FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies.

BACKGROUND: The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations. PATIENTS AND METHODS: Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant. RESULTS: Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)]. CONCLUSIONS: Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.

Genetic testing approaches for hereditary breast cancer: Perspectives from a private diagnostic laboratory.

Breast cancer is highly prevalent in South Africa, and up to 10% of breast cancer cases may be hereditary. The landscape of genetic testing options for hereditary breast cancer (HBC) has changed significantly over the past decade, and healthcare providers are faced with multiple options when referring breast cancer patients for genetic testing. We have performed a retrospective study of 3 years' worth of breast cancer genetic testing referrals to our laboratory. While Afrikaner and Ashkenazi Jewish founder screens may be appropriate as first-line tests in a limited subset of patients, we have shown that in the majority of cases it is more effective to adopt a multigene panel approach. While variants in the BRCA1 and BRCA2 genes still account for a significant proportion of cases, close to 40% of pathogenic variants were found in genes other than BRCA1 or BRCA2. There are many factors that healthcare providers should consider when requesting genetic testing for breast cancer patients and families, including family history, ancestral background, cost, medical aid scheme reimbursement and scope of testing. We summarise our findings and provide advantages and disadvantages of each approach, with the aim of assisting clinicians and genetic counsellors to make appropriate testing decisions.

Measuring depth of anaesthesia using changes in directional connectivity: a comparison with auditory middle latency response and estimated bispectral index during propofol anaesthesia.

General anaesthesia is associated with changes in connectivity between different regions of the brain, the assessment of which has the potential to provide a novel marker of anaesthetic effect. We propose an index that quantifies the strength and direction of information flow in electroencephalographic signals collected across the scalp, assess its performance in discriminating 'wakefulness' from 'anaesthesia', and compare it with estimated bispectral index and the auditory middle latency response. We used a step-wise slow induction of anaesthesia in 10 patients to assess graded changes in electroencephalographic directional connectivity at propofol effect-site concentrations of 2 µg.ml-1 , 3 µg.ml-1 and 4 µg.ml-1 . For each stable effect-site concentration, connectivity was estimated from multichannel electroencephalograms using directed coherence, together with middle latency response and estimated bispectral index. We used a linear support vector machine classifier to compare the performance of the different electroencephalographic features in discriminating wakefulness from anaesthesia. We found a significant reduction in the strength of long-range connectivity (interelectrode distance > 10 cm) (p < 0.008), and a reversal of information flow from markedly postero-frontal to fronto-posterior (p < 0.006) between wakefulness and a propofol effect-site concentration of 2 µg.ml-1 . This then remained relatively constant as effect-site concentration increased, consistent with a step change in directed coherence with anaesthesia. This contrasted with the gradual change with increasing anaesthetic dose observed for estimated bispectral index and middle latency response. Directed coherence performed best in discriminating wakefulness from anaesthesia with an accuracy of 95%, indicating the potential of this new method (on its own or combined with others) for monitoring adequacy of anaesthesia.

Electron Acceleration to MeV Energies at Jupiter and Saturn.

The radiation belts and magnetospheres of Jupiter and Saturn show significant intensities of relativistic electrons with energies up to tens of megaelectronvolts (MeV). To date, the question on how the electrons reach such high energies is not fully answered. This is largely due to the lack of high-quality electron spectra in the MeV energy range that models could be fit to. We reprocess data throughout the Galileo orbiter mission in order to derive Jupiter's electron spectra up to tens of MeV. In the case of Saturn, the spectra from the Cassini orbiter are readily available and we provide a systematic analysis aiming to study their acceleration mechanisms. Our analysis focuses on the magnetospheres of these planets, at distances of L > 20 and L > 4 for Jupiter and Saturn, respectively, where electron intensities are not yet at radiation belt levels. We find no support that MeV electrons are dominantly accelerated by wave-particle interactions in the magnetospheres of both planets at these distances. Instead, electron acceleration is consistent with adiabatic transport. While this is a common assumption, confirmation of this fact is important since many studies on sources, losses, and transport of energetic particles rely on it. Adiabatic heating can be driven through various radial transport mechanisms, for example, injections driven by the interchange instability or radial diffusion. We cannot distinguish these processes at Saturn with our technique. For Jupiter, we suggest that the dominating acceleration process is radial diffusion because injections are never observed at MeV energies.

Directional connectivity in the EEG is able to discriminate wakefulness from NREM sleep.

