Hemophilia gene therapy: first, do no harm.

The introduction of adeno-associated virus-mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also considerable uncertainty to a community that has a history punctuated by the devastating effects of HIV and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past 5 decades, considerable advances in hemophilia treatment have improved the survival, quality of life, and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic, and shared decision-making approach must be employed. Bias on the part of health care professionals and people with hemophilia must be addressed and minimized. Here, we review data leading to the regulatory authorization of valoctocogene roxaparvovec, an adeno-associated virus 5 gene therapy, in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety of and optimal outcomes for people with hemophilia who choose to receive a gene therapy product.

Virtual Reality Provides an Effective Platform for Functional Evaluations of Closed-Loop Neuromyoelectric Control.

Although recent advances in neuroprostheses offer opportunities for improved and intuitive control of advanced motorized and sensorized robotic arms, practical complications associated with such hardware can impede the research necessary for clinical translation. These hurdles potentially can be reduced with virtual reality environments (VREs) with embedded physics engines using virtual models of physical robotic hands. These software suites offer several advantages over physical prototypes, including high repeatability, reduced human error, elimination of many secondary sensory cues, and others. There are limited demonstrations of closed-loop prostheses in the VRE, and it is unclear whether VRE performance translates to the physical world. Here we describe how two trans-radial amputees with neural and intramuscular implants identified objects and performed activities of daily living with closed-loop control of prostheses in the VRE. Our initial evidence further suggests that capabilities with virtual prostheses may be predictors of physical prosthesis performance, demonstrating the utility of VREs for neuroprosthetic research.

Selective Decrease in Allodynia With High-Frequency Neuromodulation via High-Electrode-Count Intrafascicular Peripheral Nerve Interface After Brachial Plexus Injury.

OBJECTIVES: Kilohertz high-frequency alternating current (KHFAC) electrical nerve stimulation produces a reversible nerve block in peripheral nerves in human patients with chronic pain pathologies. Although this stimulation methodology has been verified with nonselective extrafascicular electrodes, the effectiveness of producing a selective nerve block with more-selective intrafascicular electrodes has not been well documented. The objective of this study was to examine whether intrafascicular electrodes can block painful stimuli while preserving conduction of other neural activity within the implanted nerve. MATERIALS AND METHODS: We analyzed the effects of various stimulation waveforms delivered through Utah Slanted Electrode Arrays (USEAs) implanted in the median nerve of a male human subject with a left brachial plexus injury. We compared KHFAC stimulation with a sham control. RESULTS: KHFAC stimulation through USEA electrodes produced a reduction in pain sensitivity in the palmar aspect of the left middle finger. KHFAC had limited effects on the patient's ability to feel tactile probing in the same area or move the digits of his left hand. Other tested stimulation parameters either increased or showed no reduction in pain. CONCLUSIONS: KHFAC stimulation in peripheral nerves through intrafascicular electrodes demonstrated a selective reduction in pain sensitivity while preserving other nerve functions. This treatment may benefit patient populations who have chronic pain originating from peripheral nerves, but who do not want to block whole-nerve function in order to preserve sensory and motor function reliant on the implanted nerve. Furthermore, KHFAC may benefit patients who respond negatively to other forms of peripheral nerve stimulation therapy.

Temporal Poisson Square Root Graphical Models.

We propose temporal Poisson square root graphical models (TPSQRs), a generalization of Poisson square root graphical models (PSQRs) specifically designed for modeling longitudinal event data. By estimating the temporal relationships for all possible pairs of event types, TPSQRs can offer a holistic perspective about whether the occurrences of any given event type could excite or inhibit any other type. A TPSQR is learned by estimating a collection of interrelated PSQRs that share the same template parameterization. These PSQRs are estimated jointly in a pseudo-likelihood fashion, where Poisson pseudo-likelihood is used to approximate the original more computationally-intensive pseudo-likelihood problem stemming from PSQRs. Theoretically, we demonstrate that under mild assumptions, the Poisson pseudo-likelihood approximation is sparsistent for recovering the underlying PSQR. Empirically, we learn TPSQRs from Marshfield Clinic electronic health records (EHRs) with millions of drug prescription and condition diagnosis events, for adverse drug reaction (ADR) detection. Experimental results demonstrate that the learned TPSQRs can recover ADR signals from the EHR effectively and efficiently.

Restoration of motor control and proprioceptive and cutaneous sensation in humans with prior upper-limb amputation via multiple Utah Slanted Electrode Arrays (USEAs) implanted in residual peripheral arm nerves.

