GLMs to generalized additive models (GAMs) fit to mammal relative abundance data. In the second case study we tested for linearity in occupancy models using passerine point-count data. We reviewed 162 studies published in the last 5 years in five leading ecology journals and found less than 15% reported testing for linearity. These studies used transformations and GAMs more often than they reported a linearity test. In the first case study, GAMs strongly out-performed GLMs as measured by AIC in modeling relative abundance, and GAMs helped uncover nonlinear responses of carnivore species to landscape development. In the second case study, 14% of species-specific models failed a formal statistical test for linearity. We also found that differences between linear and nonlinear (i.e., those with a transformed independent variable) model predictions were similar for some species but not for others, with implications for inference and conservation decision-making. Our review suggests that reporting tests for linearity are rare in recent studies employing GLMs. Our case studies show how formally comparing models that allow for nonlinear relationships between the dependent and independent variables has the potential to impact inference, generate new hypotheses, and alter conservation implications. We conclude by suggesting that ecological studies report tests for linearity and use formal methods to address linearity assumption violations in GLMs.

White Matter Hyperintensities and Mild TBI in Post-9/11 Veterans and Service Members.

INTRODUCTION: The neurobehavioral significance of white matter hyperintensities (WMHs) seen on magnetic resonance imaging after traumatic brain injury (TBI) remains unclear, especially in Veterans and Service Members with a history of mild TBI (mTBI). In this study, we investigate the relation between WMH, mTBI, age, and cognitive performance in a large multisite cohort from the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. MATERIALS AND METHODS: The neuroimaging and neurobehavioral assessments for 1,011 combat-exposed, post-9/11 Veterans and Service Members (age range 22-69 years), including those with a history of at least 1 mTBI (n = 813; median postinjury interval of 8 years) or negative mTBI history (n = 198), were examined. RESULTS: White matter hyperintensities were present in both mTBI and comparison groups at similar rates (39% and 37%, respectively). There was an age-by-diagnostic group interaction, such that older Veterans and Service Members with a history of mTBI demonstrated a significant increase in the number of WMHs present compared to those without a history of mTBI. Additional associations between an increase in the number of WMHs and service-connected disability, insulin-like growth factor-1 levels, and worse performance on tests of episodic memory and executive functioning-processing speed were found. CONCLUSIONS: Subtle but important clinical relationships are identified when larger samples of mTBI participants are used to examine the relationship between history of head injury and radiological findings. Future studies should use follow-up magnetic resonance imaging and longitudinal neurobehavioral assessments to evaluate the long-term implications of WMHs following mTBI.

Evidence of thermophilization in Afromontane forests.

Thermophilization is the directional change in species community composition towards greater relative abundances of species associated with warmer environments. This process is well-documented in temperate and Neotropical plant communities, but it is uncertain whether this phenomenon occurs elsewhere in the tropics. Here we extend the search for thermophilization to equatorial Africa, where lower tree diversity compared to other tropical forest regions and different biogeographic history could affect community responses to climate change. Using re-census data from 17 forest plots in three mountain regions of Africa, we find a consistent pattern of thermophilization in tree communities. Mean rates of thermophilization were +0.0086 °C·y-1 in the Kigezi Highlands (Uganda), +0.0032 °C·y-1 in the Virunga Mountains (Rwanda-Uganda-Democratic Republic of the Congo) and +0.0023 °C·y-1 in the Udzungwa Mountains (Tanzania). Distinct from other forests, both recruitment and mortality were important drivers of thermophilzation in the African plots. The forests studied currently act as a carbon sink, but the consequences of further thermophilization are unclear.