A reliable measure of consciousness is of great interest for various clinical applications including sleep studies and the assessment of depth of anaesthesia. A number of measures of consciousness based on the EEG have been proposed in the literature and tested in studies of dreamless sleep, general anaesthesia and disorders of consciousness. However, reliability has remained a persistent challenge. Despite considerable theoretical and experimental effort, the neural mechanisms underlying consciousness remain unclear, but connectivity between brain regions is thought to be disrupted, impairing information flow. OBJECTIVE: The objective of the current work was to assess directional connectivity between brain regions using directed coherence and propose and assess an index that robustly reflects changes associated with non-REM sleep. APPROACH: We tested the performance on polysomnographic recordings from ten healthy subjects and compared directed coherence (and derived features) with more established measures calculated from EEG spectra. We compared the performance of the different indexes to discriminate the level of consciousness at group and individual level. MAIN RESULTS: At a group level all EEG measures could significantly discriminate NREM sleep from waking, but there was considerable individual variation. Across all individuals, normalized power, the strength of long-range connections and the direction of functional links strongly correlate with NREM sleep stages over the experimental timeline. At an individual level, of the EEG measures considered, the direction of functional links constitutes the most reliable index of the level of consciousness, highly correlating with the individual experimental time-line of sleep in all subjects. SIGNIFICANCE: Directed coherence provides a promising new means of assessing level of consciousness, firmly based on current physiological understanding of consciousness.

The hereditary ataxias: Where are we now? Four decades of local research.

The hereditary ataxias have been studied at the University of Cape Town for more than 40 years, following from initial clinical investigations by Beighton and colleagues in the early 1970s. This group of inherited disorders is characterised by progressive neurodegeneration and associated symptoms, including the inability to coordinate movement. Following initial local and international linkage studies, and the discovery of the genes responsible for the key dominant and recessive inherited ataxias in the 1990s, a local molecular testing service was established at Groote Schuur Hospital. More than 1 600 individuals have been referred through this testing service (now offered by the National Health Laboratory Service), leading to the molecular diagnosis of 253 families with spinocerebellar ataxia types 1, 2, 3, 6 or 7, and 30 families with Friedreich's ataxia. This is likely to be an under-representation of the number of South Africans affected with hereditary ataxia, and future research efforts will focus on increasing the awareness of this group of disorders, both locally and throughout the rest of Africa. Next-generation technologies will be beneficial in identifying additional genes underlying inherited ataxia in indigenous patients to enable more appropriate management and treatment of individuals with molecularly undiagnosed forms of the disease.

Spinocerebellar ataxia type 7 in South Africa: Epidemiology, pathogenesis and therapy.

Disorders of the nervous system represent a significant proportion of the global burden of non-communicable diseases, due to the trend towards ageing populations. The Department (now Division) of Human Genetics at the University of Cape Town (UCT) has been involved in pioneering research into these diseases since the appointment of Prof. Peter Beighton as Head of Department in 1972. Beighton's emphasis on understanding the genetic basis of disease laid the groundwork for investigations into several monogenic neurodegenerative conditions, including Huntington's disease and the polyglutamine spinocerebellar ataxias (SCAs). In particular, SCA7, which occurs at an unusually high frequency in the South African (SA) population, was identified as a target for further research and therapeutic development. Beginning with early epidemiological surveys, the SCA7 project progressed to molecular genetics-based investigations, leading to the identification of a founder effect in the SA SCA7 patient population in the mid-2000s. Capitalising on the founder haplotype shared by many SCA7 patients, UCT researchers went on to develop the first population-specific gene-silencing approach for the disease. More recently, efforts have shifted to the development of a more accurate model to decipher the precise mechanisms of neurodegeneration, using induced pluripotent stem cells derived from SA SCA7 patients. In many ways, the SA SCA7 journey reflects the legacy and vision of Prof. Peter Beighton, and his efforts to establish world-class, collaborative research into diseases affecting the African continent.

Electrodeposition from supercritical fluids.

Recent studies have shown that it is possible to electrodeposit a range of materials, such as Cu, Ag and Ge, from various supercritical fluids, including hydrofluorocarbons and mixtures of CO2 with suitable co-solvents. In this perspective we discuss the relatively new field of electrodeposition from supercritical fluids. The perspective focuses on some of the underlying physical chemistry and covers both practical and scientific aspects of electrodeposition from supercritical fluids. We also discuss possible applications for supercritical fluid electrodeposition and suggest some key developments that are required to take the field to the next stage.

Enhanced radial transport and energization of radiation belt electrons due to drift orbit bifurcations.