BACKGROUND: Despite advances in sophisticated robotic hands, intuitive control of and sensory feedback from these prostheses has been limited to only 3-degrees-of-freedom (DOF) with 2 sensory percepts in closed-loop control. A Utah Slanted Electrode Array (USEA) has been used in the past to provide up to 81 sensory percepts for human amputees. Here, we report on the advanced capabilities of multiple USEAs implanted in the residual peripheral arm nerves of human amputees for restoring control of 5 DOF and sensation of up to 131 proprioceptive and cutaneous hand sensory percepts. We also demonstrate that USEA-restored sensory percepts provide a useful source of feedback during closed-loop virtual prosthetic hand control. METHODS: Two 100-channel USEAs were implanted for 4-5 weeks, one each in the median and ulnar arm nerves of two human subjects with prior long-duration upper-arm amputations. Intended finger and wrist positions were decoded from neuronal firing patterns via a modified Kalman filter, allowing subjects to control many movements of a virtual prosthetic hand. Additionally, USEA microstimulation was used to evoke numerous sensory percepts spanning the phantom hand. Closed-loop control was achieved by stimulating via an electrode of the ulnar-nerve USEA while recording and decoding movement via the median-nerve USEA. RESULTS: Subjects controlled up to 12 degrees-of-freedom during informal, 'freeform' online movement decode sessions, and experienced up to 131 USEA-evoked proprioceptive and cutaneous sensations spanning the phantom hand. Independent control was achieved for a 5-DOF real-time decode that included flexion/extension of the thumb, index, middle, and ring fingers, and the wrist. Proportional control was achieved for a 4-DOF real-time decode. One subject used a USEA-evoked hand sensation as feedback to complete a 1-DOF closed-loop virtual-hand movement task. There were no observed long-term functional deficits due to the USEA implants. CONCLUSIONS: Implantation of high-channel-count USEAs enables multi-degree-of-freedom control of virtual prosthetic hand movement and restoration of a rich selection of both proprioceptive and cutaneous sensory percepts spanning the hand during the short 4-5 week post-implant period. Future USEA use in longer-term implants and in closed-loop may enable restoration of many of the capabilities of an intact hand while contributing to a meaningful embodiment of the prosthesis.

Assessing fracture risk in early stage breast cancer patients treated with aromatase-inhibitors: An enhanced screening approach incorporating trabecular bone score.

INTRODUCTION: Aromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of-care screening tool for fracture risk is bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX®) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX®, respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs. METHODS: 100 patients with early stage hormone-positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX® scores were calculated from review of clinical records. EFR was defined as either: BMD ≤-2.5 or BMD between -2.5 and -1 plus either increased risk by FRAX® or degraded microstructure by TBS. RESULTS: At baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX® increased detection to 13%, whereas the combination of BMD, FRAX® and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX® identified 3 additional patients (3%), and BMD+FRAX®+TBS identified 7 additional patients (7%). CONCLUSIONS: The combination of FRAX®, TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs.

The importance of both potency and mechanism in dose-response analysis: an example from exposure of Pacific herring (Clupea pallasi) embryos to low concentrations of weathered crude oil.

This paper reanalyzes data from an earlier study that used effluents from oiled-gravel columns to assess the toxicity of aqueous fractions of weathered crude oil to Pacific herring embryos and larvae. This reanalysis has implications for future similar investigations, including the observance of two distinct dose-response curves for lethal and sublethal endpoints for different exposures in the same experiment, and the need to consider both potency and slope of dose-response curves for components of a toxicant mixture that shows potentially different toxicity mechanisms/causation. Contrary to conclusions of the original study, the aqueous concentration data cannot support the hypothesis that polycyclic aromatic hydrocarbons (PAHs) were the sole cause of toxicity and that oil toxicity increased with weathering. Confounding issues associated with the oiled gravel columns include changes in the concentration and composition of chemicals in exposure water, which interfere with the production of reliable and reproducible results relevant to the field.

Evaluating the aquatic toxicity of complex organic chemical mixtures: lessons learned from polycyclic aromatic hydrocarbon and petroleum hydrocarbon case studies.