[1]Relativistic electron intensities in Earth's outer radiation belt can vary by multiple orders of magnitude on the time scales ranging from minutes to days. One fundamental process contributing to dynamic variability of radiation belt intensities is the radial transport of relativistic electrons across their drift shells. In this paper we analyze the properties of three-dimensional radial transport in a global magnetic field model driven by variations in the solar wind dynamic pressure. We use a test particle approach which captures anomalous effects such as drift orbit bifurcations. We show that the bifurcations lead to an order of magnitude increase in radial transport rates and enhance the energization at large equatorial pitch angles. Even at quiet time fluctuations in dynamic pressure, radial transport at large pitch angles exhibits strong deviations from the diffusion approximation. The radial transport rates are much lower at small pitch angle values which results in a better agreement with the diffusion approximation.

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium.

BACKGROUND: Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC). METHODS: Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m(-2) intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (≥50% PSA reduction confirmed ≥28 days apart). According to the Simon two-stage design, ≥3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available. RESULTS: In all, 53 patients received ≥2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m(-2) during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity. CONCLUSION: This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

Inherited polyglutamine spinocerebellar ataxias in South Africa.

OBJECTIVE: To determine the frequency and distribution of polyglutamine spinocerebellar ataxias (SCAs) from referrals over a 24-year period to the National Health Laboratory Service (NHLS) in South Africa (SA). METHODS: Paper-based clinical reports in the University of Cape Town laboratory and the NHLS electronic patient record database spanning a 24-year period were mined for information regarding the molecular diagnosis, ethnicity and CAG repeat length for individuals referred for molecular genetic testing for the polyglutamine SCAs. RESULTS: SCA1 and 7 are the most frequent types of polyglutamine SCA in the SA patient population, followed by SCA2, 3 and 6. SCA1 is the most common type in the coloured, white and Indian populations, whereas the majority of indigenous black African patients are affected with SCA7 and 2. Of individuals tested, 22% were found to be positive for one of the polyglutamine SCAs. CONCLUSION: Although trends in the frequency and distribution of the polyglutamine SCAs in SA have not changed significantly since our previous study in 2003, they differ remarkably from those reported elsewhere, and reflect the unique genetic and demographic background of SA. The provision of accurate and complete patient information and family history is crucial to the diagnostic process, to enable comprehensive epidemiological studies and assist in developing therapeutic and patient management strategies.

On the mechanism of carbon nanotube formation: the role of the catalyst.

This work examines the recent developments in non-traditional catalyst-assisted chemical vapour deposition of carbon nanotubes (CNTs) with a view to determining the essential role of the catalyst in nanotube growth. A brief overview of the techniques reliant on the structural reorganization of carbon to form CNTs is provided. Additionally, CNT synthesis methods based upon ceramic, noble metal, and semiconducting nanoparticle catalysts are presented. Experimental evidence is provided for CNT growth using noble metal and semiconducting nanoparticle catalysts. A model for CNT growth consistent with the experimental results is proposed, in which the structural reorganization of carbon to form CNTs is paramount.

Auditory evoked potentials for monitoring during anaesthesia: a study of data quality.

UNLABELLED: The auditory evoked potential termed the middle latency response (MLR) has been suggested as an indicator of adequacy of anaesthesia during surgery. However, the response is small and must be extracted from high levels of background noise. A key consideration in using the MLR for clinical monitoring is whether data quality is sufficient to detect small changes. The aim of this study was to investigate the quality of the MLR recorded during anaesthesia, as a rigorous analysis of data quality is lacking in many studies. MLR recordings from patients sedated in intensive care after cardiac surgery were compared to recordings from a reference group of young volunteers with normal hearing. Data quality was measured with the F(sp) parameter. A bootstrap analysis was used to measure statistical response presence and to detect within-subject changes during clinical anaesthesia. Noise levels were high in the normative group probably due to myogenic and EEG activity. With 5 Hz click stimulation, MLR presence in the normative group was below 30%. Response presence improved using stimulation paradigms with chirps or maximum length sequences and reached 100% with a combination of maximum length sequences and chirps. F(sp) values generally improved during anaesthesia as noise levels reduced and MLR presence was 100% for MLS click stimulation. Changes in the MLR amplitude with propofol infusion rate were small. Some within-subject changes in MLR amplitude were detected using the bootstrap analysis, but 100% detection was not possible. CONCLUSION: Obtaining good quality MLR data in awake subjects is challenging. Data quality improves during clinical anaesthesia and with advanced stimulation methods, but reliable detection of changes in the MLR for clinical monitoring remains a challenge.