Experimental designs for evaluating complex mixture toxicity in aquatic environments can be highly variable and, if not appropriate, can produce and have produced data that are difficult or impossible to interpret accurately. We build on and synthesize recent critical reviews of mixture toxicity using lessons learned from 4 case studies, ranging from binary to more complex mixtures of primarily polycyclic aromatic hydrocarbons and petroleum hydrocarbons, to provide guidance for evaluating the aquatic toxicity of complex mixtures of organic chemicals. Two fundamental requirements include establishing a dose-response relationship and determining the causative agent (or agents) of any observed toxicity. Meeting these 2 requirements involves ensuring appropriate exposure conditions and measurement endpoints, considering modifying factors (e.g., test conditions, test organism life stages and feeding behavior, chemical transformations, mixture dilutions, sorbing phases), and correctly interpreting dose-response relationships. Specific recommendations are provided.

Exposure of sea otters and harlequin ducks in Prince William Sound, Alaska, USA, to shoreline oil residues 20 years after the Exxon Valdez oil spill.

We assessed whether sea otters and harlequin ducks in an area of western Prince William Sound, Alaska, USA (PWS), oiled by the 1989 Exxon Valdez oil spill (EVOS), are exposed to polycyclic aromatic hydrocarbons (PAH) from oil residues 20 years after the spill. Spilled oil has persisted in PWS for two decades as surface oil residues (SOR) and subsurface oil residues (SSOR) on the shore. The rare SOR are located primarily on the upper shore as inert, nonhazardous asphaltic deposits, and SSOR are confined to widely scattered locations as small patches under a boulder/cobble veneer, primarily on the middle and upper shore, in forms and locations that preclude physical contact by wildlife and diminish bioavailability. Sea otters and harlequin ducks consume benthic invertebrates that they collect by diving to the bottom in the intertidal and subtidal zones. Sea otters also dig intertidal and subtidal pits in search of clams. The three plausible exposure pathways are through the water, in oil-contaminated prey, or by direct contact with SSOR during foraging. Concentrations of PAH in near-shore water off oiled shores in 2002 to 2005 were at background levels (<0.05 ng/L). Median concentrations of PAH in five intertidal prey species on oiled shores in 2002 to 2008 range from 4.0 to 34 ng/g dry weight, indistinguishable from background concentrations. Subsurface oil residues are restricted to locations on the shore and substrate types, where large clams do not occur and where sea otters do not dig foraging pits. Therefore, that sea otters and harlequin ducks continue to be exposed to environmentally significant amounts of PAH from EVOS 20 years after the spill is not plausible.

A randomized controlled trial of calcium plus vitamin D supplementation and risk of benign proliferative breast disease.

Experimental evidence provides strong support for anti-carcinogenic effects of calcium and vitamin D with respect to breast cancer. Observational epidemiologic data also provide some support for inverse associations with risk. We tested the effect of calcium plus vitamin D supplementation on risk of benign proliferative breast disease, a condition which is associated with increased risk of breast cancer. We used the Women's Health Initiative randomized controlled trial. The 36,282 participants were randomized either to 500 mg of elemental calcium as calcium carbonate plus 200 IU of vitamin D(3) (GlaxoSmithKline) twice daily (n = 18,176) or to placebo (n = 18,106). Regular mammograms and clinical breast exams were performed. We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. After an average follow-up period of 6.8 years, 915 incident cases of benign proliferative breast disease had been ascertained, with 450 in the intervention group and 465 in the placebo group. Calcium plus vitamin D supplementation was not associated with altered risk of benign proliferative breast disease overall (hazard ratio = 0.99, 95% confidence interval = 0.86-1.13), or by histologic subtype. Risk varied significantly by levels of age at baseline, but not by levels of other variables. Daily use of 1,000 mg of elemental calcium as calcium carbonate plus 400 IU of vitamin D(3) for almost 7 years by postmenopausal women did not alter the overall risk of benign proliferative breast disease.

Distribution and weathering of crude oil residues on shorelines 18 years after the Exxon Valdez spill.