Anaesthetic effects of propofol polymeric micelle: a novel water soluble propofol formulation.

BACKGROUND: As a result of its very low water solubility, propofol is generally presented as a lipid-based formulation with well-characterized limitations. METHODS: Propofol (99.7%) was added directly to an aqueous solution of poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide)copolymers (PVP-PLA) block copolymers and stirred in order to obtain a clear solution. This formulation was filtered sterile and then lyophilized to its solid form Propofol-PM (propofol polymeric micelle) which reconstitutes to a propofol 1%w/v (10 mg ml(-1)) clear aqueous solution of 30-60 nm propofol-containing micelles. Population pharmacokinetic data from whole blood and plasma were obtained by administering reconstituted Propofol-PM formulations and a 1% oil in water formulation, Diprivan to male Sprague-Dawley rats (n = 40) at a dose of 10 mg kg(-1). Preliminary recovery data were obtained from a further small study. RESULTS: The pharmacokinetics were best described using a two-compartment mamillary population model, which incorporated sample matrix (blood or plasma) and propofol formulation (Diprivan) or Propofol-PM) as covariates. Sample matrix was applied to all structural model parameters as a dichotomous covariate. An influence of propofol formulation was observed for all parameters (excluding distributional clearance) but only when plasma was used for propofol quantification. In this preliminary pharmacodynamic study, there was no statistically significant difference in the timing of the recovery endpoints between the Propofol-PM formulation and Diprivan groups. CONCLUSIONS: Propofol-PM formulations produce anaesthesia in rats. Whole blood pharmacokinetics of Propofol-PM did not differ from those observed with Diprivan.

The effect of mannitol on renal function after cardiopulmonary bypass in patients with established renal dysfunction.

The usefulness of mannitol in the priming fluid for cardiopulmonary bypass is uncertain in patients with normal renal function, and has not been studied in patients with established renal dysfunction. We studied 50 patients with serum creatinine between 130 and 250 micromol.l(-1) having cardiac surgery. Patients were randomised to receive mannitol 0.5 g.kg(-1), or an equivalent volume of Hartmann's solution, in the bypass prime. There were no differences between the groups in plasma creatinine or change in creatinine from baseline, urine output, or fluid balance over the first three postoperative days. We conclude that mannitol has no effect on routine measures of renal function during cardiac surgery in patients with established renal dysfunction.

The effect of mannitol on renal function following cardio-pulmonary bypass in patients with normal pre-operative creatinine.

Mannitol is often added to the cardiopulmonary bypass pump prime to reduce the incidence of renal dysfunction, but studies so far have been inconclusive. Urinary excretion of microalbumin and retinol binding protein are more sensitive than routine biochemical tests of renal function after cardiac surgery. We performed a double-blind, randomised, controlled trial in cardiac surgical patients with pre-operative plasma creatinine < 130 micromol x l(-1). Twenty patients received 0.5 g x kg(-1) of mannitol in the pump prime, whereas 20 control patients received an equivalent volume of Hartmann's solution. Blood and urine samples were taken on the day before surgery and daily for 5 days postoperatively for measurement of plasma urea and creatinine, urinary creatinine, retinol binding protein and microalbumin. We found no differences between the mannitol and control patients for any measured variable, and conclude that mannitol has little impact on renal function in patients with normal pre-operative plasma creatinine concentrations.

Endovascular treatment of carotid and vertebral pseudoaneurysms with covered stents.

BACKGROUND AND PURPOSE: Endovascular treatment of vascular lesions has revolutionized the treatment of arterial pseudoaneurysms. We describe our experience in treating carotid or vertebral pseudoaneurysms with covered stents. MATERIALS AND METHODS: Ten patients with carotid or vertebral pseudoaneurysms treated with self-expanding or balloon-expandable covered stents were retrospectively reviewed after we obtained institutional review board approval. Distal protection devices were not used. All patients except 1 received anticoagulation therapy. Antiplatelet therapy was used in 8 of 10 patients. Follow-up was performed from 5 days to 25 months. Patients were followed with digital subtraction angiography, CT angiography (CTA), and/or sonography (US). RESULTS: Pseudoaneurysm occlusion was obtained in all 10 patients. None of the pseudoaneurysms recanalized during the follow-up period. One patient had a distal embolization to the middle cerebral artery despite anticoagulation and antiplatelet therapy. One patient who did not receive any anticoagulation had stent occlusion at 4.5 months. Anticoagulation was stopped after 6 months in 2 patients with persistent stent patency and no neurologic complications for >1 year. Both US and CTA were useful for extracranial stent surveillance. CTA was helpful for intracranial stent surveillance. CONCLUSION: In this small series, the use of covered stents allowed safe and effective treatment of pseudoaneurysms occurring in the cervical and cephalic segments of the carotid and vertebral arteries.

Survival impact of lymph node dissection in endometrial adenocarcinoma: a surveillance, epidemiology, and end results analysis.

The therapeutic benefit of lymph node dissection (LND) in women with endometrial cancer remains controversial. The purpose of this study is to analyze the impact of LND on survival. Data were obtained from the Surveillance, Epidemiology, and End Results program of the US National Cancer Institute for the years 1988-2003. Women with adenocarcinoma of the endometrium who underwent surgery as primary management of their disease were eligible. Multivariate analyses of pertinent variables were performed for the end points of overall survival and cause-specific survival. Women included in the analysis were 42,184. The average frequency of LND was 31%, 40%, 47%, and 53%, for the years 1988-1991, 1992-1995, 1996-1999, and 2000-2003, respectively (P < 0.0001). On multivariate analysis, presence of LND was associated with overall and uterine-specific survival benefits with hazard ratios (HR) of 0.81 (P < 0.0001) and 0.78 (P < 0.0001) and removal of greater than 11 lymph nodes (LN) associated with a HR of 0.74 (P < 0.0001) and 0.69 (P < 0.0001), respectively. Further multivariate analyses demonstrated greater than 11 LN to associate with all other cause-specific and cardiac-specific survival benefits, with HR of 0.77 (P < 0.0001) and 0.82 (P = 0.0062), respectively. We conclude that the presence of LND and increased number of nodes dissected predicted for improved overall and uterine-specific survival in women with adenocarcinoma of the endometrium. Improved cause-specific survival was most pronounced for greater than 11 nodes removed and stage II or higher disease. The improvement in noncancer-related mortality with LND predicted by this data suggests the presence of inherit biases, and the need for caution in analyzing retrospective data.

Cortical edema in moderate fluid percussion brain injury is attenuated by vagus nerve stimulation.

Development of cerebral edema (intracellular and/or extracellular water accumulation) following traumatic brain injury contributes to mortality and morbidity that accompanies brain injury. Chronic intermittent vagus nerve stimulation (VNS) initiated at either 2 h or 24 h (VNS: 30 s train of 0.5 mA, 20 Hz, biphasic pulses every 30 min) following traumatic brain injury enhances recovery of motor and cognitive function in rats in the weeks following brain injury; however, the mechanisms of facilitated recovery are unknown. The present study examines the effects of VNS on development of acute cerebral edema following unilateral fluid percussion brain injury (FPI) in rats, concomitant with assessment of their behavioral recovery. Two hours following FPI, VNS was initiated. Behavioral testing, using both beam walk and locomotor placing tasks, was conducted at 1 and 2 days following FPI. Edema was measured 48 h post-FPI by the customary method of region-specific brain weights before and after complete dehydration. Results of this study replicated that VNS initiated at 2 h after FPI: 1) effectively facilitated the recovery of vestibulomotor function at 2 days after FPI assessed by beam walk performance (P<0.01); and 2) tended to improve locomotor placing performance at the same time point (P=0.18). Most interestingly, results of this study showed that development of edema within the cerebral cortex ipsilateral to FPI was significantly attenuated at 48 h in FPI rats receiving VNS compared with non-VNS FPI rats (P<0.04). Finally, a correlation analysis between beam walk performance and cerebral edema following FPI revealed a significant inverse correlation between behavior performance and cerebral edema. Together, these results suggest that VNS facilitation of motor recovery following experimental brain injury in rats is associated with VNS-mediated attenuation of cerebral edema.

Depth-mediated reversal of the effects of climate change on long-term growth rates of exploited marine fish.

The oceanographic consequences of climate change are increasingly well documented, but the biological impacts of this change on marine species much less so, in large part because of few long-term data sets. Using otolith analysis, we reconstructed historical changes in annual growth rates for the juveniles of eight long-lived fish species in the southwest Pacific, from as early as 1861. Six of the eight species show significant changes in growth rates during the last century, with the pattern differing systematically with depth. Increasing temperatures near the ocean surface correlate with increasing growth rates by species found in depths <250 m, whereas growth rates of deep-water (>1,000 m) species have declined substantially during the last century, which correlates with evidence of long-term cooling at these depths. The observations suggest that global climate change has enhanced some elements of productivity of the shallow-water stocks but also has reduced the productivity, and possibly the resilience, of the already slow-growing deep-water species.