In 2007, a systematic study was conducted to evaluate the form and location of residues of oil buried on Prince William Sound (PWS) shorelines, 18 years after the 1989 Exxon Valdez Oil Spill (EVOS). We took 678 sediment samples from 22 sites that were most heavily oiled in 1989 and known to contain the heaviest subsurface oil (SSO) deposits based on multiple studies conducted since 2001. An additional 66 samples were taken from two sites, both heavily oiled in 1989 and known to be active otter foraging sites. All samples were analyzed for total extractable hydrocarbons (TEH), and 25% were also analyzed for saturated and aromatic hydrocarbon weathering parameters. Over 90% of the samples from all sites contained light or no SSO at all. Of samples containing SSO, 81% showed total polycyclic aromatic hydrocarbon (TPAH) losses greater than 70%, relative to cargo oil, with most having >80% loss. Samples with SSO were observed in isolated patches sequestered by surface boulder and cobble armoring. Samples showing lowest TPAH loss correlated strongly with higher elevations in the intertidal zones. Of the 17 atypical, less-weathered samples having less than 70% loss of TPAH (>30% remaining), only two were found sequestered in the lower intertidal zone, both at a single site. Most of the EVOS oil in PWS has been eliminated due to natural weathering. Some isolated SSO residues remain because they are sequestered and only slowly affected by natural weathering processes that normally would bring about their rapid removal. Even where SSO patches remain, most are highly weathered, sporadically distributed at a small number of sites, and widely separated from biologically productive lower intertidal zones where most foraging by wildlife occurs.

Potential for sea otter exposure to remnants of buried oil from the Exxon Valdez oil spill.

A study was conducted in 2005 and 2006 to examine the hypothesis that sea otters (Enhydra lutris) continue to be exposed to residues of subsurface oil (SSO) while foraging on shorelines in the northern Knight Island (NKI) area of Prince William Sound, Alaska more than 17 years after the Exxon Valdez oil spill. Forty-three shoreline segments, whose oiling history has been documented by prior surveys, were surveyed. These included all shoreline segments reported by a 2003 NOAA random site survey to contain SSO residues in NKI. Sites were surveyed for the presence and location of otter foraging pits. Only one of 29 SSO sites surveyed was identified as an otter foraging site. Most buried SSO residues are confined to tide elevations above +0.8 m above mean lower low water (MLLW), above the range of intertidal clam habitat. More than 99% of documented intertidal otter pits at all sites surveyed are in the lower intertidal zone (-0.2 to +0.8 m above MLLW), the zone of highest clam abundance. The spatial separation of the otter pits from the locations of SSO residues, both with regard to tidal elevation and lateral separation on the study sites, coupled with the lack of evidence of intertidal otter foraging at SSO sites indicates a low likelihood of exposure of foraging otters to SSO on the shores of the NKI area.

Alcohol and folate consumption and risk of benign proliferative epithelial disorders of the breast.

Alcohol consumption has been associated with increased breast cancer risk and the increase in risk may be attenuated by adequate folate intake. However, their associations with the risk of benign proliferative epithelial disorders (BPEDs) of the breast, possible precursors of breast cancer, are not well understood. To investigate these associations, we conducted a cohort study among 68,132 postmenopausal women participating in the Women's Health Initiative randomized clinical trials. Women were prospectively followed and those reporting a breast procedure (open surgical biopsy or core needle biopsy) had histological sections obtained for central pathology review. A total of 1,792 women with BPED of the breast were identified over an average of 7.8 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence limits (CLs) for the associations of interest. Compared to nondrinkers, total current alcohol intake of 30 g/day or more was not associated with BPED risk (HR = 0.98, 95% CL = 0.70, 1.38). The risk of BPED was not associated with folate intake from diet (highest vs. lowest quartile: HR = 1.10, 95% CL = 0.96, 1.26), from supplements (yes vs. no: HR = 1.05, 95% CL = 0.96, 1.16) or from all sources combined (highest vs. lowest quartile: HR = 1.11, 95% CL = 0.96, 1.27). Furthermore, there was no effect modification between alcohol and folate in relation to the risk of BPED. In conclusion, we observed that alcohol consumption and folate intake were not associated with altered risk of BPED, and that there was no effect modification between them in relation to the risk of BPED.

A hierarchical approach measures the aerial extent and concentration levels of PAH-contaminated shoreline sediments at historic industrial sites in Prince William Sound, Alaska.

A field study was conducted in 2003 to estimate the areal distribution and concentrations of polycyclic aromatic hydrocarbons (PAH) in intertidal sediments at sites of past human and industrial activity (HA sites) in Prince William Sound (PWS), Alaska, the site of the 1989 Exxon Valdez oil spill. More than 50 HA sites, primarily in western PWS, were identified through analysis of historic records and prior field studies, and nine sites were selected for detailed surveys. The areal assessment process consisted of seven steps: (1) identify site from historic records and field surveys; (2) locate visual evidence of surface oil/tar at a site; (3) prepare a site map and lay out a sampling grid over the entire site with 10-m grid spacing; (4) excavate pits to 50 cm depth on the grid; (5) perform a field colorimetric test to estimate total PAH (TPAH) in sediments from the wall of each pit and record the results in the ranges <1 ppm; 1-10 ppm; >10 ppm TPAH; (6) expand grid size if necessary if elevated PAH levels are detected colorimetrically; (7) select 20 samples from each site for same-day shipboard PAH analysis by immunoassay (SDI RaPID PAH) and, based on these results, select sediment samples from each site for full PAH analysis in the laboratory to identify PAH sources. A total of 416 pits were dug at the nine sites. Nine acres of sediments with TPAH >2500 ppb dry wt. were mapped at the nine sites. TPAH concentrations obtained by immunochemical analysis of 181 samples from the nine sites ranged from 20 to 1,320,000 ppb (wet wt.). The contaminants are mixtures of petroleum products (2-3 ring PAH) and combustion products (4-6 ring PAH) unrelated to the 1989 Exxon Valdez oil spill. Mussels and clams collected at these sites have elevated levels of PAH that are compositionally similar to the PAH in the sediments. These findings indicate that at least a portion of the sediment PAH is bioavailable. The PAH sources at these historic industrial sites are chronic. They include relict fuel oil tanks and works located above and within the intertidal zone, with contamination at some locations extending into nearshore sub-tidal sediments. This study shows how a hierarchical approach can be used to quickly and successfully map, quantify, and subsequently, identify sources of PAH in shoreline sediments.

Comparison of mussels and semi-permeable membrane devices as intertidal monitors of polycyclic aromatic hydrocarbons at oil spill sites.

Side-by-side comparisons of polycyclic aromatic hydrocarbon (PAH) concentrations in resident blue mussels (Mytilus trossulus) and in semi-permeable membrane devices (SPMDs) were made at four sites in Prince William Sound, Alaska. SPMDs were deployed for approximately 30 days on the surface of the beach sediment at three tidal elevations on each shore and in 0.5 m deep open pits in the middle intertidal zone. Total PAH (TPAH) concentrations in mussels and in SPMDs were correlated, but the PAH compositions were different. The lower molecular weight PAH were relatively more abundant in the SPMDs than in the mussels at oiled and HA sites. TPAH concentrations in SPMDs deployed in pits and mussels collected adjacent to those pits at oiled sites were higher than in SPMDs and mussels from non-pitted SPMD locations approximately 3-15 m from the pits. Pitting released buried oil making its PAH bioavailable. SPMDs deployed in the supratidal zone (+4.0 m tidal elevation) were exposed to atmospheric contaminants for a large fraction of the deployment time and accumulated primarily pyrogenic (combustion-sourced) PAH from the atmosphere. The SPMD strips supplied by the manufacturer contained significant amounts (approximately 125 ng/strip) of primarily alkylated 2-3 ring PAH. These blank levels make SPMDs unsuitable for shoreline assessments when environmental PAH concentrations are low. Consequently, where available, mussels are recommended for use in assessments of the bioavailability of buried oil residues sequestered in intertidal sediments following an oil spill. Mussels are the preferred monitoring tool when the assessments involve food-chain effects. At locations where the absence of mussels necessitates the use of SPMDs or other passive sampling devices, their limitations need to be carefully considered in the interpretation of results.

Mussels document loss of bioavailable polycyclic aromatic hydrocarbons and the return to baseline conditions for oiled shorelines in Prince William Sound, Alaska.

Polycyclic aromatic hydrocarbons (PAH) were measured in mussels (Mytilus trossulus) collected between 1990 and 2002 from 11 sites on the shores of Prince William Sound (PWS), Alaska, that were heavily oiled by the 1989 Exxon Valdez oil spill (EVOS). This study, utilizing the methods of the NOAA Status and Trends Mussel Watch Program, found that concentrations of PAH released from spill remnants have decreased dramatically with time and by 2002 were at or near the range of total PAH (TPAH) of 3-355 ng/g dry weight obtained for mussels from unoiled reference sites in PWS. Time-series TPAH data indicate a mean TPAH half-life in mussel tissues of 2.4 years with a range from 1.4 to 5.3, yielding an annual mean loss of bioaccumulated TPAH of 25%. The petroleum-derived TPAH fraction in mussel tissues has decreased with time, reflecting the decreasing release of EVOS residues in shoreline sediments. These results show that PAH from EVOS residues that remain buried in shoreline sediments after the early 1990s are in a form and at locations that have a low accessibility to mussels living in the intertidal zone.